Gut Microbiota and Pathogenesis of Organ Injury (Advances in Experimental Medicine and Biology, 1238) 9811523843, 9789811523847

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Advances in Experimental Medicine and Biology 1238

Peng Chen   Editor

Gut Microbiota and Pathogenesis of Organ Injury

Advances in Experimental Medicine and Biology Volume 1238

Series Editors Wim E. Crusio, Institut de Neurosciences Cognitives et Intégratives d’Aquitaine, CNRS and University of Bordeaux UMR 5287, Pessac Cedex, France John D. Lambris, University of Pennsylvania, Philadelphia, PA, USA Heinfried H. Radeke, Institute of Pharmacology & Toxicology, Clinic of the Goethe University Frankfurt Main, Frankfurt am Main, Hessen, Germany Nima Rezaei, Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran

Advances in Experimental Medicine and Biology provides a platform for scientific contributions in the main disciplines of the biomedicine and the life sciences. This series publishes thematic volumes on contemporary research in the areas of microbiology, immunology, neurosciences, biochemistry, biomedical engineering, genetics, physiology, and cancer research. Covering emerging topics and techniques in basic and clinical science, it brings together clinicians and researchers from various fields. Advances in Experimental Medicine and Biology has been publishing exceptional works in the field for over 40 years, and is indexed in SCOPUS, Medline (PubMed), Journal Citation Reports/Science Edition, Science Citation Index Expanded (SciSearch, Web of Science), EMBASE, BIOSIS, Reaxys, EMBiology, the Chemical Abstracts Service (CAS), and Pathway Studio. 2018 Impact Factor: 2.126.

More information about this series at http://www.springer.com/series/5584

Peng Chen Editor

Gut Microbiota and Pathogenesis of Organ Injury

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Editor Peng Chen Department of Pathophysiology Southern Medical University Guangzhou, Guangdong, China

ISSN 0065-2598 ISSN 2214-8019 (electronic) Advances in Experimental Medicine and Biology ISBN 978-981-15-2384-7 ISBN 978-981-15-2385-4 (eBook) https://doi.org/10.1007/978-981-15-2385-4 © Springer Nature Singapore Pte Ltd. 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

Contents

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Peng Chen

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Gut Microbiota and Alimentary Tract Injury . . . . . . . . . . . . . . . . . Ye Chen, Guangyan Wu, and Yongzhong Zhao

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Gut Microbiota and Liver Injury (I)—Acute Liver Injury . . . . . . . Guangyan Wu, Sanda Win, Tin A. Than, Peng Chen, and Neil Kaplowitz

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Gut Microbiota and Liver Injury (II): Chronic Liver Injury . . . . . Susan S. Baker and Robert D. Baker

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Gut Microbiota and Lung Injury . . . . . . . . . . . . . . . . . . . . . . . . . . Ji-yang Tan, Yi-chun Tang, and Jie Huang

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Gut Microbiota and Neurologic Diseases and Injuries . . . . . . . . . . T. Tyler Patterson and Ramesh Grandhi

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Gut Microbiota and Renal Injury . . . . . . . . . . . . . . . . . . . . . . . . . . Lei Zhang, Wen Zhang, and Jing Nie

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Gut Microbiota and Heart, Vascular Injury . . . . . . . . . . . . . . . . . . 107 Cheng Zeng and Hongmei Tan

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Gut Microbiota and Endocrine Disorder . . . . . . . . . . . . . . . . . . . . 143 Rui Li, Yifan Li, Cui Li, Dongying Zheng, and Peng Chen

10 Gut Microbiota and Immune Responses . . . . . . . . . . . . . . . . . . . . . 165 Lijun Dong, Jingwen Xie, Youyi Wang, and Daming Zuo 11 Gut Microbiota and Multiple Organ Dysfunction Syndrome (MODS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 Peng Chen and Timothy Billiar

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Contributors

Susan S. Baker Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, USA Robert D. Baker Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, USA Timothy Billiar Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA Peng Chen Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China Ye Chen Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China Lijun Dong The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, China; Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China Ramesh Grandhi Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, Utah, USA Jie Huang Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China Neil Kaplowitz USC Research Center for Liver Disease, Department of Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA Cui Li Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China

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Contributors

Rui Li Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China Yifan Li Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China Jing Nie State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of Education), Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China Hongmei Tan Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China Ji-yang Tan Peking Union Medical College, Chinese Academy of Medical Sciences, Plastic Surgery Hospital, Graduate School of Peking Union Medical College, Beijing, China Yi-chun Tang The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China Tin A. Than USC Research Center for Liver Disease, Department of Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA T. Tyler Patterson Department of Neurosurgery, University of Texas Health Science Center School of Medicine, San Antonio, TX, USA Youyi Wang Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China; School of Laboratory Medicine and Biotechnology, Institute of Molecular Immunology, Southern Medical University, Guangzhou, China Sanda Win USC Research Center for Liver Disease, Department of Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA Guangyan Wu Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China Jingwen Xie Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China Cheng Zeng Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China Lei Zhang State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of Education), Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China

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Wen Zhang State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of Education), Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China Yongzhong Zhao Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland, OH, USA Dongying Zheng Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China Daming Zuo School of Laboratory Medicine and Biotechnology, Institute of Molecular Immunology, Southern Medical University, Guangzhou, China; Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China

Chapter 1

Introduction Peng Chen

Abstract In the past decade, research focusing on the gut microbiota has attracted a growing number of scientists. We increasingly realize that the gut microbiota plays a key role in both maintaining host homeostasis and affecting the progression of multiple diseases, which means that the microorganisms living in the intestines would not only influence the gastrointestinal tract but also impact other important organs such as the liver, brain, kidney, and lung. The underlying modulatory mechanism is complicated; however, we can expand the existing insight on the development of organ damage pathogenesis and discover novel therapeutic targets for organ injury-related diseases by investigating this “hot-topic”. In this chapter, we will present a broad overview of the gut microbiota and organ injury, as well as the latest research achievements regarding the linkage between them. Keywords Gut microbiota

1.1


Organ injury
Pathogenesis

Overview of the Gut Microbiota

There are approximately 100 trillion microbes living in our body, mainly residing in the gastrointestinal tract, skin, oral cavity, and vagina [1]. Of these habitats, the microbes in gastrointestinal tract comprise approximately 80% of the total microbiota. To support their survival, the gut microbiota also encodes many more unique genes than the host genome, and they generate more than 1000 metabolites [2, 3]. The distribution of the gut microbiota varies throughout the gastrointestinal tract. In particular, the total microbial load is approximately 103–107/ml in the upper gastrointestinal tract (stomach and small intestine), while in the cecum and colon, the number of total microbes increases up to 1012/ml [4]. This variation could be P. Chen (&) Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, N.No 1838 Guangzhou Ave., Guangzhou 510515, China e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 P. Chen (ed.), Gut Microbiota and Pathogenesis of Organ Injury, Advances in Experimental Medicine and Biology 1238, https://doi.org/10.1007/978-981-15-2385-4_1

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explained by multiple potential mechanisms; for example, gastric juices could penetrate into the small intestine and inhibit bacterial growth [5]. Bile acids derived from the liver are also able to restrict bacterial overgrowth in the small intestine [6]. Besides bacteria, other microorganisms such as viruses and fungi are also present in the gut [7]; however, the majority of gut microbiota are bacteria. Over 99% of the bacteria in the gut are anaerobes, which is consistent with the low-oxygen environment in the intestines [8]. Gut microbiota is not only located in the lumen, but they also exist in the mucosal layer and intestinal epithelial cells [9]. To assess the diversity of species in the bacterial communities of certain habitats, such as the intestine, alpha-diversity, and beta-diversity measurements are employed. Alpha-diversity is used to evaluate the richness of each sample [10]. It normally includes four parameters: Chao1 index, Shannon index, Simpson index, and Observed species (Table 1.1). Beta-diversity is employed to evaluate the compositional difference between different samples. Principal component analysis (PCA) and principal coordinates analysis (PCoA) are widely used to display the outcomes of beta-diversity. The composition signature of the intestinal bacteria in humans was disclosed recently. Scientists found that the overall composition of intestinal bacteria is completely different from the bacteria located in other habitats of the body [11]. Specifically at the phylum level, Firmicutes and Bacteroidetes are the predominant bacteria, comprising approximately 90% of all the bacteria in the gut. Other phyla, including Proteobacteria, Actinobacteria, Verrucomicrobia, Cyanobacteria, Fusobacteria, and Spirochaetes, are also present in the intestines. Notably, the entire gut flora should be recognized as “commensal” microbes, even though a number of potential pathogens such as Helicobacter pylori and Escherichia coli could be detected in healthy individuals [12]. The composition of gut microbiota varies dynamically; namely, the composition is different at two different time points in the same individual. It is also shifted among different persons. However, the within-subject variation over time is more stable than the between-subject variation. The gut microbiota could be affected by many endogenous and exogenous factors. Host intestinal alpha-defense secretions, as well as immunologic activity,

Table 1.1 Introduction of alpha-diversity Significance Observed species Chao1 index Shannon index

Simpson index

Represents community operational taxonomic units (OTUs) numbers The larger the value, the richer is the species in the sample Represents community richness The higher the value, the higher is the richness of the communities Represents community richness and equiability The larger the value, the higher is the sample community equiability in the sample Represents community richness and equiability The larger the Simpson index, the higher is the community equiability in the sample

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could impact the microbial balance in the gut [13, 14]. Besides, reports have revealed that the mode of delivery determines the “inoculation” of our gut microbiota [15]. The gut microbiota of vaginally delivered infants showed significantly more resemblance to the mothers’ gut microbiota than that of infants delivered by C-section, indicating that the mother-to-infant transmission was compromised in the C-section. Specifically, C-section markedly delayed the richness of Bifidobacterium in the gut, compared to vaginal delivery [16]. Breastfeeding is also more helpful than formula feeding for the gut microbiota to mature into adult-like microbiota [17]. The composition of gut microbiota was also influenced by geography. People from the USA have completely different microbial communities than Malawians [18]. Diet is another key determining factor in the shaping of gut microbiota. For example, a short-term plant-based diet versus an animal-based diet could rapidly alter the gut microbial composition in humans [19]. Other processes such as aging and exercise are also able to change the bacterial communities in the gut [20, 21]. Collectively, the composition and function of the gut microbiota could be influenced by multiple factors. Owing to the development of sequencing technology, as well as other “omics” analyses, great advances have been made in the past decade on the study of gut microbiota. Overall, the methods used in microbiota research include: 1. The 16S rRNA gene sequencing and diversity analysis. The 16S ribosomal RNA is the key component of the ribosome in prokaryotes [22]. Around 30 years ago, scientists started to use the 16S rDNA gene sequencing for phylogenetic studies [23]. The 16S rRNA gene contains nine variable regions (V1–V9) and ten conservative regions. The conservative regions normally exhibit a similar structure among the different bacterial strains, while variable regions display different structures depending on the strain. Hence, we can amplify the variable regions using specific primers in the conservative regions and sequence the PCR products to analyze the bacterial composition. The V3 and V4 regions are widely used for sequencing nowadays. The outcome of 16S ribosomal RNA gene sequencing contains alpha-diversity, beta-diversity, and the relative compositions of specific strains from the phylum to the genus levels. 2. Metagenomics. Generally, metagenomics is defined as the study of the whole genetic material obtained from the intestine and other bacterial habitats. Unlike the 16S rRNA gene sequencing and diversity analysis, metagenomics analyzes the whole genome. At present, it is mainly executed by two sequencing methods: shotgun sequencing and next-generation high-throughput sequencing. Metagenomics would reveal much more information than the 16S rRNA gene sequencing and diversity analysis. It not only discloses information about the bacterial composition but also predicts the genes’ functions, and further provides a functional comparison between different samples based on public databases such as the Kyoto Encyclopedia of Genes and Genomes (KEGG). Thus, one main usage of metagenomics analysis in biomedical research is to explore the differences in the function of metabolism-associated genes among various pathophysiological states. Since the database is not fully completed, the

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functions of many sequenced genes are still unknown; thus, future research would improve our knowledge of gene function predictions and amplify the application of metagenomics. 3. Metabolomics. Gut microbial metabolomics analysis is recognized as the measurement of all the microbial metabolites. It can directly reflect the microbial function. Briefly, it can be divided into two types: untargeted metabolomics and targeted metabolomics. The former searches all the compounds detected in the system, while targeted metabolomics focuses on the specific type of molecule. The commonly used methods for metabolomics analysis are mass spectrometry (MS, like GC-MS, LC-MS) and nuclear magnetic resonance (NMR) spectroscopy-based techniques. With the development of metabolomics, we are closer to understanding the pathogenesis of many important diseases, since gut microbial metabolites are believed to not only support bacterial survival but also be involved in the progression of host diseases, such as digestive and cardiovascular diseases. Similar to metagenomics, many unknown or undetectable molecules must be explored in future. 4. Metaproteomics. Bacterial-derived protein is an important indicator for microbial function and plays an important role in the host’s pathophysiological changes. Metaproteomics is recognized as the study of all the proteins generated from environmental sources such as the gut microbiota. Previously, metaproteomics analyses were performed using two-dimensional polyacrylamide gel electrophoresis (2D-PAGE), but recent studies have been performed using mass spectrometry-based techniques, yielding higher accuracy and throughput. This approach could reveal the abundance of all the proteins existing in the system and other important information such as post-translational modifications (PTM). It would also be able to identify novel peptides. Hence, it is a powerful method to help us investigate the gut microbial function and their impact on host homeostasis. Besides the techniques mentioned above, more attention is being given to bacterial cultures in vitro, although the majority intestinal bacteria are currently unculturable [24]. Obtaining a single strain is helpful for us to understand their detailed function and for the basic and translational biomedical research on gut microbiota.

1.2

Overview of Organ Injury

As a main topic in biomedical research, organ injury is widely studied and many mediators have been revealed. Generally, organ injury is the phenomenon that results from cell death or dysfunction, and it could negatively influence organ function. The spectrum of organ injury may be broad, ranging from mild reversible degeneration, such as steatosis, to end-stage organ failure, such as organ cirrhosis,

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and it also comprises acute phase and chronic phase processes. The effectiveness of the current therapeutic approach for organ injury treatment is still limited. The pathogenesis of organ injury is complex, but it can be classified into three general points: 1. Immune responses. The host immune system can be classified into two types: innate immune system and adaptive immune system. Both of these could elicit injury. For example, there are a large number of macrophages in the lungs called pulmonary macrophages. This cell population is responsible for the clearance of dust and other potential pathogens; however, upon infection, they are over-activated and exert phenotypic alterations, as characterized by cytokine over-expression and secretion [25]. Over-produced cytokines such as TNF-a would further bind their receptor located in the surface of the pneumonocyte and trigger apoptotic signaling transduction, followed by lung cell dysfunction and death. Such inflammatory response is also the main contributor to other organ injury processes. Besides the innate immune reaction mentioned above, the adaptive immune reaction is another key contributor to injury. For example, T cells are responsible for destroying the infected cells; during infection with the hepatitis virus, if the T cells are activated and start to clear the virus-infected hepatocytes, large amounts of liver cells become damaged, resulting in organ dysfunction [26]. The immune reaction is believed to be the most important mediator in the development of organ injury. 2. Oxidative stress. Redox balance is important in maintaining normal cellular function. Upon disruption, the imbalanced oxidative status could lead to cell damage and finally cause organ injury [27, 28]. For example, during renal ischemia-reperfusion injury, large amounts of hypoxanthine, metabolized from ATP and xanthine oxidase, are accumulated at the hypoxia phase; when oxygen is present after reperfusion, xanthine oxidase can catalyze hypoxanthine into xanthine and uric acid, which is accompanied by the generation of superoxide radicals. Superoxide would directly or indirectly destroy the function of biomacromolecules, resulting in disruption of the cells’ functions [29]. This radical would also be released from the cell and exert harmful effects onto other cells. Beside superoxide, other radicals like hydroxyl radicals, hydrogen peroxide, and reactive nitrogen species would also be harmful to the host cells and organs when they become abnormally accumulated. 3. Circulatory defect. Our circulation system enables all of our organs and cells to obtain enough oxygen and nutrients so that they can “work” smoothly to support our life. However, when the circulation is negatively influenced, the organ may be injured because of hypoxia. For example, sepsis-induced multiple organ dysfunction is the main cause of death [30]. Sepsis development is normally associated with a dysfunction in coagulation, which leads to microcirculation defects. Consequently, the hypoxia would augment the cell damage and promote the development of organ injury. Hence, it is widely recognized that improving the circulation is an important approach to alleviating septic organ injury.

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Collectively, organ injury may be influenced by many endogenous or exogenous factors. Studying the pathogenesis and developing more effective treatment methods are leading topics in medical research.

1.3

The Gut Microbiota Influence the Pathogenesis of Organ Injury Development

An increasing number of scientists believe that the gut microbiota is involved in both intestinal and extraintestinal organ injury development based on recent strong evidence. Regardless of acute or chronic processes, the gut microbiota is able to mediate the progression or severity of organ damage in response to multiple etiologic factors. It is expected that the gut microbiota could regulate gastrointestinal injury. Helicobacter pylori is recognized as a key risk factor for gastric ulcers and cancer development [31]. Intestinal abnormality induced by infection with Clostridium difficile is a common syndrome in gastroenterology [32]. Inflammatory bowel disease (IBD) is closely associated with gut microbial dysbiosis [33]. It has been reported that the diversity of microbiota is lower in IBD patients than in healthy individuals. Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria are all altered during IBD development. Notably, Enterobacteriaceae is markedly enriched in IBD patients. The dysbiotic status is believed to promote IBD; however, the detailed mechanism is complex. The levels of intestinal short-chain fatty acids (SCFAs), which serve as the beneficial nutrients for intestinal epithelial cells (IECs), are disrupted by dysbiosis [34]. Additionally, shifted microbial composition and function could directly disrupt host immune responses, causing harmful mucosal inflammation [35]. Besides the alimentary tract, the liver is the most connected organ that tightly communicates with intestinal bacteria. This results from (1) the primary bile acids generated by hepatocytes, which enter the intestine and regulate the bacterial composition, or the bacteria that could metabolize these compounds into secondary bile acids, which would be reabsorbed into liver and react with liver cells to influence hepatic function [36]; (2) the gut microbial products could penetrate into the circulatory system and reach the liver through the portal vein to modulate the pathophysiologic function of the liver. Hence, the gut microbiota has a deep crosstalk with the liver and can directly influence liver damage development, including both acute and chronic injury [37]. For examples, enteric dysbiosis is observed in both alcoholic and nonalcoholic fatty liver disease, and some important strains such as Akkermansia directly influence these chronic liver injury developments [38, 39]. Moreover, gut microbial metabolites could directly modulate drug-induced acute liver injury [40, 41]. Many scientists believe that some liver diseases are actually intestinal disease, especially because of the gut microbial abnormalities.

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Gut microbiota has also been demonstrated to be able to regulate the injury of other remote organs in response to multiple challenges, such as renal injury, cardiovascular injury, lung injury, and psychological disorder [42–45]. We previously discovered that gut microbial compositional disorder was linked to chronic high salt intake, and such microbial disruption could promote early renal injury [35]. Microbial metabolite indoxyl-sulfate is recognized as a key driver for chronic kidney disease (CKD) development [46]. Trimethylamine (TMA) that is generated from choline by intestinal bacteria could be further metabolized into trimethylamine oxide (TMAO), which causes atherosclerosis [47]. Hypertension is reported to be closely related to enteric dysbiosis, and similar to other diseases, the dysbiotic microbiota in hypertension patients could independently enhance their blood pressure [48]. Moreover, autism is associated with microbial disturbances, and treatment of Bacteroides fragilis could serve as an efficient approach to restore the gut barrier dysfunction, microbial changes, and behavioral abnormalities during the progression of autism spectrum disorders [49]. Moreover, the gut microbiota could regulate sepsis-induced multiple organ dysfunction [50]. We recently found that the susceptibility of mice to sepsis-induced multiple organ damage was modulated by the gut microbiota, specifically by the microbial metabolite granisetron, which could reduce inflammatory responses [50]. In addition, gut microbial-generated lipids may activate intestinal immune cells such as the natural killer T cells (NKT), and these important immune cells can further translocate to remote organs to exacerbate organ injury [51]. Hence, it is clear that gut microbiota plays a key role in the development of multiple organ damage. In this book, we will summarize the latest research regarding the modulatory effects of gut microbiota on organ injury and conclude with the underlying mechanisms. Also, targeting the gut microbiota is recognized as a novel effective approach to combat diseases involved in multiple organ damage.

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28. Sener G, Toklu H, Ercan F, Erkanli G (2005) Protective effect of beta-glucan against oxidative organ injury in a rat model of sepsis. Int Immunopharmacol 5(9):1387–1396 29. Ihara N, Schmitz S, Kurisawa M, Chung JE, Uyama H, Kobayashi S (2004) Amplification of inhibitory activity of catechin against disease-related enzymes by conjugation on poly (epsilon-lysine). Biomacromolecules 5(5):1633–1636 30. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, Reinhart CK, Suter PM, Thijs LG (1996) The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 22 (7):707–710 31. Amieva M, Peek RM Jr (2016) Pathobiology of helicobacter pylori-induced gastric cancer. Gastroenterology 150(1):64–78 32. Banaei N, Anikst V, Schroeder LF (2015) Burden of Clostridium difficile infection in the United States. N Engl J Med 372(24):2368–2369 33. Kaur N, Chen CC, Luther J, Kao JY (2011) Intestinal dysbiosis in inflammatory bowel disease. Gut Microbes 2(4):211–216 34. Rodríguez-Carrio J, López P, Sánchez B, González S, Gueimonde M, Margolles A, de Los Reyes-Gavilán CG, Suárez A (2017) Intestinal dysbiosis is associated with altered short-chain fatty acids and serum-free fatty acids in systemic lupus erythematosus. Front Immunol 8:23 35. Hu J, Luo H, Wang J, Tang W, Lu J, Wu S, Xiong Z, Yang G, Chen Z, Lan T, Zhou H, Nie J, Jiang Y, Chen P (2017) Enteric dysbiosis-linked gut barrier disruption triggers early renal injury induced by chronic high salt feeding in mice. Exp Mol Med 49(8):e370 36. Merrick MV, Eastwood MA, Anderson JR, Ross HM (1982) Enterohepatic circulation in man of a gamma-emitting bile-acid conjugate, 23-selena-25-homotaurocholic acid (SeHCAT). J Nucl Med 23(2):126–130 37. Chassaing B, Etienne-Mesmin L, Gewirtz AT (2014) Microbiota-liver axis in hepatic disease. Hepatology 59(1):328–339 38. Wu W, Lv L, Shi D, Ye J, Fang D, Guo F, Li Y, He X, Li L (2017) Protective effect of Akkermansia muciniphila against immune-mediated liver injury in a mouse model. Front Microbiol 8:1804 39. Grander C, Adolph TE, Wieser V, Lowe P, Wrzosek L, Gyongyosi B, Ward DV, Grabherr F, Gerner RR, Pfister A, Enrich B, Ciocan D, Macheiner S, Mayr L, Drach M, Moser P, Moschen AR, Perlemuter G, Szabo G, Cassard AM, Tilg H (2018) Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates alcoholic liver disease. Gut 67(5):891–901 40. Gong S, Lan T, Zeng L, Luo H, Yang X, Li N, Chen X, Liu Z, Li R, Win S, Liu S, Zhou H, Schnabl B, Jiang Y, Kaplowitz N, Chen P (2018) Gut microbiota mediates diurnal variation of acetaminophen induced acute liver injury in mice. J Hepatol 69(1):51–59 41. Clayton TA, Baker D, Lindon JC, Everett JR, Nicholson JK (2009) Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. Proc Natl Acad Sci U S A 106(34):14728–14733 42. Gong J, Noel S, Pluznick JL, Hamad ARA, Rabb H (2019) Gut Microbiota-kidney cross-talk in acute kidney injury. Semin Nephrol 39(1):107–116 43. Tang WH, Kitai T, Hazen SL (2017) Gut microbiota in cardiovascular health and disease. Circ Res 120(7):1183–1196 44. Kapur R, Kim M, Rebetz J, Hallström B, Björkman JT, Takabe-French A, Kim N, Liu J, Shanmugabhavananthan S, Milosevic S, McVey MJ, Speck ER, Semple JW (2018) Gastrointestinal microbiota contributes to the development of murine transfusion-related acute lung injury. Blood Adv. 2(13):1651–1663 45. Cryan JF, O’Riordan KJ, Cowan CSM, Sandhu KV, Bastiaanssen TFS, Boehme M, Codagnone MG, Cussotto S, Fulling C, Golubeva AV, Guzzetta KE, Jaggar M, Long-Smith CM, Lyte JM, Martin JA, Molinero-Perez A, Moloney G, Morelli E, Morillas E, O’Connor R, Cruz-Pereira JS, Peterson VL, Rea K, Ritz NL, Sherwin E, Spichak S, Teichman EM, van de

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Chapter 2

Gut Microbiota and Alimentary Tract Injury Ye Chen, Guangyan Wu, and Yongzhong Zhao

Abstract The gastrointestinal (GI) tract is inhabited by a diverse array of microbes, which play crucial roles in health and disease. Dysbiosis of microbiota has been tightly linked to gastrointestinal inflammatory and malignant diseases. Here we highlight the role of Helicobacter pylori alongside gastric microbiota associated with gastric inflammation and cancer. We summarize the taxonomic and functional aspects of intestinal microbiota linked to inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS), and colorectal cancer in clinical investigations. We also discuss microbiome-related animal models. Nevertheless, there are tremendous opportunities to reveal the causality of microbiota in health and disease and detailed microbe–host interaction mechanisms by which how dysbiosis is causally linked to inflammatory disease and cancer, in turn, potentializing clinical interventions with a personalized high efficacy.













Keywords Microbiota Microbiome Chronic gastritis Gastric cancer Inflammatory bowel disease Irritable bowel syndrome Colorectal cancer Dysbiosis










Y. Chen Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China e-mail: [email protected] G. Wu Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China Y. Zhao (&) Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 P. Chen (ed.), Gut Microbiota and Pathogenesis of Organ Injury, Advances in Experimental Medicine and Biology 1238, https://doi.org/10.1007/978-981-15-2385-4_2

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Introduction

The alimentary tract comprises the oral cavity, pharynx, esophagus, stomach (fundus and antrum), duodenum (Du), jejunum (Je), ileum, cecum (Ce), colon (ascending colon, transverse colon, and descending colon), sigmoid colon (SC), and rectum (Re). Owing to this consistent basic structure, the gastrointestinal (GI) tract is colonized by a diverse array of microbiota. The complicated bi-directional relationship between the GI microbiota and host underscores the crucial role of dysbiosis (a microbial imbalance or maladaptation on or inside the body, such as an impaired microbiota) in complex disease etiology [1–5]. Here we review advances on studying gut microbiota in GI diseases, focusing on Helicobacter pylori (H. pylori) infection on the upper GI tract, bacterial dysbiosis in inflammatory bowel disease (IBD), colorectal cancer (CRC), and irritable bowel syndrome (IBS).

2.2

The Role of Helicobacter pylori Infection and Microbiome Dysbiosis in Chromic Gastritis and Gastric Cancer

Chronic gastritis, one of the most common serious pandemic infections with even more than half of people infected worldwide, is a clinical condition due to an inflammation of gastric mucosa with multistep, progressive, and life-long process, which can progress into peptic ulcer or even gastric cancer [6]. The typical symptoms of chronic gastritis patients comprise upper abdominal pain, indigestion, bloating, nausea, vomiting, belching, loss of appetite, and weight loss. Many different conditions and factors cause or contribute to the development of chronic gastritis, including bacteria (bacterial gastritis, H. pylori), bile reflux, HIV/AIDS, and celiac disease. Chronic gastritis is linked to gastric cancer, which is the fifth leading cause of cancer and the third leading cause of death from cancer, making up 7% of case and 9% of deaths [7, 8]. In 1982, Australian scientists Barry Marshall and Robin Warren identified that H. pylori was present in a person with chronic gastritis and gastric ulcers [9]. H. pylori belongs to Campylobacter pylori, a germ-negative, microaerophilic bacterium generally found in the stomach as an essential risk factor in 65–80% of gastric cancers, but only 2% of people with H. pylori infections develop stomach cancer [10]. Given that the disease-etiology paradigm has been shifting to germ-organ theory, in which human microbiota is the essential component of health and disease beyond the canonical Koch’s postulates, gastric microbiota is not an exception [1, 7]. Thus, as anticipated, the bacterial diversity has altered in the present with H. pylori infection, following the criteria of gastric mucosal microbiome dysbiosis definition [11–13]. Taxonomic changes have been revealed, including blooming of Escherichia Shigella, Burkholderia of the Proteobacteria

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phylum, Lactobacillus, Lachnospiraceae, Streptococcus, and Veillonella of the Firmicutes phylum, and Prevotella of the Bacteroidetes phylum [14, 15]. Taxonomic composition and diversity of microbial communities in the stomach are associated with the development of gastric cancer [11–19]; however, functional impact is anticipated to play critical molecular role, such as urea and lipopolysaccharide and the encoding biosynthetic clusters [20–24]. Of particular note, cagA encoded in H. pylori is the first identified bacterial oncogene [25]. Moreover, H. pylori could have a beneficial effect to human health, indicating a promising complexity of studying the H. pylori-centered gastric microbiome [26].

2.3

Microbiome Dysbiosis and Inflammatory Bowel Disease

IBD with a complex disease etiology comprises ulcerative colitis (UC) and Crohn’s disease (CD), resulting from dysregulated mucosal immune response to commensal intestinal microbiota and epithelium, which usually happens in genetically susceptible individuals [27]. UC is characterized by diffuse inflammation restricted to the mucosal layer of the colon that causes recurrent symptoms, while the inflammation of CD can be typically transmural, patchy, and segmental, occurring in any part of the GI tract [28]. The prevalence of IBD is more common in developed than in developing nations as reported that an estimate of 1.8 million (0.9%) U.S. adults in 1999 and 3.1 million (1.3%) U.S. adults in 2015 were diagnosed of IBD, with a rising disease rate in developing nations, including China and India [29–34]. Given that IBD is a complex genetics-microbiome-environment disease with a myriad of studies published [28, 35], here we focus on microbiome dysbiosis and IBD, including significant discoveries with 16S DNA sequencing, metaproteomics, metagenome shot-gun sequencing, integrative human microbiome project (HMP2) [36], as well as fecal microbiota transplantation and mouse models. Microbiome can be measured by 16S ribosomal DNA sequencing, albeit with the limitation of resolution at the genus level [37]. Reduced alpha-diversity has been consistently observed, including reduced Firmicutes abundance and decreased strict anaerobic bacteria abundance and increased facultative anaerobic proteobacteria [38–40]. Blakeley-Ruiz et al. found that gut microbiota was sustained, and revealed phylum-redundant metabolic functional stability in CD patients in the year after resection surgery [41]. Besides bacteria, fungi also play critical role in the pathogenesis of IBD, albeit with a great potential to clarify due to conflicted reports. Fungi Saccharomyces cerevisiae and Candida albicans increased with CD, particularly in setting of more serious bacterial dysbiosis, while increased Candida albicans alongside decreased Saccharomyces cerevisiae was observed in patients with IBD [38, 42–46].

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IBD is fundamentally caused by the aberrant host–microbe interactions. Thus, microbiome-related host response is pivotal to the pathogenesis of IBD. Dextran sodium sulfate (DSS), a chemical reagent that can damage the integrity of the epithelial barrier, is an extensively induced experimental colitis. With the development of intestinal organoid culture systems, the modular gut inflammation-on-a-chip provides a research tool for DSS-induced colitis models. Shin et al. have provided significant experimental evidence that the integrity of the epithelial barrier is necessary to maintain the normal intercellular host–microbiome cross-talk [47]. In a cohort of sigmoid colon biopsies of active UC, 29 core proteins were reduced, including MUC2, a secretory mucin glycoprotein as one of the major structural components with the function of protecting the host against the pathogenic bacterial invasion in the mucus layer [48]. The Predicting Response to Standardized Pediatric Colitis Therapy (PROTECT) study for UC patients showed that severity and treatment response gene signatures of mucosal transcriptomes are associated with changes in flora involved in mucosal homeostasis [49]. Mucosa-associated bacterial species, such as Burkholderia cepacia, Flavonifractor plautii, and Rumminococcus sp., were more prone to be recognized selectively by pediatric IBD patient-derived IgG at intestinal mucosal surface compared with non-IBD [50, 51]. Exclusive enteral nutrition (EEN) appears to modulate the gut microbiome, for example, the CD Treatment-with-EATing diet (CD-TREAT), an individualized, food-based diet-enabled replicating EEN changes in the inflammatory gut microbiome [52–54]. Since FMT was broadly reported as an effective and safe treatment for recurrent or refractory Clostridium difficile infection, it has attracted increasing research attention in FMT as a potential therapeutic option in other diseases related to the gut microbiome, such as the IBD. In recent randomized controlled trials, Costello et al. revealed that patients with mild-to-moderate UC received treatment with anaerobically prepared donor FMT compared to patients who received autologous stool; the former was more effective in achieving clinical remission at 8 weeks [55]. According to the transcriptomic and microbiome data, Hyams et al. revealed that the gut microbiome before treatment with standardized protocols was associated with achieving clinical remission in the PROTECT study. For example, patients with lower relative abundance of Sutterella and higher relative abundance of Ruminococcaceae were more prone to 52-week corticosteroid-free remission [56]. We summarized the known microbiome pathophysiology of IBD, as shown in Fig. 2.1. It appears that microbiome lays the foundation of pathogenesis of IBD, thereby leading to potential interventions, including synthetic ecology approach of integrating prebiotics and engineered probiotics [57]. Meanwhile, the host–microbe interactions are pivotal in the disease mechanism of IBD.

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Fig. 2.1 Altered microbiome-linked pathogenesis features of IBD. Nine aspects have been illustrated, with an emphasis of the immune mechanism of host–microbe interaction

2.4

Irritable Bowel Syndrome

IBS, a functional GI disorder, is characterized by recurrent abdominal pain related to defecation and associated with a change in frequency and/or form of stool, with diarrhea or constipation, or mixed symptoms of diarrhea and constipation, according to the Rome IV diagnostic criteria. IBS is one of the most common diagnoses in functional GI disorder associated with the dysbiosis of gut microbiota [58, 59]. A variety of gut microbial signatures have been generated, for example, relative abundance of Clostridiales and Prevotella and Bacteroides based on 16S ribosomal DNA sequencing, being claimed to have the capacity to discriminate the IBS symptom severity and healthy, however, highly controversial [60–63]. It is most likely that the poor replicability is due to the pathogenesis of IBS at the strain level, that is, those available data had not reached the right resolution. Distinct intestinal fungal dysbiosis was observed in patients with IBS [64–66], as well as well-established rat maternal separation model [64–66]. By combining fecal calprotectin and the top 20 selected taxonomies, it led to highest prediction accuracy in distinguishing patients with IBD from those with IBS [64–66]. A fermentable oligo-, di-, monosaccharides, and polyols (FODMAPs) restricted diet (low FODMAPs diet) has been reported to ameliorate symptoms in IBS patients [67]. Yet, previous studies demonstrated that the low FODMAPs diet could lead to altered gut microbiota, such as the reductions of probiotic Bifidobacterium

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[68–85]. In a randomized controlled trial, it showed that the low FODMAPs diet was more effective in IBS patient group compared with the placebo diet. And co-administration of the multistrain probiotic and low FODMAPs diet could restore Bifidobacterium [86]. Bennet et al. demonstrated that change in Bifidobacterium in low FODMAPs diet was related to the lactose consumption [66]. Future research needs to explore whether a combination of low FODMAPs, probiotic, and prebiotic will play an even greater role in predicting and modulating gut microbiota for IBS patients. The first randomized, double-blind, placebo-controlled trial aimed at exploring the effect of FMT in patients with IBS was implemented by Johnsen and colleagues. They reported that IBS patients in the active treatment group treated with FMT via colonoscopy-induced effective symptom relief at 3 months post-FMT, yet less remarkable at 12 months post-FMT compared with those in placebo group [87]. In addition, unlike delivered to the lower-gut through colonoscopy, FMT via oral capsules is a form of upper-gut delivery method. Halkjær et al. reported that patients with IBS orally administered FMT capsules were exhibited changes to the gut microbiota, however, those individuals after 3 months have poor effects in symptom improvement compared to patient treatment with placebo [88, 89]. Therefore, there is an urge to determine whether FMT protocol is related to the outcome of patients with IBS.

2.5

Colorectal Cancer

Colorectal cancer (CRC) is a common malignancy, including colon cancer and rectal cancer. According to the global cancer statistics in 2018, CRC ranks third in terms of incidence but second in the matter of mortality among estimated cases and deaths for males and females [90]. Several species of bacteria and bacterial metabolites have been investigated in CRC. For example, Fusobacterium nucleatum, a causal opportunistic infections pathogen, has been implicated in CRC. Several systematic reviews have emphatically described that the intestinal microbiota Fusobacterium nucleatum, colibactin-producing Escherichia coli, and enterotoxigenic Bacteroides fragilis were involved in DNA damage and tumor progression in CRC [91, 92]. In a large-scale, long-term retrospective study, Kwong et al. reported that the risk of CRC was enhanced in patients with bacteremia from specific intestinal microbes, including Bacteroides fragilis, Streptococcus gallolyticus, Fusobacterium nucleatum, Clostridium septicum, Clostridium perfringens, and Gemella morbillorum [93]. Predictive microbiome signature could facilitate the early intervention of CRC. Thus, a set of signatures have been revealed [94–98]. In a large cohort of 616 participants who underwent colonoscopy to assess taxonomic and functional characteristics of gut microbiota and metabolites, the relative abundance of Fusobacterium nucleatum spp. was significantly (P < 0.005) elevated continuously from intramucosal carcinoma to more advanced stages, and Atopobium parvulum

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and Actinomyces odontolyticus, which co-occurred in intramucosal carcinomas, were significantly (P < 0.005) increased only in multiple polypoid adenomas and/ or intramucosal carcinomas [94]. A meta-analysis of eight geographically and technically diverse fecal shotgun metagenomic studies of 768 cases of CRC identified a core set of 29 species significantly enriched in CRC metagenomes (false discovery rate (FDR) < 1  10(−5)), with that functional analysis of CRC metagenomes revealed enriched protein and mucin catabolism genes and depleted carbohydrate degradation genes [95]. On two additional cohorts with total 969 fecal metagenomes, the gut microbiome in CRC showed reproducibly higher richness than controls partially due to expansion of species typically derived from the oral cavity, with identification of gluconeogenesis and the putrefaction and fermentation pathways as being associated with CRC [96]. Nevertheless, the microbial molecules and/or pathways contribute to the pathogenic drivers of CRC that is still in its infancy at this stage. The intestinal microbiota also consists of both fungi and viruses, yet their role in the contribution of CRC is still largely unknown. Commensal gut fungi are one of the most important components of the gut microbiota. Coker et al. reported that fecal mycobiome is a predictive biomarker for the diagnosis of CRC with independent bacteria and other clinical parameters, and disruptions are involved in colorectal carcinogenesis [99]. Targeting one of the immune sensing pathways associated with fungi, Malik et al. reported that gut fungi through SYK-CARD9 pathway enhanced the inflammasome activation and IL-18 maturation, and then promoted epithelial barrier repair and IFN-c production, which was protected from colitis and CRC [100]. In another study, aiming at the gut virome, Nakatsu and colleagues first reported that the diversity of bacteriophage virome was increased in CRC patients, and the dysbiosis of the enteric virome was related to CRC prognosis [101]. These findings collectively indicated the potential effectiveness of gut fungi and virome in the development of CRC. Recent study has revealed that activating transcription factor 6 (ATF6) in intestinal epithelial cells contributes to microbial dysbiosis, and promotes microbiota-dependent colorectal tumorigenesis in mice [102]. It indicated that interruption of the ATF6 signaling pathways and modulation of the gut microbiome to reverse dysbiosis may provide the precise therapeutic targets in CRC. This study underscores the critical role of the host side in the pathogenesis of IBD. In addition, Cremonesi et al. reported that CRC cells were recognized as an essential chemokine source, expressing a range of chemokines. And specific gut microbiota promoted production of chemotactic factors in CRC cells and recruited more T cells into tumor sites, and thereby improved the prognosis of CRC [99]. He et al. recently reported that Campylobacter jejuni, a strain that produces cytolethal distending toxin (CDT), could disturb both host and microbial genes expression, and finally promotes tumorigenesis in mice [103]. This novel piece of evidence strengthened the tight association between gut microbiota and CRC development.

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Future Aspects

Gut microbiota study in common gastrointestinal complex diseases is still in its early-infancy, looking forward to discovery of mechanistic predictive microbiome biomarkers and host–microbe interaction mechanisms. In addition to examining the replicability of association studies in clinical investigations, the future focus will lie in the causality approaches, such as randomized controlled trials, gnotobiotic rodent models, mediation analysis, as well as Mendelian randomization [104, 105]. We envision that the future research will be focusing on the host–microbe interface, or treating host and microbiome as a whole, namely holobiont [106, 107]. Under the germ-organ theory framework, novel individualized clinical interventions, such as targeting the microbiome and the host–microbe interface, are emerging in the arena of fighting those devastating diseases, including IBD and CRC.

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44. Sabino J et al (2016) Primary sclerosing cholangitis is characterised by intestinal dysbiosis independent from IBD. Gut 65(10):1681–1689 45. Lemoinne S et al (2019) Fungi participate in the dysbiosis of gut microbiota in patients with primary sclerosing cholangitis. Gut 69(1):92–102 46. Imhann F et al (2018) Interplay of host genetics and gut microbiota underlying the onset and clinical presentation of inflammatory bowel disease. Gut 67(1):108–119 47. Shin W, Kim HJ (2018) Intestinal barrier dysfunction orchestrates the onset of inflammatory host-microbiome cross-talk in a human gut inflammation-on-a-chip. Proc Natl Acad Sci U S A 115(45):E10539–E10547 48. van der Post S et al (2019) Structural weakening of the colonic mucus barrier is an early event in ulcerative colitis pathogenesis. Gut 68(12):2142–2151 49. Haberman Y et al (2019) Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response. Nat Commun 10(1):38 50. Armstrong H et al (2019) Host immunoglobulin G selectively identifies pathobionts in pediatric inflammatory bowel diseases. Microbiome 7(1):1 51. Palm NW et al (2014) Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease. Cell 158(5):1000–1010 52. Svolos V et al (2019) Treatment of active Crohn’s disease with an ordinary food-based diet that replicates exclusive enteral nutrition. Gastroenterology 156(5):1354–1367 e6 53. Ashton JJ, Beattie RM (2019) Treatment of active Crohn’s disease with an ordinary food-based diet that replicates exclusive enteral nutrition. Gastroenterology 157(4):1160– 1161 54. Quince C et al (2015) Extensive modulation of the fecal metagenome in children with Crohn’s disease during exclusive enteral nutrition. Am J Gastroenterol 110(12):1718–29; quiz 1730 55. Costello SP et al (2019) Effect of fecal microbiota transplantation on 8-week remission in patients with ulcerative colitis: a randomized clinical trial. JAMA 321(2):156–164 56. Hyams JS et al (2019) Clinical and biological predictors of response to standardised paediatric colitis therapy (PROTECT): a multicentre inception cohort study. Lancet 393 (10182):1708–1720 57. Cleary B et al (2017) Efficient generation of transcriptomic profiles by random composite measurements. Cell 171(6):1424–1436 e18 58. Drossman DA (2016) Functional gastrointestinal disorders: history, pathophysiology, clinical features and Rome IV. Gastroenterology pii: S0016-5085(16)00223-7 59. Ford AC, Lacy BE, Talley NJ (2017) Irritable bowel syndrome. N Engl J Med 376 (26):2566–2578 60. Precup G, Vodnar DC (2019) Gut Prevotella as a possible biomarker of diet and its eubiotic versus dysbiotic roles: a comprehensive literature review. Br J Nutr 122(2):131–140 61. Peter J et al (2018) A microbial signature of Psychological distress in irritable bowel syndrome. Psychosom Med 80(8):698–709 62. Hugerth LW et al (2019) No distinct microbiome signature of irritable bowel syndrome found in a Swedish random population. pii: gutjnl-2019-318717 63. Collins SM (2016) The intestinal microbiota in the irritable bowel syndrome. Int Rev Neurobiol 131:247–261 64. Mandarano AH et al (2018) Eukaryotes in the gut microbiota in myalgic encephalomyelitis/ chronic fatigue syndrome. PeerJ 6:e4282 65. Gu Y et al (2019) The potential role of gut mycobiome in irritable bowel syndrome. Front Microbiol 10:1894 66. Bennet SMP et al (2018) Multivariate modelling of faecal bacterial profiles of patients with IBS predicts responsiveness to a diet low in FODMAPs. Gut 67(5):872–881 67. Staudacher HM, Whelan K (2017) The low FODMAP diet: recent advances in understanding its mechanisms and efficacy in IBS. Gut 66(8):1517–1527

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68. Zhou SY et al (2018) FODMAP diet modulates visceral nociception by lipopolysaccharidemediated intestinal inflammation and barrier dysfunction. J Clin Invest 128(1):267–280 69. Wilder-Smith CH et al (2018) Breath methane concentrations and markers of obesity in patients with functional gastrointestinal disorders. United European Gastroenterol J 6(4): 595–603 70. Wilder-Smith CH et al (2018) Fermentable sugar ingestion, gas production, and gastrointestinal and central nervous system symptoms in patients with functional disorders. Gastroenterology 155(4):1034–1044 e6 71. Valeur J et al (2018) Exploring gut microbiota composition as an indicator of clinical response to dietary FODMAP restriction in patients with irritable bowel syndrome. Dig Dis Sci 63(2):429–436 72. Vakil N (2018) Dietary fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) and gastrointestinal disease. Nutr Clin Pract 33(4):468–475 73. Tuck CJ et al (2019) The impact of dietary fermentable carbohydrates on a postinflammatory model of irritable bowel syndrome. Neurogastroenterol Motil 31(10):e13675 74. Su H et al (2019) Effects of low-FODMAPS diet on irritable bowel syndrome symptoms and gut microbiome. Gastroenterol Nurs 42(2):150–158 75. Sloan TJ et al (2018) A low FODMAP diet is associated with changes in the microbiota and reduction in breath hydrogen but not colonic volume in healthy subjects. PLoS ONE 13(7): e0201410 76. Rodino-Janeiro BK et al (2018) A review of microbiota and irritable bowel syndrome: future in therapies. Adv Ther 35(3):289–310 77. Rinninella E et al (2019) Food components and dietary habits: keys for a healthy gut microbiota composition. Nutrients 11(10) 78. Rej A, Sanders DS (2018) Gluten-free diet and its ‘cousins’ in irritable bowel syndrome. Nutrients 10(11) 79. Rej A et al (2019) The role of diet in irritable bowel syndrome: implications for dietary advice. J Intern Med 286(5):490–502 80. Rej A et al (2018) Clinical application of dietary therapies in irritable bowel syndrome. J Gastrointestin Liver Dis 27(3):307–316 81. Panacer K, Whorwell PJ (2019) Dietary lectin exclusion: the next big food trend? World J Gastroenterol 25(24):2973–2976 82. Ooi SL, Correa D, Pak SC (2019) Probiotics, prebiotics, and low FODMAP diet for irritable bowel syndrome—what is the current evidence? Complement Ther Med 43:73–80 83. Mitchell H et al (2019) Review article: implementation of a diet low in FODMAPs for patients with irritable bowel syndrome-directions for future research. Aliment Pharmacol Ther 49(2):124–139 84. Konturek PC, Zopf Y (2017) Therapeutic modulation of intestinal microbiota in irritable bowel syndrome. From probiotics to fecal microbiota therapy. MMW Fortschr Med 159 (Suppl 7):1–5 85. Kay E et al (2019) Nonpharmacologic options for treating irritable bowel syndrome. JAAPA 32(3):38–42 86. Huaman JW et al (2018) Effects of prebiotics vs. a diet low in FODMAPs in patients with functional gut disorders. Gastroenterology 155(4):1004–1007 87. Johnsen PH et al (2018) Faecal microbiota transplantation versus placebo for moderate-tosevere irritable bowel syndrome: a double-blind, randomised, placebo-controlled, parallel-group, single-centre trial. Lancet Gastroenterol Hepatol 3(1):17–24 88. Halkjaer SI et al (2018) Faecal microbiota transplantation alters gut microbiota in patients with irritable bowel syndrome: results from a randomised, double-blind placebo-controlled study. Gut 67(12):2107–2115 89. De Palma G et al (2017) Transplantation of fecal microbiota from patients with irritable bowel syndrome alters gut function and behavior in recipient mice. Sci Transl Med 9(379)

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90. Bray F et al (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424 91. Brennan CA, Garrett WS (2016) Gut microbiota, inflammation, and colorectal cancer. Annu Rev Microbiol 70:395–411 92. Tilg H et al (2018) The intestinal microbiota in colorectal cancer. Cancer Cell 33(6):954–964 93. Kwong TNY et al (2018) Association between bacteremia from specific microbes and subsequent diagnosis of colorectal cancer. Gastroenterology 155(2):383–390 e8 94. Yachida S et al (2019) Metagenomic and metabolomic analyses reveal distinct stage-specific phenotypes of the gut microbiota in colorectal cancer. Nat Med 25(6):968–976 95. Wirbel J et al (2019) Meta-analysis of fecal metagenomes reveals global microbial signatures that are specific for colorectal cancer. Nat Med 25(4):679–689 96. Thomas AM et al (2019) Metagenomic analysis of colorectal cancer datasets identifies cross-cohort microbial diagnostic signatures and a link with choline degradation. Nat Med 25(4):667–678 97. Nakatsu G et al (2015) Gut mucosal microbiome across stages of colorectal carcinogenesis. Nat Commun 6:8727 98. Zeller G et al (2014) Potential of fecal microbiota for early-stage detection of colorectal cancer. Mol Syst Biol 10:766 99. Cremonesi E et al (2018) Gut microbiota modulate T cell trafficking into human colorectal cancer. Gut 67(11):1984–1994 100. Malik A et al (2018) SYK-CARD9 signaling axis promotes gut fungi-mediated inflammasome activation to restrict colitis and colon cancer. Immunity 49(3):515–530 e5 101. Nakatsu G et al (2018) Alterations in enteric virome are associated with colorectal cancer and survival outcomes. Gastroenterology 155(2):529–541 e5 102. He Z, Gharaibeh RZ, Newsome RC, Pope JL, Dougherty MW, Tomkovich S, Pons B, Mirey G, Vignard J, Hendrixson DR, Jobin C (2019) Campylobacter jejuni promotes colorectal tumorigenesis through the action of cytolethal distending toxin. Gut 68(2): 289–300 103. Coleman OI et al (2018) Activated ATF6 induces intestinal dysbiosis and innate immune response to promote colorectal tumorigenesis. Gastroenterology 155(5):1539–1552 e12 104. Sanna S et al (2019) Causal relationships among the gut microbiome, short-chain fatty acids and metabolic diseases. Nat Genet 51(4):600–605 105. Sun BB et al (2018) Genomic atlas of the human plasma proteome. Nature 558(7708):73–79 106. Richardson LA (2017) Evolving as a holobiont. PLoS Biol 15(2):e2002168 107. Planes S et al (2019) The Tara Pacific expedition-A pan-ecosystemic approach of the “-omics” complexity of coral reef holobionts across the Pacific Ocean. PLoS Biol 17(9): e3000483

Chapter 3

Gut Microbiota and Liver Injury (I)—Acute Liver Injury Guangyan Wu, Sanda Win, Tin A. Than, Peng Chen, and Neil Kaplowitz

Abstract Over the last few decades, intestinal microbial communities have been considered to play a vital role in host liver health. Acute liver injury (ALI) is the manifestation of sudden hepatic injury and arises from a variety of causes. The studies of dysbiosis in gut microbiota provide new insight into the pathogenesis of ALI. However, the relationship of gut microbiota and ALI is not well understood, and the contribution of gut microbiota to ALI has not been well characterized. In this chapter, we integrate several major pathogenic factors in ALI with the role of gut microbiota to stress the significance of gut microbiota in prevention and treatment of ALI. Keywords Gut microbiota

3.1


Acute liver injury
DILI

Introduction

Acute liver injury (ALI) can present as a life-threatening disorder and has emerged as a public health issue around the world. ALI can be caused by a series of risk factors, including drug-induced liver injury (DILI), acute viral hepatitis, acute alcohol-induced liver injury, and so on. A wide range of medications and herbal supplements can give rise to DILI, and DILI is one of the major causes of ALI. Acute liver failure (ALF) is a severe manifestation of ALI that seriously threatens human life and health. So far liver transplantation is the most effective therapy for ALF [1]. Nevertheless, many patients with ALF die due to the scarcity of liver G. Wu
P. Chen Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, N.No 1838 Guangzhou Ave., Guangzhou 510515, China e-mail: [email protected] S. Win
T. A. Than
N. Kaplowitz (&) USC Research Center for Liver Disease, Department of Medicine, Keck School of Medicine of USC, Los Angeles, CA 90089, USA e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 P. Chen (ed.), Gut Microbiota and Pathogenesis of Organ Injury, Advances in Experimental Medicine and Biology 1238, https://doi.org/10.1007/978-981-15-2385-4_3

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sources and expensive healthcare costs. Therefore, the limited availability of liver transplantation justifies the need to seek other promising therapies in patients with ALF. For decades, accumulating evidence has demonstrated the close relationship between the gut microbiota and liver injury [2]. However, these researches had mostly focused on chronic liver disease. For example, it is widely discussed that dysbiosis of gut microbiota, including composition and function, is associated with nonalcoholic fatty liver disease (NAFLD) [3]. Recently, based on modulating the intestinal microbiota, an increasing number of preventive and adjuvant therapies have been proposed for ALI. In this section, we highlight the current knowledge of preclinical work to clinical studies about gut microbiota and its contribution in ALI.

3.2

The Gut Microbiota and Drug-Induced Liver Injury

It is well demonstrated that the majority of drugs are metabolized by liver, and some of them associated with hepatotoxicity causing DILI. DILI is a diagnosis of exclusion and is made only after elimination of common causes of liver disease, such as alcoholic liver disease, metabolic and genetic liver diseases, bile duct obstruction, hepatitis virus infection, hepatic ischemia, and autoimmune hepatitis. DILI is often detected during routine testing of serum chemistries [4]. Alanine aminotransferase (ALT) values greater than three times the upper limits of normal (ULN) have been suggested as a sensitive but not necessarily specific DILI signal. It is commonly recognized that DILI is the most predominant cause for acute liver failure in the United States [5, 6]. It is well known that liver transplantation is the most effective measures for the acute liver failure at the present time, but the limitation of liver source scarcity and high surgery expense is a serious threat against patients’ life. An immediate result of DILI is the withdrawal or restricted usage of otherwise efficacious drugs, leading to deficits in therapy [7, 8]. Therefore, DILI is not only a major financial burden for society but also a leading public health problem. DILI can be broadly classified into two types, intrinsic (predictable) or idiosyncratic DILI (IDILI) (unpredictable). The former is related to the drug dosage and all individuals are susceptible. A typical example is acetaminophen (APAP)induced liver injury. IDILI is defined as toxicity that is dose-independent, occurs in a minority of patients during clinical drug therapy, and is exemplified by isoniazid, troglitazone, various antibiotics, and tacrine. Troglitazone was the first peroxisomal proliferator-activated receptor (PPAR-c) agonist available to treat Type 2 diabetes. It was withdrawn from the market by the U.S. Food and Drug Administration (FDA) in 2000 [9]. Tacrine was the first centrally acting cholinesterase inhibitor approved for the treatment of Alzheimer’s disease was withdrawn from clinical use in 2013 [10]. In the past few decades, the gut microbiota is gradually being accepted as an environmental factor that affects host metabolism and contributes to associated host

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health and diseases. The gastrointestinal tract contains trillions of microorganisms that play an important role in host health. Currently, the connection between an altered gut microbiota and liver disorders such as alcoholic liver disease, nonalcoholic fatty liver disease, and primary sclerosing cholangitis [11] is well demonstrated. Although it is also extensively reported that some clinical drugs are metabolized by the liver to metabolites, and then causing DILI. However, the contribution of gut microbiota to interindividual variation in DILI is rarely reported. The process of drug metabolism is complicated and governed by a serious of drug transporters and metabolic enzymes, including cytochrome P450 enzymes (CYPs), N-acetyl transferases, sulfotransferases, and glucuronosyl transferases. However, only a small number of clinical drugs are demonstrated to be metabolically influenced by the gut microbiota. The role of gut microbiota in hepatotoxic responses induced by drugs is not well understood. Thus, it is noteworthy and imperative to investigate the functional link between gut microbiota and DILI. Understanding hepatotoxicity–microbiome interaction is critical for prevention and treatment of DILI. As of 2018, a total of 1356 agents were presented and discussed independently in Livertox Database. It is well known that the liver is a major metabolic organ involved in drug disposition and detoxification activities. It is now generally accepted that the gut microbiota exhibits a broad spectrum of enzymatic activities with profound impact on the metabolism of drugs. Therefore, to elucidate the roles of the gut microbiota on DILI, it has been suggested that the variation in the drug hepatotoxicity may be due to interindividual variability of gut microbiome. DILI is a major public health issue, and improving its prediction remains an enormous challenge. Currently, despite the continual advances of medical science and technology, the most commonly applied metric for potential hepatotoxicity is ALT levels higher than three times ULN. In addition, there are no other effective metrics and therapies available to prevent or treat drug-induced hepatotoxicity. Most of investigations have focused on the effects of drug metabolism or pharmacokinetics on the gut microbiota. In this section, which primarily focuses on the effect of gut microbiota on DILI, we examined the connection between gut microbiota and DILI, and provide several examples of drugs whose activities have been shown to be altered by gut microbiota, including drugs associated with intrinsic and idiosyncratic DILI.

3.2.1

APAP-Induced Liver Injury

Dose-dependent APAP-induced liver injury is referred to as intrinsic DILI, which is predictable and reproducible in preclinical models. In 1966, the first reports of APAP-induced hepatotoxicity were described [12]. From that time on, as a widely used analgesic and antipyretic drug, the overdose of APAP is the most striking example of direct hepatotoxicity and the cause of severe intrinsic DILI. Even at therapeutic dose, a study reported that healthy adults who used the maximum daily

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recommended dose of 4 g APAP for 5 days frequently cause elevations in serum aminotransferases [13]. However, another study demonstrated that it is safe to take APAP at half the maximum recommended daily dosage (2 g) in the long-term, and the elevation in aminotransferases are clinically insignificant [14]. Further research is warranted to determine the effects on liver function of maximum therapeutic doses of APAP. Case reports of acute liver injury due to APAP toxicity have appeared but the extent of the problem is not fully known. Overdose, either in suicidal or therapeutics settings, represents nearly half of all cases of ALF in the US and UK. Because of APAP dose dependence and similar metabolism in rodents, toxicity in mice is the reproducible experimental animal model and has helped to define the pathways leading to hepatotoxicity. Generally, the majority of a therapeutic dose of APAP is conjugated by O-sulfation or glucuronidation and then excreted into the bile or urine. More than 20 different CYPs exist in the CYP450 family in human liver. Especially, isozymes of families CYP1, CYP2, and CYP3 are commonly involved in most phase I biotransformation of drugs and other xenobiotics [15, 16]. A small part of APAP dose is transformed to toxic N-acetyl-p-benzoquinone imine (NAPQI) by the CYPs, (mainly CYP2E1 and CYP3A4) [17]. NAPQI can be detoxified by conjugation with glutathione (GSH) in the hepatocyte. Early mechanistic studies of APAP demonstrated that N-acetylcysteine (NAC) scavenges the reactive metabolite NAPQI of APAP by replenishment of GSH [18]. Subsequent studies suggested that mitochondrial damage and nuclear DNA fragmentation are likely to be predominant terminal events in APAP-induced cellular necrosis [19]. With the technologic development of metagenomics and pharmacometabonomics in recent decades, increasing evidence shows that gut microbiota and microbial metabolites contribute to the hepatotoxicity of APAP [20]. P-cresol is largely produced by the intestinal anaerobic flora [21] and recognized as a substrate for the human cytosolic sulfotransferases SULT1A1 related to the O-sulfation of APAP [22]. In addition, it has been reported that the conjugated APAP is deconjugated by b-glucuronidase and sulfatase of the liver and gut microbiota [23]. Clayton et al. reported that a person’s intestinal tract exhibits high p-cresol generation, leading to competitive inhibition of SULT1A1 by p-cresol which reduces the hepatic sulphation capacity of APAP [22], indicating the gut-derived microbial metabolite p-cresol may contribute to APAP-induced liver injury. Circadian clocks play a vital role in coordinating host daily physiology and metabolism. In the recent investigation, it has been shown that APAP-induced liver injury exhibits diurnal variation and chronotoxicity [24–26]. Chronology has largely been focused on the central clock and hepatocyte clock. The circadian feeding/ fasting-associated metabolism is controlled by the central clock and the transcriptional oscillations of APAP-metabolizing genes are driven by the hepatocyte clock, which may have mutual influence on APAP chronotoxicity. However, the detailed mechanisms responsible for the APAP chronotoxicity are not fully demonstrated. Interestingly, it is established that gut microbiota exhibits diurnal oscillations at the compositional and functional level and affects metabolic homeostasis in both mice and humans [27]. Thaiss et al. also showed that the diurnal oscillations in intestinal

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microbiota regulate the circadian liver transcriptome and detoxification pattern [28]. A novel area of recent work relates to the analysis of the interaction of the APAP-induced diurnal variation of liver injury with the gut microbiota. APAP-induced liver injury exhibits diurnal variation, it shows more severe liver injury when APAP was given at night (ZT12 = when the light is off—start of active period) compared with in the morning (ZT0 = when the light is on—start of resting period). Mice received fecal microbiota transplantation (FMT) separately from ZT12 and ZT0 and ZT12 microbiota enhanced morning toxicity. Specifically, as a type of gut microbial metabolite, the level of 1-phenyl-1,2-propanedione (PPD) was significantly enhanced at ZT12 compared with ZT0 based on metabonomics. Further study found that the PPD is involved in the rhythmic liver injury induced by APAP, by depleting hepatic GSH levels. What’s more, oral administration of Saccharomyces cerevisiae could reduce the PPD level and then ameliorate APAP-induced liver injury at ZT12 [29]. It indicated that a novel mechanism is providing the hepatotoxic rhythmicity of APAP mediated by gut microbial functional oscillations (Fig. 3.1). It is widely reported that dietary polyphenols are natural compounds existing in plants and contribute to health through gut microbiota in humans [30] and animals [31]. It has been estimated that majority of polyphenols (more than 90% of total polyphenol intake) are subjected to the enzymatic activities of the gut microbiota in the colon [32, 33]. The flavonol quercetin is one of the most abundant polyphenols

ZT 0

ZT 12

APAP

APAP

GSH

PPD

GSH

PPD

Saccharomyces cerevisiae

Fig. 3.1 Gut microbiota and the diurnal variation of APAP hepatotoxicity

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which exist in vegetables, fruits, and officinal plants. It has been reported that 3,4-dihydroxyphenylacetic acid (DOPAC), a microbiota-derived metabolite of quercetin, protected against APAP-induced liver injury via Nrf-2 activation [34]. Previous studies showed that 4-hydroxyphenylacetic acid (4-HPA), the major microbial metabolite of polyphenols, is associated with the antianxiety, antiplatelet, and antioxidative activities. Recently, Zhao et al. [35] reported that 4-HPA has a beneficial impact on the detoxification of APAP hepatotoxicity. It is related to the inhibition of CYP2E1 and the enhancement of antioxidant enzymes and phase II enzymes via Nrf2 activation. What’s more, molecular docking study by Zhao and coworkers pointed out that 4-HPA has a higher docking score for binding sites on CYP2E1 compared with the antidote for APAP poisoning, NAC [35]. Taken together, this finding indicated 4-HPA, the microbial metabolite of polyphenol, could be an effective preventive intervention for APAP-induced liver injury, although such a hypothesis warrants future investigation. These studies support the notion that gut microbiota and microbial metabolites play a key role in APAP-induced liver injury. Gut microbiota produce metabolites from dietary sources, which can promote or inhibit APAP toxicity. The gut microbiota exhibited diurnal differences which may influence exposure to the gut-derived metabolites. Furthermore, gut permeability promotes inflammatory responses in the liver which may influence APAP toxicity. Continued research within this field is warranted in order to predict the progression of APAP chronotoxicity and help in better understanding of the role and the mechanisms of the gut microbiota in APAP metabolism.

3.2.2

Tacrine-Induced Liver Injury

Alzheimer’s disease (AD) is a complex age-related neurodegenerative disease and one of the major factors that cause dementia, mainly occurring in the elderly [36]. With the aggravating trend of an aging population, AD prevention and therapy studies require significant attention. As we have known, tacrine, a reversible acetylcholinesterase inhibitor, was the first drug approved for the treatment of dementia of AD. However, due to its hepatotoxicity characterized by elevation in aminotransferase [37], tacrine was discontinued by FDA. It is important to explore the mechanism of tacrine-induced liver injury, so that the researchers can better develop new derivative drugs for the prevention and cure of AD in the future. A recent study conducted by Yip et al. revealed the role of gut microbiota in tacrine-induced liver injury [10]. According to pharmacokinetic studies, they showed enhanced enterohepatic recycling of deglucuronidated tacrine correlated with tacrine hepatotoxicity in rats. Metabonomic studies suggested that gut microbial activities play a pivotal role in tacrine-induced transaminitis. Metagenomics studies demonstrated that an enrichment of b-glucuronidase-producing bacteriae (Bacteroides and Enterobacteriaceae), an abatement of b-glucuronidase-inhibiting bacteriae (Lactobacillus) and an increase in b-glucuronidase genes was exhibited in

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strong responders of tacrine. Ultimately, in the validation study, pretreatment with b-glucuronidase increased the tacrine-induced hepatotoxicity in rats, and pretreatment of antibiotics (vancomycin and imipenem) decreased the susceptibility to the hepatotoxicity of tacrine. Together with the new scientific techniques, Yip et al. supported the hypothesis that the gut microbiota, especially the intestinal b-glucuronidase activities, have an impact on tacrine-induced liver injury through enhancing enterohepatic exposure of the liver to the toxic parent drug. b-glucuronidase, as a toxicologically relevant intestinal bacterial enzyme, which has been demonstrated as newly developed selective bacterial b-glucuronidase inhibitors became available [38]. The specific inhibition of bacterial b-glucuronidase was shown to ameliorate tacrine-induced hepatotoxicity. The relevance of this research to other therapeutic agents with hepatotoxic potential and large interindividual variation is intriguing. Therefore the contribution of the gut microbiota in personalized medicine research is strongly suggested and needs further investigation.

3.2.3

Diclofenac-Induced Liver Injury

Diclofenac (DCLF) is a widely used nonsteroidal anti-inflammatory drug (NSAIDs) that commonly causes intestinal damage as a side effect. The main metabolic pathway of DCLF is through 4′-hydroxylation by CYP2C9 [39], and the formation of a toxic metabolite leads to acute lethal cell injury [40]. DCLF is partly metabolized to DCLF-acyl glucuronides which then are cleaved by bacterial b-glucuronidase, producing the potentially harmful aglycone. Besides, in vitro, it was confirmed that DCLF-acyl glucuronides were wildly catalyzed to DCLF by purified Escherichia coli b-glucuronidase, and bacterial-specific b-glucuronidase inhibitor restrained this reaction [41]. In addition, another major adverse reaction of DCLF is implicated in hepatotoxicity that is associated with IDILI [42]. Owing to the dose-independence, the variable temporal relationship with drug exposure, and the lack of experimental animal models, the mechanisms of DCLF-induced liver injury remain mostly unclear. However, a few years ago, Yano et al. developed a DCLF-induced ALF model in normal mice and demonstrated the Th17 and IL-1b-related immunological factors are involved in the pathogenesis of DCLF-induced liver injury in mice [43]. Therefore, it indicated that gut microbiota and its enzymes, such as bacterial b-glucuronidase, may be involved in DCLF-induced liver injury. A potential model of DCLF-induced IDILI was established by Deng et al. in 2006. Bacteria/lipopolysaccharide (LPS) contributed to a nontoxic dose of DCLF to induce liver injury. Gut sterilization attenuated DCLF-induced liver injury, indicating that hepatotoxicity induced by high concentrations of DCLF is caused in part by its ability to enhance intestinal permeability to LPS or other bacterial products [44]. Further study found that intestinal bacteria/LPS are involved in DCLF-induced liver injury in

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a neutrophil-independent manner and indicate that hypoxia plays a crucial role in the pathogenesis [45]. In this section, gut microbiota involving DILI were categorized based on published documented cases of hepatotoxicity in recent years. We mainly integrate several typical drugs with the role of gut microbiota in DILI to stress the clinical significance of gut microbiota for safe and effective use of drugs. In addition to the abovementioned drugs whose toxicity may be mediated by metabolism by gut microbiota, there are many studies of drug–drug interactions influenced by the gut microbiota. The ability to elucidate the mechanisms underlying the gut microbiota responses in DILI is paramount in developing personalized medicine research. Much progress has been recently made in the field of the gut microbiota in DILI. This section provided several cases of the interindividual responses to DILI which contributed to both the influence of the host and the gut microbiota. Accumulating evidence indicates that the gut microbiota may be a target for monitoring susceptibility to DILI. Understanding the relationship of gut microbiota and DILI may enhance our ability to identify and predict susceptible interindividual variability, and then prevent serious adverse reactions. These studies shed new light on the interaction of gut microbiota in DILI. This is an emerging field with enormous potential.

3.3

The Gut Microbiota and D-Galactosamine-Induced Acute Liver Injury

D-galactosamine (GalN) specifically inhibits RNA and protein synthesis in the hepatocytes, while the hypomethylation of ribosomal RNA is involved in protein synthesis defect [46]. GalN is a well-established ALI animal model induced by intraperitoneal injection of GalN that is similar to human viral infections (hepatitis A, B, and E). More generally, the combined injection of a subtoxic dose of GalN and LPS or TNF has been extensively used in the highly reproducible experimental animal model, which more closely resembles fulminant hepatic failure in the clinic. Previous study has shown that bacterial translocation from gut both to the blood and intraabdominal organs occurred in ALI induced by GalN and then decreased by 70% liver resection with improvement of liver function in rats [47]. However, liver resection in patients can be performed only under strict indications; it is important to explore the relationship of gut microbiota and GalN-induced liver injury. It is reported that the gut microbiota was altered in rats with GalN-induced ALF, which is associated with the translocation of endotoxin from lumen [48]. Studies lead to a hypothesis that administration of probiotic may decrease the bacterial translocation and reduce the bacterial endotoxin exposure. Administration of probiotic Lactobacillus, Bifidobacterium with or without blueberry exhibited therapeutic effects on LPS/GalN-induced liver injury in various degree [49]. Further, when rats were pretreated by gavage with probiotic Bifidobacterium adolescentis CGMCC

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15058, GalN-induced liver injury were alleviated with anti-inflammatory effects. This indicated that these protective effects might be correlated with enhanced intestinal barrier and modified composition of the gut microbiota [50]. It is generally known that the mitogen-activated protein kinase (MAPK) signaling pathway is involved in the mediation and regulation of a variety of physiological processes, such as proliferation, differentiation, stress response, and apoptosis. However, little research had been published to discuss the effect of MAPK signaling pathway on LPS/GalN-induced ALF. A report by Wang et al. showed that when rats given LPS/ GalN were orally administrated pretreatment with probiotic Lactobacillus casei Zhang, pro-inflammatory cytokine production were reduced and liver injury was attenuated by modulating the TLR-MAPK-PPAR-c signaling pathways and gut microbiota [51]. Taken together, these findings suggest that the administration of probiotic might provide a new and effective way for the prevention and treatment of ALI.

3.4

The Gut Microbiota and Acute Alcohol-Induced Liver Injury

Alcohol abuse has been recognized as a major cause of liver injury, including acute and chronic liver injury. The metabolic mechanism of alcohol is complicated, which has been described elsewhere [52]. CYP2E1 in the endoplasmic reticulum is also involved in process of oxidative metabolism of ethanol to acetaldehyde. It has been well demonstrated that acetaldehyde, as the main toxic metabolite of ethanol, can cause direct damage to mitochondria [53]. In addition to alcohol consumption, endogenous ethanol production can be fermented by the commensal microbiota, then being metabolized via the portal vein in the liver, but also further metabolized by the gut microbiota [54]. Many previous studies have addressed the effects of gut microbiota on long-term ethanol consumption, focusing on alcoholic liver disease both in animals and humans. It is widely documented that long-term alcohol consumption disrupts the intestinal epithelial barrier and tight junctions, resulting intestinal hyperpermeability [55]. Alcoholic liver disease is the most common chronic liver injury, and numerous reviews have described the bidirectional communication between gut and liver [56– 58]. It indicates that gut microbiota is inextricably linked to alcohol-induced liver injury. However, published studies on the effects of gut microbiota on acute alcohol-induced liver injury are encouraging but are limited. Studies have shown that acute exposure to ethanol at high concentration can cause the dysbiosis of gut microbiota and mucosal damage, and then increase intestinal permeability, leading to the translocation of enteral bacteria and its endotoxin from the intestine into the liver [59, 60]. It was reported that probiotics Lactobacillus rhamnosus GG culture supernatant pretreatment for 5 days improved intestinal integrity and liver injury in a “binge-drinking” mouse model [60]. Pretreatment with rhubarb extract for 17 days

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ameliorated alcohol-induced liver damage by improving intestinal homeostasis and restoring gut barrier function in a mouse model of binge drinking, especially the relative abundance of Akkermansia muciniphila was increased in the cecal content [61]. Akkermansia muciniphila, a Gram-negative, anaerobic bacterium, is recognized as potential probiotic that strengthens the integrity of intestinal barrier [62], as well as reverses high-fat diet-induced abnormal intestinal permeability [63]. Whether the protective effects observed here extend to the progress of ethanol-induced mucosal damage is less clear. A recent study by Grander et al. revealed that patients with alcoholic steatohepatitis showed a decreased abundance of faecal Akkermansia muciniphila. In experimental acute and chronic alcoholic liver disease, oral supplementation with Akkermansia muciniphila protected against ethanol-induced gut leakiness and ameliorated alcohol-induced liver injury [64]. Consequently, the administration of probiotic may have a beneficial effect in patients with acute ethanol-induced liver injury, although such a hypothesis warrants future investigation in clinical studies. Canesso and colleagues reported that germ-free mice showed no liver injury and less inflammation compared with conventional mice after acute alcohol intake, which indicated gut microbiota contribute either directly or indirectly to liver injury due to acute alcohol consumption [65]. Interestingly, another study reached completely different conclusions. In a binge drinking-induced liver injury model, germ-free mice exhibited more liver damage and inflammation compared with the conventional mice, which suggested the commensal microbiota have a certain protective effect on acute alcohol-induced liver injury [66]. A possible explanation for this difference may be due to the different doses of ethanol and the duration of exposure in mouse models. Furthermore, this could represent an example of hormesis, e.g., microbiota exposure may sustain expression of defensive factors whereas complete absence of such phenomena may weaken defense. In any case, these studies shed new light on the gut microbiota in acute alcohol-induced liver injury. In the future, more research is needed to confirm these preliminary results and to determine whether the gut microbiota is a contributor or a therapeutic target in this area.

3.5

The Gut Microbiota and Viral Hepatitis-Related ALI

Viral hepatitis can cause acute or chronic liver injury. Hepatitis A, B, C, D, and E viruses infection can lead to ALI and even ALF [67]. In recent decades, more and more studies on gut microbiota have provided novel insights for the prevention and treatment of hepatitis viruses infection, mostly about the chronicity of hepatitis viruses infection [68, 69]. So far, however, there is no evidence for a direct relation between gut microbiota and viral hepatitis-related ALI. A study by Zhang et al. showed that patients with hepatitis B-related acute-on-chronic liver failure have increased circulating bacterial DNA and decreased microbial diversity. Also, gut-derived bacterial translocation may be one of the causes of the increased

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peripheral bacterial load [70]. Although less well described, it suggests that gut microbiota may be associated with the development of acute viral hepatitis.

3.6

The Gut Microbiota and Transplantation Linked Liver Injury

Liver transplantation is the most effective approaches to cure end-stage liver diseases. However, due to ischemia and reperfusion (ischemia/reperfusion injury, IRI) during the surgery, recipient may develop hepatic injury, which is the main problem for the allograft dysfunction. The mechanism of IRI is complex, involving redox imbalance and inflammation responses. Recently, Nakamura et al. reported that amoxicillin pretreatment could alleviate liver transplantation linked hepatic damage, which may be through decreasing CCAAT/enhancer-binding protein homologous protein (CHOP) expression, enhancing autophagy, and inhibiting inflammation [71]. They further validate the finding in humans. This interesting study directly linked gut microbiota and IRI. However, the authors used amoxicillin alone which could only deplete part of the gut microbiota. Whether depletion of all of gut microbiota would differently influence IRI still requires further investigation.

3.7

Conclusion

It is recognized that the gut microbiota plays a vital role in body health maintenance, and a well-balanced gut microbiota is critical in the regulation of host homeostasis. Actually, the gut microbiota is a complex community, including bacteria and the nonbacterial microbiome such as fungi, archaea, and viruses. Most studies focus on bacteria in liver disease. So far, little progress has been made toward understanding the contribution of nonbacterial microbiome in this field. This chapter mainly summarizes the current state of knowledge on the role of the gut microbiota in ALI, especially bacteria. Future studies need to pay more attention to investigation of both the bacteria and the nonbacterial components of microbiota in the development and progression of liver disease, especially in ALI.

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Chapter 4

Gut Microbiota and Liver Injury (II): Chronic Liver Injury Susan S. Baker and Robert D. Baker

Abstract Chronic liver injury mainly comprises viral hepatitis, fatty liver disease, autoimmune hepatitis, cirrhosis and liver cancer. It is well established that gut microbiota serves as the key upstream modulator for chronic liver injury progression. Indeed, the term “gut–liver axis” was mostly applied for chronic liver injury. In the current chapter, we will summarize the relationship between gut microbiota and chronic liver injury, including the interaction between them based on latest clinic and basic research.







Keywords Gut microbiota Viral hepatitis Nonalcoholic fatty liver disease Alcoholic liver disease Autoimmune hepatitis Cirrhosis Hepatocellular carcinoma




4.1










Overview

The term “chronic liver disease” includes any condition that affects the liver and is present for a prolonged period of time. The etiology is variable and encompasses infection, metabolic disease, inflammatory, autoimmune, toxin and, at times, the cause cannot be identified. Chronic liver disease progresses to cirrhosis and liver failure unless treatment is available and implemented. It is important to note that the initiation and development of chronic liver disease is complex and likely involves the juxtaposition and interaction of several factors, including genetics, environmental factors, toxins, infections, behaviors and the gut microbiome. Chronic liver disease is the 15th leading cause of mortality in the United States and is responsible for the deaths of more than 25,000 Americans each year [1]. Globally, cirrhosis was S. S. Baker (&)
R. D. Baker Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, USA e-mail: [email protected] S. S. Baker 39 Irving Place, Buffalo, NY 14201, USA © Springer Nature Singapore Pte Ltd. 2020 P. Chen (ed.), Gut Microbiota and Pathogenesis of Organ Injury, Advances in Experimental Medicine and Biology 1238, https://doi.org/10.1007/978-981-15-2385-4_4

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the 11th leading cause of death and accounted for more than 1.2 million deaths in 2016 [2]. The gut microbiome is considered to be a complex ecosystem that involves communication among the organisms, bacteria, fungi, phages, that reside in the ecosystem as well as within the gastrointestinal tract itself and likely other organs, notably the liver, that have access to this ecosystem through the portal circulation. The organisms are estimated to number about 100 trillion and vary with the site along the approximately 9 m adult gastrointestinal tube and location within any given site (luminal, mucosal, submucosal [3]). There is evidence that diet has an important effect on the gut microbiome [4–6]. The ecosystem is generally considered beneficial as its members serve to strengthen gut integrity, harvest energy, contribute to the regulation of host immunity and make vitamin B12, among other functions. Disruption of this ecosystem, often times labeled as dysbiosis, has been associated with many chronic diseases. The liver is particularly vulnerable to the influence of the gut microbiome, its metabolites and inflammatory factors because it has direct access to these through the portal vein. The relationship between the liver and the gut microbiome as a cause or contributor to chronic disease is intriguing because manipulation of the microbiome could lead to improvement of the disease. However, to date the relationship between liver disease and the gut microbiome is descriptive as a causal relationship has not been identified in humans.

4.2

Hepatitis B Virus (A DNA Virus)

Hepatitis B continues to be a global health problem. It is estimated that 270 million people worldwide are infected with the hepatitis B virus. However, among this large number of individuals, there are illuminating details. In endemic areas, the majority of the infected individuals have vertically acquired chronic hepatitis B which they contracted at the time of birth from their chronically infected mothers [7]. This is due to a difference in the way neonates and adults deal with the infection. Hepatitis B infection in neonates becomes chronic 90% of the time, while almost all who become infected as adults eventually clear the virus [8]. The difference in viral clearance has led to a close investigation of the way neonates and adults respond to the infection. There are several obvious differences between neonates and adults. Importantly for the present discussion is the fact that the neonate’s gastrointestinal tract is initially characterized by a paucity of microbes, but rapidly gains bacteria. The early gut microbiome varies considerably but at about a year of age switches to a more adult-like distribution and subsequently remains relatively stable [9]. In a mouse study of age dependency and chronicity of hepatitis B virus infection, Chou et al. report that in C3H/HeN mice the gut microbiome stabilized at about 8 weeks. Mice injected with HBV at 6 weeks (prior to stabilization) became persistently infected while mice injected at 12 weeks (post stabilization) cleared the

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virus. If the gut microbiome was obliterated using antibiotics, persistent infection occurred in the 12-week-old injected mice. Chou et al. hypothesized that their findings could be due to TLR4 and its ligand, LPS. When young mice with either a mutation in TLR4 or Kupffer cell depletion were injected, they cleared the virus rapidly [10]. Another obvious difference is that the neonatal gut has the function of defining what is recognized as a foreign protein. To accomplish this function the neonatal gut is necessarily more permeable than the adult gut. Lipopolysaccharide (LPS), derived from gram negative bacteria, enters the portal system and reaches the liver, where with its ligand TLR4 participates in a number of important immunologic pathways. However, there are other bacterial cell components, designated pathogen-associated molecular patterns (PAMPs) that enter the portal circulation, exerting immunologic reactions in the liver and beyond. Conversely, hepatitis B infection alters the gut microbiome. Lu et al. looked at the microbiome of adults with hepatitis B infections: asymptomatic carriers, individuals with chronic hepatitis B, and those with decompensated cirrhosis due to hepatitis B and normal controls. The microbiome of the individuals who were asymptomatic carriers revealed an increase in Faecalibacterium prausnitzii, Enterococcus faecalis and Enterobacteriaceae when compared to controls. The differences were even more pronounced for those with chronic hepatitis B and decompensated cirrhosis [11]. In summary, there is evidence that in hepatitis B infection, the gut microbiome affects changes in the liver and likewise the liver infection induces changes in the microbiome. It should be made clear that at this point these changes are associations. Whether they represent detrimental attacks on liver or a positive response to infection or merely neutral is not known.

4.3

Hepatitis C Virus (An RNA Virus)

Hepatitis C is another infection of global importance. It is estimated that 79 million people currently have hepatitis C [12]. Unlike hepatitis B vertical transmission is infrequent. There is presently no effective vaccine for hepatitis C; however, recently there has been a proliferation of direct-acting antivirals that can eradicate the virus. This opens up an opportunity to study the long-term effects of the viral infection after elimination of the virus itself. Clinical studies have revealed alterations in the microbiota of hepatitis C patients compared to controls. There is an increase in Enterobacteriaceae and Bacteriodetes abundance and a decreased abundance of Firmicutes [13]. Several hypotheses have been put forward to explain the alteration in the microbiota. The hepatitis virus invades not only hepatocytes but also gastric cells and B lymphocytes. B lymphocytes regulate synthesis of secretory IgA, which, in turn, modulates the intestinal microbiota and intestinal permeability. A second mechanism that could theoretically influence the microbiome is increased carbohydrate present in the gut of patients with hepatitis C, allowing fermenting bacteria species such as Prevotella

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to overgrow. The increase in gastrointestinal carbohydrate is part of generalized malabsorption presumably driven by changes in bile acids [14]. An avenue of research into the pathogenesis of hepatitis C infection and its progression to cirrhosis has focused on the increased permeability of the GI tract and the translocation of bacteria and bacterial products. There is clear evidence that LPS and PAMPs gain access to the liver via the portal system. In a cross-sectional study that used normal values as reference values, Manteanu et al. found increased LPS and tissue necrosis factor-a (TNFa) levels in hepatitis C patients; however, they were unable to demonstrate a correlation between levels of LPS and TNFa and the degree of fibrosis present in the liver [15]. Taking advantage of the newly available treatment for hepatitis C that results in sustained viral response (SVR = no evidence of viremia for 12 months), Bajaj et al. hypothesized that following successful treatment of the virus there would be a return to a “normal” microbiome and a decrease in systemic inflammation. Contrary to their hypothesis, they could not demonstrate a change either in the microbiome or in the systemic inflammation, the two factors important in progression to cirrhosis and liver failure and hepatic cancer [16]. This finding suggests that patients who successfully clear the virus need to be monitored for further progression toward fibrosis. Possible manipulation of the microbiome may be efficacious in the future. As with other hepatotrophic viruses, hepatitis C virus infection is associated with changes in the microbiome and these changes may influence the course of the infection. Manipulation of the gut microbiota as a means of altering the course of hepatitis C seems worth pursuing, especially as the changed microbiome in hepatitis C appears to persist even after viral eradication. Prior to such attempts at treatment, wide-ranging, in-depth study of the microbiome of hepatitis C patients both before and after virus eradication must be undertaken.

4.4

Autoimmune Hepatitis

Autoimmune hepatitis (AIH) is a rare cause of chronic, progressive hepatic inflammation which exists as two phenotypes, type 1 and type 2; both occur in all ethnic groups with a female predominance. Type 1 is characterized by the presence of the auto antibodies ANA (antinuclear antibody) and/or ASMA (anti smooth muscle antibody), while type 2 is characterized by anti-liver-kidney microsomal antibody (ALKM) and liver cytosolic antibody (LC-1). Both types are associated with elevated serum IgG and elevated aminotransferases. There is a strong association with the alleles HLA-DR3 and HLA-DR4. Reports of prevalence range from 1 per 200,000 to 20 per 100,000 [17]. The pathogenesis is as yet unknown; however, it may involve molecular mimicry and promiscuous targeting. For example, ALKM cross reacts with hepatitis C virus [18]. However, changes in the microbiome may help initiate and sustain the disease. In accordance with the general pattern of gut microbiome and liver disease, gut dysbiosis, including a decrease in Bifidobactderium and Lactobacillus, and increased plasma LPS has

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been documented in AIH. Increased permeability is implied [19, 20]. Bacteria, viruses and their derivatives can stimulate Toll-like receptors and induce inflammasomes via a number of pathways. These alterations in liver and gut are not all detrimental. Some act as a defense [21]. The occurrence of AIH is clearly multifactorial. Genetics, gender, environment, diet and medications are among the factors that influence the pathogenesis of AIH. The gut microbiome and the gut–liver axis undoubtedly also play important roles. Realization of these roles may lead to new and novel avenues for treatment [22]. Primary Biliary Cholangitis Primary biliary cholangitis (PBC) is a chronic autoimmune disease occurring mostly in women and characterized by destructive cholangitis of intrahepatic small ducts by inflammatory cells, mainly lymphocytes and plasma cells. Elevated serum alkaline phosphatase combined with the presence of serum anti-mitochondrial autoantibodies or PBC-specific antinuclear antibodies and a high serum IgM are characteristics of the disease. In most patients the disease is progressive resulting in bile duct loss, fibrosis and cirrhosis. The mechanism of bile duct injury is unknown, but exposure to infectious microbes and/or xenobiotics has been suggested to initiate an immune reaction in genetically predisposed individuals [23, 24]. Treatment is with ursodeoxycholic acid (UDCA) as first line. If there is no or inadequate response, obetacholic acid (OCA), a synthetically modified bile acid and potent agonist of the farnesoid X nuclear receptor, can be offered. Farnesoid X receptor is a nuclear bile acid receptor found in the liver and gastrointestinal tract that regulates the expression of bile acid transporters. The impaired flow of bile acids results in their accumulation within the liver and contributes to liver disease. This suggests that the regulation of bile acid (BA) synthesis and homeostasis, as well as the resistance of the hepatocytes to BA, is important in the initiation and progression of PBC. The gut microbiome likely interacts with BA in a bi-directional manner and thus holds promise for diagnosis and treatment [25]. Lv et al. assessed the fecal microbiome in 42 subjects with early-stage PBC [26] and 30 healthy controls and found that the gut was depleted of potentially beneficial bacteria, including Acidobacteria, Lachnobacterium sp., Bacteroides eggerthii and Ruminococcus bromii, and enriched with opportunistic pathogens, Proteobacteria, Enterobacteriaceae, Neisseriaceae among others. Tang et al. studied the fecal microbiome in PBC before and after treatment with UDCA [27]. The investigators studied three groups: The first group consisted of 60 UDCA naïve patients with PBC and 80 healthy controls, the second group was an independent cohort used to confirm the findings in the first group and the third group consisted of 37 patients with PBC who were assessed prior to the treatment with UDCA and prospectively followed for 6 months after treatment. In the first cross-sectional study they found biodiversity was decreased in patients with PBC compared to the healthy controls and the eight genera that were enriched in the PBC patients were rare in the normal controls. Interestingly, they found that an unknown genus in the Enterobacteriaceae family was most significantly associated with PBC. This dysbiosis was partially

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relieved after treatment with UDCA, suggesting a link between the gut microbiome and bile metabolism in PBC. The gut microbiome holds promise for patients with PBC by providing diagnostic markers and perhaps altering the course of the disease by targeting the gut microbiome, either directly, or through the homeostasis of bile acids. Primary Sclerosing Cholangitis Primary sclerosing cholangitis (PSC) is a progressive, cholestatic, inflammatory disease of the intra- and extra-hepatic ducts. It is characterized by a fibro-obstructive process. It typically, but not always, affects patients with inflammatory bowel disease. The only approved drug treatment is UDCA; but even this limited treatment option is controversial. Up to 25% of transplanted patients will develop recurrent disease. While the cause of PSC is not known, four hypotheses exist: (1) alteration in the bile acid pool (toxic bile hypothesis), (2) abnormal homing of lymphocytes (aberrant gut lymphocyte hypothesis), (3) abnormal pathways of fibrogenesis and (4) changes in microbiome leading to gut permeability (leaky gut hypothesis) [28]. The four hypotheses are not mutually exclusive. For this discussion only the “leaky gut” hypothesis will be addressed, although other mechanisms may also play roles. Evidence to support the leaky gut hypothesis include bacteria found in the bile of explanted livers, H. pylori in proximal hepatic ducts and serum antibodies against Chlamydia in the patients with PSC [29–31]. The suggestion that gut bacteria may play a role in PSC has triggered a number of trials employing oral antibiotics. The first report, 60 years ago, documented improvement using oral tetracycline [32]. This study was followed by several others using other antibiotics [33–35]. To date, the trials of antibiotic use have been small; however, results have been positive and larger, hence controlled studies are warranted. PSC is a serious, life-threatening disease which frequently occurs as a complication of IBD but also can stand alone. Oral antibiotics appear to offer a long-term treatment. The optimal antibiotic or combination of antibiotics needs to be determined. A definitive cure remains elusive.

4.5

Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, affecting 20–30% of the general population. The hallmark of NAFLD is hepatic steatosis, which is characterized by fat accumulation in more than 5% of hepatocytes in the absence of excessive alcohol intake, or other cause of fat deposition such as viral infections, medications and genetic disorders. Nonalcoholic steatohepatitis (NASH) is the severe form of NAFLD. The histology of NASH includes inflammation and fibrosis that can progress to hepatic cirrhosis and hepatocellular carcinoma [36]. NASH is associated with obesity, insulin resistance and cardiovascular disease. Liver histology in NASH recalls that of alcoholic liver disease. Children [37] and adults [38] with NASH have elevated serum alcohol

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concentrations. Children also have increased hepatic levels of genes related to inflammation and fibrosis and most strikingly have increased gene transcription of the alcohol dehydrogenases [39]. Since there is no identifiable source of dietary alcohol in children [37], and the altered gut microbiome in NASH produces alcohol [37], likely the gut microbiome is a source of alcohol and this alcohol contributes to the initiation and/or the progression of the disease. Wu et al. [40] showed that diet strongly affects the gut microbiome composition and although changes can be seen within 24 h of a dietary change, it is long-term diet that correlates with the microbiome. The microbiome in NAFLD is similar to the microbiome in obesity. Firmicutes are increased and Bacteroidetes are decreased and the ratio is a potential phenotypic marker for obesity. However, in NASH, Firmicutes are decreased. Zhu et al. [37, 41] found that the increased abundance of Proteobacteria in the obese and NASH groups was mainly explained by the increased abundance of Enterobacteriaceae. Importantly, Enterobacteriaceae was the only abundant family (within the whole bacteria domain) exhibiting a significant difference between the obese group and the NASH group and most of the Enterobacteriaceae sequences belonged to Escherichia, which is the only abundant genus within the whole bacteria domain exhibiting a significant difference between the obese group and the NASH group. This genus had been shown to produce significant amounts of alcohol [42]. Alcohol is known to increase permeability of the gut [43] and allow bacterial products as well as toxins and infectious agents to relocate from the gut through the portal system assuring that these agents have direct access to the liver. This suggests the pathology could be driven by gut microbial generation of alcohol. The gut microbiota may contribute to NAFLD via energy salvage of diets. Short-chain fatty acids (SCFA), mostly identified as acetate, butyrate and propionate, are the major fermentation products of the gut microbes [41]. The concentrations of SCFA can reach 50–100 mM and provide a significant portion of energy. It is estimated that SCFA produced by the gut microbiota account for about 30% of energy extraction from the diet [44] and in obese individuals SCFA production is increased [45], suggesting that the gut microbiota could contribute to the development of steatosis by increasing delivery of SCFA to the liver. Although this hypothesis is appealing, others have suggested that SCFA are protective against the development of the metabolic syndrome [46, 47]. An area of gut–hepatocyte interaction that has not been explored in NASH is that of the metabolism of the D-amino acids. Among all domains of life, bacteria have the largest capacity to produce a wide variety of D-amino acids, major components of their cell walls, while mammals are thought to synthesize generally two kinds of D-amino acids, D-serine and D-aspartate, both of which are important in the neurological system. D-amino acid oxidase (DAO) is distributed in the proximal tubules in the kidney with the highest expression, hepatocytes (except not in mice), astrocytes in the hindbrain, neutrophils and epithelium of the small intestines [48]. The product of DAO is hydrogen peroxide, a strong oxidizing agent. Oxidative stress is considered to be a factor in the initiation and progression of NASH. Dr. Lixin Zhu (personal communication) noted that children with a histologic

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diagnosis of NASH showed increased gene expression of DAO and peptidoglycan recognition protein 2 (PGLYRP-2, a liver secreted protein that recognizes and hydrolyzes bacterial peptidoglycans) compared to normal controls by microarray analysis, confirmed by quantitative real-time PCR analysis. As articulated by Dr. Zhu, these findings support his hypothesis that the bacterial cell wall components derived from the gastrointestinal tract microbiome cause increased oxidative stress via generation of hydrogen peroxide and contribute to the pathogenesis of NASH. The microbiome in patients with NASH appears to be important in the initiation and progress of NASH and represents an opportunity to alter the course of the disease if the microbiota can be appropriately manipulated.

4.6

Alcoholic Liver Disease

Alcohol-related liver disease consists of steatohepatitis in its mildest form and can progress to alcoholic hepatitis, fibrosis, cirrhosis and liver cancer. According to the American Liver Foundation [49], alcohol is the second most common cause of liver cirrhosis after hepatitis C infection in the USA. About 88,000 people die from alcohol-related causes annually, making alcohol the fourth leading preventable cause of death in the USA. It is likely that the gut microbiota play a role in alcoholic liver disease, but it is unclear if changes in the gut microbiome drive the progression of liver disease in some alcoholics or the ingestion of alcohol drives the changes in the microbiome. Alcohol itself causes increased permeability of the intestinal barrier as studied in CaCo2 cells [43]. The diet of alcoholics is not always of high quality [50], and as noted above, diet can influence the composition of the gut microbiome. Whether or not liver disease is present, patients with chronic alcohol abuse have increased gut permeability [51] as suggested by an increased level of plasma endotoxin compared to healthy controls. In cirrhosis a worsening of the clinical condition is thought to be associated with the translocation of gut bacteria and their products; treatment with antibiotics and or lactulose improve the condition [52]. Mutlu et al. [53] studied alcoholics with liver disease (19 subjects), who fulfilled the National Institute on Alcohol Abuse and Alcoholism and DSM-IV criteria for alcoholism, had a regular drinking history of at least 10 years, clinically significant liver disease and radiographic or histological evidence of liver disease. They also studied active alcoholics without liver disease (14 subjects), sober alcoholics without liver disease (15 subjects) and 18 healthy controls. They assessed biopsies from an unprepped flexible sigmoidoscopy. They did not assess stool specimens. They found that some, but not all subjects in the alcoholic groups were “dysbiotic” as compared to the control group. The dysbiotic group had no significant differences in phyla, but at the class level there was a uniform reduction of Bacteroidetes and Clostridia, and an increase in Bacilli and Gammaproteobacteria. The investigators concluded that alcohol alone appeared to affect the microbiome. They then

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correlated some clinical features of alcoholic liver disease with the microbiome and found that the dysbiotic group had a higher frequency of diabetes and a higher mean hemoglobin A1c. Further they showed that in the dysbiotic group of alcoholics, the microbiome was persistent and correlated with endotoxemia. In contrast, Tuomisto et al. [54] assessed stool samples from 13 autopsies of alcoholics with cirrhosis, 15 alcoholics without liver cirrhosis and 14 nonalcoholic men. Sterile samples were also obtained from their liver. Finally, stool samples from seven healthy volunteers were analyzed. Similar to the findings of Mutlu, stool from cirrhotics had a significant increase in Enterobactericaea. When compared to all other groups, the stool of alcoholic cirrhotics had significantly more gram negative Enterobactericaea, Enterobacter and bacteroides, but no differences in Bifidobacterium and Lactobacillus. Bacterial DNA was found in all autopsy liver samples and was not significantly different among the three groups. Bacterial DNA was also found in ascitic fluid, but all had a white blood count below 250. These results differed from those of Chen [55] who found decreased Bifidobacterium and increased Clostridium. The ability of the intestinal microbiome to promote the development of HCC is not well known, although it is likely that TLR4 signaling is involved.

4.7

Cirrhosis

The end stage of chronic liver disease is cirrhosis, characterized histologically by fibrosis and the formation of regenerative nodules. Fibrosis progresses with the length of time cirrhosis is present, culminating in liver failure, which results in death if liver transplantation is not possible. Life expectancy is reduced in cirrhosis, and cirrhosis is associated with several complications including variceal hemorrhage, ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatocellular carcinoma, hepatorenal syndrome and hepatopulmonary syndrome. Clinically cirrhosis can be compensated or decompensated and the time to progression to decompensation is not fixed. Compensated cirrhosis has few, if any, clinical symptoms and no major complications [56]. Decompensated cirrhosis is characterized by the development of any complication of cirrhosis, most commonly variceal bleeding, spontaneous bacterial peritonitis, hepatocellular carcinoma, hepatorenal syndrome and hepatopulmonary syndrome. In a study of 219 cirrhotic patients, 121 had compensated cirrhosis and 54 decompensated, and in 25 age-matched healthy controls Bajaj et al. [57] found the fecal microbiome in cirrhosis was characterized by a lack of diversity of organisms and a significant reduction in the beneficial organisms, Clostridiales XIV, Ruminococcaceae and Lachnospiraceae with a significant increase in the potentially toxic organisms, Enterococcaeae, Staphylococcaceae and Enterobacteriaceae compared to normal controls. As cirrhosis progressed, a reduction in Veillonellaceae and Porphyromonadaceae occurred. These investigators also showed that the microbiome in the cirrhotic patients who remained stable did not

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change over the 4 months of the study. Based on these observations the investigators developed a cirrhosis–dysbiosis ratio (CDR), Lachnospiraceae + Ruminococcacea + Clostridiales incertase sedic XIV + Veillonellaceae divided by the sum of Enterobacteriaceae + Bacteroidaceae. They found that the CDR decreased as patients went from a compensated to a decompensated state characterized by hepatic encephalopathy or infection. They explained this change by an increase in the denominator organisms. Changes in the gut microbiome in cirrhosis can contribute to the explanation for some of the complications such as spontaneous bacterial peritonitis and hepatic encephalopathy. The beneficial organisms produce short-chain fatty acids that are a source of fuel for the colonocyte and may prevent or ameliorate the increased gut permeability that occurs with cirrhosis as well as reduce colonic inflammation. In addition, they can compete with pathogenic bacteria for nutrients and produce antibacterial peptides. These observations are intriguing, but do not necessarily describe the changes in the microbiome that are relevant to the progression of disease since the fecal microbiome differs significantly from that found at the sigmoid mucosal level [58]. Acute-on-chronic liver failure (ACLF) occurs in patients who have chronic liver disease and then experience a triggering event [59]. According to the 2013 European study [60], ACLF is characterized by an acute decompensation of cirrhosis (ascites, encephalopathy, gastrointestinal hemorrhage and/or bacterial infection) associated with organ/system failure(s) (liver, kidney, brain, coagulation, circulation and/or lung); may develop at any time during the course of the disease from compensated to long-standing decompensated cirrhosis; and is associated with a short-term (28-day) mortality rate ranging from 32 to 78.6%, depending on the number of organ failures despite standard supportive medical treatment. In Western countries, ACLF usually occurs in the context of a systemic inflammatory response, characterized by high leukocyte count and plasma C-reactive protein level, as a result of bacterial infections, severe alcoholic hepatitis or yet to be identified mechanisms [57]. Because of the high short-term mortality associated with ACLF any possible trigger that could be recognized early in the onset of ACLF could have an impact on the mortality. The systemic inflammatory response associated with ACLF suggests that microbiota may be involved with the development of ACLF especially because the gut microbiota plays an important role in the development of the immune system and its response [61]. To that end, Chen et al. [62] assessed gut microbiota in 79 Chinese patients with ACLF and followed them for four weeks after the onset of ACLF. They compared the results with 50 healthy controls. The investigators found a significant decrease in the microbial diversity and richness in the patients with ACLF; Proteobacteria phylum was significantly increased in nonsurvivors; at the family level Pasteurellaceae was significantly increased in nonsurvivors, while Lachnospiraceae was significantly lower. The 4-month longitudinal sampling showed that a new equilibrium was reached and remained stable after the onset of ACLF. Antibiotics showed a moderate impact on the composition of the gut microbiota. They concluded that gut dysbiosis occurs and the increased abundance of the family Pasteurella, a large and diverse species of Gram-negative bacteria, can serve as an independent predictor of mortality.

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In a North American study Bajaj et al. [57] collected stool from 181 patients with cirrhosis at the time of hospital admission and followed the patients for 30 days. They found that 8% of the subjects developed ACLF, 21% died. Beta-diversity was significantly different between those who developed ACLF and those who did not, but alpha-diversity was not. Similar to the observations of the Chinese group, Bajaj et al. found an increase in Proteobacteria (Enterobacteriaceae, Campylobacteriaceae and Pasteurellaceae) [58] in hospitalized patients with cirrhosis and was associated with an increased risk of extra-hepatic organ failure, ACLF, and death, independent of clinical factors. The fact that alpha-diversity did not differ over the course of the study suggests that the gut microbiome present on admission to the hospital could not be used to predict who would develop organ failure. Hepatic encephalopathy (HE) is a complication of cirrhosis. Cirrhosis is the end stage of practically all liver disease. The same pathogenic changes in the gut–liver axis evoked for other liver diseases have been suggested for HE. In the case of HE, ammonia appears to play a prominent role. Ammonia is predominantly produced by gut bacteria, where it gains entry to the portal system. In health the ammonia is metabolized and detoxified via the urea cycle. However, in end-stage liver disease, the liver can no longer processes ammonia sufficiently and serum and brain levels increase. There is poor correlation between arterial ammonia concentration and level of brain dysfunction, probably because ammonia’s neurotoxic effects are indirect via metabolites [63]. It is generally accepted that bacteria and bacterial byproducts play an important role in HE. Supporting this concept, the CDR index correlates with symptoms of HE [64]. Thus much of the effort in treating HE has focused on the microbiome. One of the more novel approached to the treatment of HE was by way of fecal microbiota transplantation. Weekly transplantation from a universal donor resulted in general improvement but the improvement was not durable after transplantations were discontinued [65]. Lactulose, a nonabsorbable pre biotic/laxative, has long been used in the treatment of overt HE. Its mechanisms of action are (1) as a laxative, reducing the number of gut bacteria and limiting the absorption of toxins, (2) as a prebiotic, stimulating bacterial proliferation and hence nitrogen uptake and (3) decreasing of glutamine uptake via inhibition of glutaminase [66]. Rifaximin, a broad spectrum, nonabsorbable antibiotic, has been shown to have beneficial effects on HE; it not only acts as an antimicrobial but also improves intestinal permeability [67].

4.8

Hepatocellular Carcinoma

Approximately 80–90% of cases of hepatocellular carcinoma (HCC) occur at the end stage of chronic liver disease, cirrhosis. Spontaneous HCC in the absence of liver disease is rare [68]. Because there are many possible causes of chronic liver disease, the tumors are heterogeneous and a possible microbiome pattern has been reported for cirrhosis as well as the specific chronic liver disease. So it would seem that there may not be specific signature for HCC. The gut microbiome in cirrhosis is

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associated with inflammation, increased gastrointestinal permeability and the presentation of gut constituents, including those of the altered microbiome, to the liver. It is also likely that the microbiome in cirrhosis modulates the immune system, further disrupting normal functions. Cirrhosis often develops on a background of inflammation that causes cellular damage and the combination of these factors leads to hepatocellular mutations that cause HCC. In general, the gut microbiome in cirrhosis is described as exhibiting a decrease in beneficial microbes and an increase in those associated with systemic inflammation. For example, in one of the few human studies on the gut microbiota and HCC, Ponziani et al. [69] studied three groups of patients, those with NAFLD and HCC, those with NAFLD-related cirrhosis, but no HCC and healthy controls. They found that plasma levels of the interleukins IL8, IL13 and chemokines CCL3, 4 and 5 were higher in the HCC group and associated with activated status of circulating monocytes. The microbiome in all the cirrhotic subjects had increased abundance of Enterobacteriaceae and Streptococcus and a reduction in Akkermansia. Bacteroides and Ruminococcacea were increased in the HCC group, while Bifidobacterium was reduced. Akkermansia and Bacteroides were inversely correlated with fecal calprotectin, a marker for intestinal inflammation. These findings support the association of the microbiota and inflammation in HCC. In another human study of the microbiome in HCC, Ren et al. [70] assessed the microbiome in 486 stool samples from East, Central and Northwest China prospectively. They characterized the gut microbiome, identified microbial markers and constructed HCC classifier in 75 early HCC, 40 cirrhosis and 75 healthy controls. They found that fecal microbial diversity was increased from cirrhosis to early HCC and that the phylum Actinobacteria was increased in early HCC compared to cirrhosis. Thirteen genera including Gemmiger and Parabacteroides were enriched in early HCC compared to cirrhosis. Butyrate-producing genres were decreased; the lipopolysaccharide producing genera were increased. They identified 30 microbial markers that had diagnostic potential and they concluded that this was the first study to characterize gut microbiome in patients with HCC. These few human studies suggest that although that gut dysbiosis occurs in HCC and inflammation and immune dysfunction is involved in the initiation and progression of HCC, many unknown factors remain.

4.9

Conclusion

A common pattern is emerging that characterizes the interaction of the gut microbiome and liver disease. The pattern involves (1) variable change in the microbiome itself. The change seems to be disease-specific but tends to favor pro-inflammatory organisms. The driving force behind the change is not understood, but one possibility is that alteration in the bile acids reaching the GI tract directly or indirectly alters the gut microbiome makeup. Another common alteration is (2) increased permeability of the GI tract. Whether this is the result of the

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Inflammation Fibrosis Cancer

Hepatocytes Stellate cell

Dysbiosis

Kupffer cell

Leaky gut Bacterial products portal vein

Fig. 4.1 General mechanism of “gut-liver axis” in chronic liver injury

changed microbiome or due to the disease itself is unclear and may differ depending on the liver disease. In some cases the increase in permeability may be the result of altered secretory IgA; however, change in sIgA does not appear to account for the totality of the change in permeability. The increased permeability allows (3) translocation of bacterial components to the portal system. LPS, PAMPs, and so on gain access to heptaocytes, kupffer cells and stellate cells via the portal system where they promote inflammation and fibrosis through their influence on Toll-like receptors (TLR) and inflammatory mediators, IL6, IL17, TNFa and others (Fig. 4.1).

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Chapter 5

Gut Microbiota and Lung Injury Ji-yang Tan, Yi-chun Tang, and Jie Huang

Abstract Gut microbiota are known to impact multiple organs including the lung. The cross talk between gut microbes and lungs, termed as the “gut–lung axis,” is vital for immune response and homeostasis in the airways. In this chapter, we summarized the coordinated development of microorganisms in the gut and lung, exogenous and endogenous factors related to the cross talk, the mechanisms of the gut–lung axis and their dysbiosis in lung diseases. Although the current understanding of the gut–lung axis is in its infancy, several gut microbiota-associated strategies have been designed to treat and prevent lung diseases.




Keywords Gut–lung axis Gut microbiota Cystic fibrosis Lung cancer




5.1


Pneumonia
COPD
Asthma


Introduction

Gut microbes, as the main component of human microbiota, benefit from a stable nutrient-balanced microenvironment and more importantly, they perform crucial roles in maintaining immune homeostasis in exchange [1]. Disturbance in the gut microbiota impacts not only gut, but also distal organs such as brain, liver, and lungs [2]. For example, about half of adults with inflammatory bowel diseases (IBD) and 33% with irritable bowel syndrome (IBS) have pulmonary involvement, J. Tan Peking Union Medical College, Chinese Academy of Medical Sciences, Plastic Surgery Hospital, Graduate School of Peking Union Medical College, Beijing, China Y. Tang The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China J. Huang (&) Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 P. Chen (ed.), Gut Microbiota and Pathogenesis of Organ Injury, Advances in Experimental Medicine and Biology 1238, https://doi.org/10.1007/978-981-15-2385-4_5

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such as inflammation or impaired lung function, although many patients have no history of acute or chronic respiratory disease [3, 4]. Accumulating evidence indicates the association between the gut microbiota and lung immunity, referred to as the “gut–lung axis,” though the underlying mechanisms are still being studied and many questions remain unanswered. In this chapter, we summarize the influence of gut microbiota on respiratory tract in physiologic and pathologic conditions and the main mechanisms that have already been uncovered. Moreover, we highlight the potential therapeutic strategies of gut microbes for lung disease.

5.2

Structural and Functional Similarities and Differences Between the Gut and Lung

The epithelial of lung and gastrointestinal tract differs in structure. The epidermis of the lung is covered with pseudostratified ciliated columnar epithelial cells while gastrointestinal epidermis is covered with laminated squamous epithelium or single columnar epithelium [5]. However, they both develop from the endoderm and are exposed to outside. Both epithelia have abundant bacterial communities [6]. The balance between the bacterial communities and the barrier on the epithelial surface protects them from pathogens.

5.3

Coordinated Development of Microbiota in Gastrointestinal Tract (GIT) and Respiratory Tract

The microflora of human epidermis is not always invariable during the whole life. In fact, since the birth of the newborn, the microflora has undergone rapid dynamic change [7]. Certain factors of birth, such as the mode of delivery, the way of breastfeeding, gestational age, etc., only have an impact on the baby surface flora in the early infancy. Afterward, after six weeks of birth, the microflora of different parts of the body is gradually differentiated, and the influence of different parts on the microflora was greater than that from the mother. The flora is first determined by different body parts, then by individuals, last by age [8–10], and gradually formed a stable structure eventually. Meanwhile, microbes from different parts of the body are not isolated from each other. On the contrary, everybody is composed of a complex and interconnected ecology. The interrelated microbiome sites are either in direct contact, proximal contact, or similar in environmental exposure, thus providing mechanisms supporting similar microbiota and demonstrating high levels of microbial coexistence [11]. And the observation of a specific community state types (CST) at a given body site was predictive of contemporaneous CSTs at other body sites [7]. But how the body forms its unique flora is not fully understood. One study

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explored the progression of human flora spatiotemporal interaction changes, which showed that the co-occurrence pattern between different body positions is very significant. Nasal CST 1, intestinal CST 2, laryngeal CST 1, and laryngeal CST 6 had the highest CST correlation (the number assigned to each CST indicates the overall frequency of occurrence at each respective site), and all trans-body pairs were positively correlated. The closest relationship shared between operational taxonomic units and coordinate is between the nose and throat, followed by the throat and intestines, and then the nose and intestines [7]. It indicates that the microflora between lung and gut influence each other during the development of differentiation. Not only in the healthy condition, but also in the pathological condition, the microflora of different parts of the body are correlated and co-developed. Serial analysis of the gut and respiratory microbiome in cystic fibrosis in infancy found that a group of microbes found in early life samples of the gut is also present in late life samples of the respiratory tract. This group of bacteria includes Enterococcus, Coprococcus, Escherichia, and Parabacteroides. Mapping populations over time showed that intestinal colonization occurred before they appeared in the respiratory tract. The microbial diversity of the airways and intestines increased significantly over time, and the diversity of the airways increased more acutely than this over time [12]. In mechanically ventilated patients, bacterial diversity tends to decrease, and a single population (usually opportunistic pathogens) may end up being an advantage. Intestinal permeability increases during sepsis and may also increase in other acute conditions involving the digestive tract, such as intestinal obstruction, ischemia, severe pancreatitis, or enterocytotoxicity due to chemotherapy [13]. Studies have shown that the lung microbiota of experimental sepsis mice and patients with confirmed ARDS has become rich in bacteria related to gut, among which Bacteroides, an anaerobic intestinal symbiotic bacteria, is the most common in both environments. Other intestinal symbionts, such as enterococcus faecalis and species belonging to the enterobacteriaceae family, were also found in the lungs of septic mice [14]. Therefore, lung microbiomes can be influenced by gut microbiomes in pathological condition.

5.4

Factors of Intestinal Microbiota that Influence the Lung

Dysbiosis of gut microbiota, with the exposure to smoke, antibiotic, or change of their diet, can lead to inflammation in the whole body and pathogenic bacterial infection, which can cause diseases at distal sites such as the lung [5]. The pathogenic factors can be divided into exogenous factors and endogenous factors. Generally, exogenous factors are comprised of smoking, antibiotics, diet, and probiotic bacteria. While endogenous factors mainly include the delivery mode of the newborns (Fig. 5.1).

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Fig. 5.1 Many exogenous and endogenous factors like diet, smoking, antibiotics, probiotic bacteria, and delivery mode can exert a significant influence on the composition of the gut microbiota. In some cases, it will lead to the dysbiosis of the intestinal tract and then cause allergic lung inflammation through the gut–lung axis. As a result, persistent inflammation of lung can finally increase the morbidity of asthma, COPD, pneumonia, cystic fibrosis, and even lung cancer

5.4.1

Exogenous Factors

1. Diet Obviously, diet can greatly change the composition of intestinal microbiota and plays an important factor in the reproduction and the stability of the intestinal microbiota. Animal experiments have demonstrated that change of the diet can affect the intestinal microbiota composition both rapidly and significantly [15]. Through the alteration of the metabolic production of intestinal microbiota, different diets can produce changes which can alter the host’s physiological state and therefore contribute to the development of lung injury.

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Different diets can promote the growth of different pathogenic microbiota strains. Human’s daily food consists mainly of protein, fat, and carbohydrates. A high-fat diet may promote the reproduction of the pro-inflammatory gut microbiota and influence the intestinal permeability consequently [16]. High-fat diets can also play an important role in the chronic intestinal inflammation [17]. As for consumption of carbohydrates, for example, dietary fiber is a kind of polysaccharides which most of the intestinal microbiota can produce and use it to escape from being digested by human digestive juice. Carbohydrate metabolism of intestinal bacteria appears to be a highly cooperative process and the knowledge of it has been supported by numerous studies [18, 19]. When it comes to the digestion of protein, which is much less studied than the consumption of carbohydrates, the dietary protein intake pattern can in some ways influence the metabolic health and the outcomes of host’s intestinal bacteria [20, 21]. As mentioned above, the composition of the intestinal microbiota can change in response to deferent consumption of fat, sugar, fiber, and protein. In addition, the diet of a certain species can exert influence on viruses, fungi, and even archaea besides bacteria in human’s intestinal tract [22]. As for the connection between dietary composition and the lung disease, recent studies have found out that dietary fibers and its products called short-chain fatty acids (SCFA) can protect human from the allergic airway inflammation [23]. Mouse studies show that high-fiber diet can increase the amount of short-chain fatty acid (SCFA) and reduce the prevalence of asthma through an increase on the number of T-regulatory cell and strengthen their function [24]. In other words, short-chain fatty acid (SCFA) can prevent the aggravation of allergic lung inflammation caused by the dysbiosis of the intestinal tract [25]. While, on the contrary, high-fat diet is closely associated with the airway hyperreactivity (AHR), which can consequently lead to asthma [26]. Excess consumption of saturated fat and limited consumption of dietary fiber like fruit, grains, and vegetables have been greatly associated with high risk of inflammatory lung diseases [27]. The consumption of raw milk, however, can decrease the morbidity of asthma and allergies, which has been confirmed by mouse studies [28]. 2. Smoking In the past, smoking was associated with lung disease mostly due to its direct damage on the respiratory mucosa and the contribution of airway inflammation, while recent studies have confirmed that smoking can cause lung injury through the change of the composition of intestinal microbiome [29]. Biedermann L’s research, performed by the observation of 5 non-smokers and 5 continuing smokers, has found that smoke cessation can change the bacterial composition of human intestinal tract with a higher proportion of Firmicutes and Actinobacteria and a decrease of Bacteroidetes and Proteobacteria. Moreover, his study also showed that

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smoking cessation can cut down on the diversity of intestinal microbiota [30]. The mechanism that can explain the ways of smoking’s effect on intestinal microbiota includes changes in intestinal epithelial tight junctions, the enhancement of oxidative stress which can lead to free radical damage and the alterations of acid– base balance [31]. 3. Antibiotics As we all know, antibiotic treatment can greatly inhibit the development of certain kinds of bacteria in intestinal tract and alter the composition of intestinal microbiome, which can eventually increase the prevalence rate of the allergic pulmonary allergic diseases such as asthma. Although the studies in this field are limited and the results of which are partly inconsistent, recent research has confirmed that the antibiotic therapy conducted in the first 3 years of life has the ability of making children more susceptible to the onset of asthma (rather than the exacerbation of asthma) [32]. Furthermore, not only the antibiotic treatment in the early life but also the antibiotic use in the pregnancy can play an important role in the development of allergic disease in lung. According to a case-control analysis, if a pregnant woman received antibiotic treatment in the third trimester of pregnancy, her baby would be more likely to get asthma at pre-school stage [33]. The association between antibiotic exposure and lung disease can also enlighten new therapies toward asthma. Allergen immunotherapy is confirmed to have a protective effect of keeping people who has been treated with antibiotics from allergic asthma [34]. 4. Probiotic Bacteria Probiotic bacteria are important components of the intestinal microbiome. They have been considered to provide healthy benefit and maintain the acid–base balance in the intestinal tract for a long time. To date, numerous researches have been conducted to interpret how probiotic bacteria can exert impact on the chronic respiratory inflammation, though for different bacterial species the results may seem inconsistent. As has been shown in many researches, the intake of lactobacillus rhamnosus GG (LGG) tablets can play an anti-inflammatory role in the inhibition of OVA-induced chronic allergic respiratory disease and therefore offers a possible treatment of airway inflammation [35]. Similarly, Bifidobacterium lactis have the same effect on alleviating airway inflammation by reducing the ratio of Th17 and Treg cells [36]. In addition, according to mouse studies, Bifidobacterium breve M-16 V (Bb) are able to decrease the number of Th2 cells and intestinal DC and contribute to the increase of Treg, thus easing the inflammatory symptoms [37]. However, the studies mentioned above are largely based on in vitro experimental data, which means that there is no firm evidence of the protective effect of the probiotics on lungs [38]. Further studies are still required.

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5.4.2

Endogenous Factors

5.4.2.1

Delivery Mode

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Many studies have revealed the relationship between the birth mode of the newborn and the morbidity of allergic lung disease. Children who were born by cesarean section, compared to those who were born by natural section, are more likely to get asthma when they grow up, partly because of the decrease of the diversity of their intestinal microbiota and the alteration of the composition of the bacteria in their gastrointestinal tract [39]. Likewise, a study conducted in Vietnam and India also confirmed the result [40]. In addition, another research performed by Sevelsted et al. has pointed out that the cesarean delivery’s effect on the morbidity of asthma can be even more pronounced if the operation is conducted before the rupture of fetal membrane [41].

5.5

The Mechanism of the Gut–Lung Axis

Recent studies have reached a deeper understanding of the complex interrelationship between the gut and lung, which can be mediated in mainly two ways— bacterial products in the circulatory system and the immune cells in the lymph node of gut and lung (Fig. 5.2). In one way, cell wall fragments, the protein parts of dead bacteria and surviving bacteria generated in the intestinal tract can travel along the mesenteric lymph node to systemic circulation and subsequently enter the pulmonary circulation, which will lead to the stimulation of DCs, macrophage, T cells, and the influx of neutrophil. As a result, lung injury and inflammation caused by uncontrolled macrophage and neutrophil activation will be observed. Another way of the gut and lung to exert influence on each other is the migration of T and B cells. First, the bacterial products and the surviving bacteria will be transferred to the mesenteric lymph node (MLN) by macrophage and DCs after phagocytosis and elimination. In the MLN, translocated bacteria and their parts could prime naïve B cells and T cells, thereby activating the differentiation of B cells to plasma cells. Plasma cells, known for its ability to produce antigen-specific immunoglobulin, can cut down the production of anti-inflammatory molecules like IL-10, leading to the priming and the differentiation of T cells. After that, some of the T cells will migrate out of the gut-associated lymphatic tissue (GALT) and finally reach the lung epithelium because the DCs of lung can influence the expression of gut-homing integrin 47 and CCR9, thus activating local APC and T cells. The activation of the immune cells mentioned above is able to improve pulmonary immune response and consequently increase the pathogen clearance and antitumor activity of lungs.

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Fig. 5.2 The pathways of the interrelationship between the gut and lung. The bacteria in the lung can improve immune response of the gut or cause chronic inflammation and cancer through the lymphatic and blood flow (the blue arrows). Similarly, microorganisms in the gut also could change the immune state of the lungs in the same way (the yellow arrows). DC: dendritic cell; IEC: intestinal epithelial cell; APC: antigen-presenting cell; LLN: lung lymph node; MLN: mesenteric lymph node; GALT: gut-associated lymphatic tissue

Likewise, the microorganisms in the lung can improve immune response of the gut, but they also may cause chronic inflammation and cancer through the lung lymphatic system and the blood flow. Additionally, DCs in gut can increase the amount of lung-homing integrin-CCR4 [42, 43].

5.6

Intestinal Dysbiosis and Lung Disease

To date, many studies have shown that various pulmonary diseases are closely related to the dysbiosis of the intestinal tract and the consequent changes of immune response. According to recent researches, the pulmonary diseases mainly include

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asthma, COPD, pneumonia, cystic fibrosis, and even lung cancer, which is usually accompanied by a deceased intestinal microbial diversity and the disorder of immune system [44].

5.6.1

Asthma

Asthma, mainly caused by the hyper-responsiveness of airway, is widely known to be one of the most common chronic allergic respiratory diseases in the world. To date, there are emerging evidences confirming the connection between asthma and the alteration of the composition of intestinal microbiome [45]. A study performed by Melli et al. compared the composition of the intestinal microorganism of allergic people to that of non-allergic people and revealed the differences between them. According to the experiment data, lower microbiome diversity and a predominance of Firmicutes can be observed in the children with asthma [46]. As mentioned above, early life exposures such as birth mode and antibiotic treatment can change the risk of asthma in childhood. While further studies conducted among Canadian infants at the age of 3 mouth interpret the relationship between the increased morbidity of asthma caused by the alteration of intestinal bacteria and the feeding mode and point out the protective effect of the direct breastfeeding [47]. Similarly, a nationwide survey performed in Japan reveals that direct breastfeeding can also inhibit the risk of asthma of children between the age of 6 and 42 months [48]. As to the interaction between the intestinal microbiome and the onset of asthma, mouse researches showed strong evidence of the view that the intestinal microbiome composition can exert impact on the function of the immune system by the way of the Treg cells’ expansion and the reduction in the IgE production [49]. What’s more, the alteration of Th2 response can also be observed to interpret the mechanism of how can intestinal microbiome be connected to asthma [38]. In addition, the studies supporting that microbiome in intestinal tract plays an important role in asthma enlighten the development of new therapies of asthma like administration of few special bacterial strains [49]. While further researches are required to evaluate the exact curative effect on the children of different ages.

5.6.2

COPD

Chronic obstructive pulmonary disease (COPD), characterized by increasing breathlessness, is a leading cause of morbidity and mortality worldwide. The mechanism of its occurrence and development has been extensively studied. It is confirmed that the pneumonia bacteria can play an important role in its development and deterioration. As is mentioned above, an increasing number of recent studies hold the view that the microbiome of our body can be considered as a whole and the composition of pneumonia bacteria can be altered by the change of

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intestinal microbiota. Thus, the bacteria in the intestinal tract can exert influence for either good or bad on the occurrence and the development of lung injury. Additionally, more and more studies suggest that the altered intestinal microbiome composition can be considered as an important component of the multisystem disorder in COPD patients [50, 51]. Research conducted by Ottiger and Nickler has also proved that the increased level of gut microflora-dependent metabolite trimethylamine-N-oxide (TMAO) in the circulation can heighten the long-term mortality of the COPD patients [52]. Still, further experiments are needed to interpret the mechanism of the interaction between COPD and the gut bacteria.

5.6.3

Pneumonia

Many recent studies have confirmed that the intestinal microorganism can play a protective role in the host defense against pneumonia. During the neonatal period, the exposure to gut commensal bacteria and the influx of the group 3 innate lymphoid cells (ILC3) produced by IL-22 induce the immunity of the host lung against pulmonary infections [53, 54]. According to recent studies, relevant pathogens include Pneumocystis pneumonia, Klebsiella pneumoniae, and Pneumococcal pneumonia. Mouse experiments made by Schuijt et al. have confirmed that the intestinal microbiota are able to resist pneumococcal pneumonia through an enhanced capacity of alveolar macrophages to phagocytose the pathogenic bacteria [55]. Likewise, gut microflora dysbiosis caused by chronic alcohol consumption can weaken the pulmonary host defense against Klebsiella pneumoniae through intestinal T cell sequestration as well [56]. In addition, besides bacterial pneumonia, the Interaction between intestinal and pulmonary microorganisms can also be regarded as an important factor in host defense against fungal pathogens like Pneumocystis carinii [57].

5.6.4

Cystic Fibrosis

Cystic fibrosis (CF) is an inherited metabolic disorder, the chief symptom of which is the production of a thick, sticky mucus that clogs the respiratory tract and the gastrointestinal tract. The occurrence of cystic fibrosis is always accompanied by intestinal inflammation and dysbiosis. Increased Firmicutes, decreased Bacteroidetes, and a significant change of bacterial metabolites can be observed in the intestinal tracts of the CF patients [58]. In the development of CF, the bacterial imbalance in digestive tract can not only contribute to inflammation through the decrease of short-chain fatty acids (SCFA) but also cause higher incidence rate of gastrointestinal malignancy by increasing the amount of carcinogenic bacteria

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[59, 60]. While the mechanism of the interactions among bacterial imbalance, gut inflammation, and the gastrointestinal malignancy in CF patients still needs further study.

5.6.5

Lung Cancer

According to previous research, fruits, hereditary and environmental factors play an important role in the occurrence and the development of the lung cancer. While the involvement of the microflora has also been confirmed by recent researches. By using the Lewis lung cancer mouse model, some researchers have found that the intestinal commensal microbiota have anti-lung cancer effect and the consumption of probiotics can contribute to the antigrowth and proapoptotic effects of cisplatin [61]. While, on the contrary, the dysbiosis in intestinal tract and airway can induce a statement of inflammation and increase the risk of developing lung cancer, the underlying mechanism is still not clear [62]. In addition, the intestinal tract is an important place for immune cells to develop, which influence the immunity of not only the intestine but also other distal organs like lung [43]. Thus, with the emerging concept of more systemic effects of the intestinal bacteria, many teams have made a huge leap in confirming the important role intestinal microbiota plays in the immunotherapy of the lung cancer [63], which will be interpreted in detail in the next section.

5.7

Intestinal Microbiome-Associated Strategies for the Treatment and Prevention of Lung Disease

Because of the link existing between gut microbiome and the lung injury, targeting intestinal flora to treat lung injury has become a strategy.

5.7.1

The Asthma and the Gut Microbiome

Asthma and allergic airway inflammation have been linked to bacterial exposure. However, it has been found that intestinal flora plays an indispensable role in the occurrence and development of asthma. A study which performed a longitudinal comparison of stool samples shows that the early development of intestinal microorganism is unique but plastic in infants at high risk for asthma [64]. Controlling the airway and gut microbiota may be a strategy to prevent asthma from starting and worsening [64]. Now, probiotics are widely used to prevent asthma, but there is no sufficient information to suggest the use of specific probiotics in allergy

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and asthma prevention [38]. Though Lactobacillus rhamnosus GG (LGG) supplementation may partially rescue endogenous disparities in gut microbial distributions, it appears unable to compensate for reduced exposure to environmental microbes [64]. For high-risk infants, a randomized controlled trial finds that supplementation with Lactobacillus rhamnose in the first 6 months of life does not seem to prevent eczema or asthma at age 2 [65]. Another randomized, placebo-controlled trial supports lactic acid bacteria is beneficial to children with asthma. They found that both Lactobacillus paracasei and Lactobacillus fermentum can reduce the severity of asthma in school-age children and improve the control of asthma [66]. How to identify the ideal effective bacteria to shape the early infants flora to prevent asthma remains to be studied. In addition to probiotics, dietary fiber is an important way to change the intestinal flora. Dietary fiber has been well demonstrated to be metabolized by local intestinal microflora into short-chain fatty acids (SCFAs), which can inhibit the inflammatory pathways of macrophages and dendritic cells (DC), promote the development of regulatory T (T reg) cells, and maintain the integrity and health of intestinal epithelium. Different amounts of dietary fiber can alter allergic airway responses and alter susceptibility to inflammatory diseases [67].

5.7.2

The Pneumonia and the Gut Microbiome

A study depleted the gut microbiota in C57BL/6 mice and subsequently infected them intranasally with S. pneumonia, and they found that the gut microbiota enhances primary alveolar macrophage function which highlights the possibility that broad-spectrum antibiotics and disruption of the intestinal microbiota may diminish innate immune defence to infection [55]. It indicates that novel therapies to treat severe pneumonia could focus on the gut–lung axis in bacterial infection. A prospective, randomized, double-blind, placebo-controlled trial in 146 mechanically ventilated patients at high risk for VAP found that in addition to routine care, patients who received probiotics twice daily received fewer antibiotic days of VAP therapy [68]. A study on mice showed that LGG treatment can significantly improve intestinal permeability after Pseudomonas aeruginosa pneumonia and normalize claudin2 expression, suggesting that probiotic treatment can reduce ventilator-associated pneumonia, especially in critically ill patients with pseudomonas aeruginosa pneumonia [69]. These evidences suggest that intestinal flora and related products can improve respiratory immunity during the process of pneumonia infection, which is also one of the directions to be considered in the future treatment of pulmonary infection. But when it comes to meta-analysis, previous studies failed to come to an agreement. Even though probiotic group showed a trend toward lower incidence of VAP, the preventative effect was not statistically valid [70]. The meta-analysis comprising 10 RCTs (1,218 patients) argued that administration of probiotics

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reduced the incidence of ICU-acquired pneumonia and was associated with a shorter stay in the ICU [71]. Clinical and statistical heterogeneity and inaccurate estimates preclude strong clinical recommendations. Further research on probiotics in critically ill patients is necessary [72]. And the specific mechanisms of benefit are complex and not fully described.

5.7.3

The Immunotherapy and the Gut Microbiome

Immunotherapy has been a great success in cancer treatment, especially in non-small cell lung cancer fields [73]. The currently marketed checkpoint inhibitors are monoclonal antibodies targeting cytotoxic T lymphocyte-associated protein 4 (CTLA4) or the programmed death 1 (PD1) located on T cell surfaces, or its ligand, programmed death ligand 1 (PD-L1), expressed by the APCs [74]. In mice and patients, T cell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA-4 favored the outgrowth of B. fragilis with anticancer properties [75]. Sequencing of the 16S ribosomal RNA showed that bifidobacterium had antitumor effects. Oral administration of Bifidobacterium alone can improve tumor control to a certain extent in programmed cell death protein 1 ligand1 (PD-L1)-specific antibody therapy [76]. In a Chinese cohort of patients with advanced non-small cell lung cancer, antibiotics treatment was significantly associated with the attenuated clinical results of immune checkpoint inhibitors based on anti-PD-1 [77]. This study provides us with a positive signal that to improve the efficacy of PD-1, we may start from the human flora. Microbiota can influence the outcome of cancer immunotherapy in a more specific way. Some symbiotic bacteria may suppress tumor immunity by tilting the balance of the immune subsets to the inhibitory phenotypes such as Tregs and MDSCs. In addition, bacterial metabolites with immunosuppressive properties may be released into the circulation to promote the function of TdLN and TME immunosuppressive cells. Chronic inflammation caused by persistent PAMPs/ MAMPs stimulation or epithelial injury may also eventually lead to immunosuppression. The immunostimulatory effects of the gut microbiota could be mediated by augmented antigenicity, adjuvanticity, or bystander T cell activation [78]. Tanoue et al., firstly, isolated a combination of 11 strains from healthy human feces which can improve the effectiveness of tumor immunotherapy without causing inflammation [79]. These species are present in the human body in low abundance. Although the exact mechanism is unclear, this study provides an idea that some rare strains have a strong potential to promote immunotherapy effect. Zitvogeld et al. found patients treated with antibiotics (which destroyed the gut microbiome) relapsed quickly and did not live long. The researchers then analyzed the differences between the intestinal bacteria of the PD-1 antibody responders and the non-responders. It was found that among responders, the bacterium

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Akkermansia muciniphila played an important role. Oral supplementation with A. muciniphila after fecal microbiota transplantation with nonresponder feces restored the efficacy of PD-1 blockade in an interleukin-12-dependent manner by increasing the recruitment of CCR9+ CXCR3+ CD4+ T lymphocytes into mouse tumor beds [80]. The strains reported in the above studies are different, but all of them suggest that human flora is very important in the process of immunotherapy. The intestinal tract contains rich flora, and the adjustment of intestinal flora is bound to be the focus of future research on the efficacy of immunotherapy. But more detailed studies and clinical trials are needed on the specific strains and effects in different people.

5.8

Conclusion

With the increasing understanding of gut microbiota, more and more attentions are paid to gut–lung axis that has important role in health and disease. The microbiota of the gut and the microbiota of the lungs interact with each other and restrict each other. However, it is unlikely this interaction is enough responsible for the functions of the microbiota. The cross talk between microbiome and the host is complex and it is widely accepted that the microbiota, especially the gut microbiota, modulate innate and adaptive immune responses in a global way [5, 81]. Dysbiosis in gut microbiota affects local and distal organs, but it is still unclear whether changes in gut microbes affect distal sites equally, and whether distal sites then would also interplay with each other. A further understanding of the systemic effects of gut microbiota requires more broad studies and clinical intervention trials. Several factors are reported to be involved in affecting gut–lung axis, including smoking, antibiotics, diet, probiotic bacteria, and the delivery mode of the newborns, which could be divided into exogenous factors and endogenous factors. But thus far, we could only say the above are related factors, and the significance of each factor is unknown. A more precise assessment model needs to be set up in the future by weighing in significant related factors. More and more evidence supports that bacterial products and immune cells mediate gut–lung cross talk. The microorganisms could be identified as beneficial and pathogenic species according to their immunomodulatory effects [81, 82]. But the mechanism is so complex that our current understanding is only the tip of the iceberg. Further studying the characteristics of the microorganisms will provide us with new insights into ways to manipulate them. In summary, it is clear that gut microbiota is closely associated to respiratory tract, and the specific species are able to influence the pathogenesis of respiratory diseases, which might be mediated by reshaping systemic immune responses. Further researches will help to present the whole picture of gut–lung axis and to identify new and effective therapeutics.

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Chapter 6

Gut Microbiota and Neurologic Diseases and Injuries T. Tyler Patterson and Ramesh Grandhi

Abstract The brain–gut axis is a bidirectional communication pathway connecting the central nervous system (CNS) and the gastrointestinal tract via nerve transmission, hormone, immune system, and other molecular signals. The bacterial flora of the human gut contributes direct and indirect signals to the CNS along the brain– gut axis. Alterations in gut flora, a state known as dysbiosis, has been tied to systemic inflammation, increased bacterial translocation, and increased absorbance of microbial by-products. An increase in recent literature has highlighted the role of the gut–brain axis in CNS pathology. This chapter reviews the association between gut flora dysbiosis and disorders of the central nervous system including autoimmune disease, developmental disorders, physiologic response to traumatic injury, and neurodegenerative disease.










Keywords Gut microbiota Autism Parkinson’s disease Alzheimer’s disease Multiple sclerosis Anxiety Depression Traumatic brain injury Stroke




6.1













Introduction

The brain–gut axis is a bidirectional pathway of communication between the central nervous system and the gastrointestinal tract. Signals along this path include mechanisms involving neurons, hormones, the immune system, and other neuro-active peptides [1, 2]. In particular, the microbial constitution of the gut appears to be a major factor affecting this axis—significantly enough to popularize the notion of a gut–brain–microbiota axis. T. Tyler Patterson Department of Neurosurgery, University of Texas Health Science Center School of Medicine, San Antonio, TX, USA R. Grandhi (&) Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, Utah, USA e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 P. Chen (ed.), Gut Microbiota and Pathogenesis of Organ Injury, Advances in Experimental Medicine and Biology 1238, https://doi.org/10.1007/978-981-15-2385-4_6

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The gut–brain–microbiota axis, which includes the microbes that live in the human gastrointestinal tract, has become a point of focus in the literature. A typical human gut has an estimated 100 trillion bacteria from more than 1000 species [3]. These microbes not only live in the intestines, but they also serve functional roles. The commensal bacteria are involved in gut motility, secretory responses, and nutrient processing [4]. A traditional example is that of vitamin K, which humans receive almost exclusively as by-products of intestinal bacteria [5]. In addition, the gut microbiota appear to heavily interact with the central nervous system (CNS). Germ-free murine studies have provided insight into various mechanisms by which the organisms affect the brain. Alterations including lowered neurotrophic factors like brain-derived neurotrophic factor, reduced blood–brain barrier (BBB) tight cell junction proteins like occludin, and impaired immune system response have been identified in germ-free mice, indicating that the commensal bacteria play a role in modulating development of the CNS [6]. In recent years, increasing emphasis has been placed on the role of gut microbiota in pathology of the brain. More specifically, deviation from a healthy or steady-state gut microbiota may be a source for disease states. Gut microbes have previously been implicated in inflammatory conditions such as irritable bowel syndrome and ulcerative colitis, in which there exists an overgrowth in clostridia, bacteroides, and enterobacteriaceae [5, 7]. This departure from the steady-state microbiota composition is termed dysbiosis, and is increasingly cited as contributing to pathology. A number of conditions have similarly been linked to alterations in the gut–brain–microbiome axis, including the neurodevelopmental disorder of autism; neurodegenerative disorders like Parkinson’s disease (PD) and Alzheimer’s disease (AD); the autoimmune-mediated multiple sclerosis (MS); neuropsychiatric diseases such as anxiety, depression, and schizophrenia; and secondary CNS injury following traumatic brain injury (TBI), spinal cord injury (SCI), and stroke. This chapter will examine the current evidence for mechanisms underlying the gut–brain–microbiota axis in CNS pathology.

6.2

Neurodevelopmental Disorder—Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders that are regularly characterized by repetitive behaviors, impaired social interaction, and deficits in communication. Its prevalence worldwide was estimated at 52 million in 2010, with an increase expected [8]. As the leading cause of disability in patients less than 5 years of age, ASD commands serious clinical consideration. Identifying the cause and possible therapies of this disorder not only has the potential to impact millions of lives currently, but it would also provide avenues to reduce its future incidence.

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The etiology of autism has become a frequent topic in the literature in recent decades. It is largely accepted that ASD is caused by a combination of genetic and environmental factors, as identified polymorphisms and de novo mutations are estimated to account for about 50% of the disease [9, 10]. A wide variety of environmental factors have been and continue to be explored. Favored hypotheses center around abnormal immune responses and neural development in utero and postnatally: viral infections, melatonin deficiencies, teratogen exposure, malnutrition, and maternal diabetes, among others [11]. More recently, the microbiota of the gut has come into focus as a source of ASD pathology. It has been noted that patients with ASD often report gastrointestinal symptoms. Even among siblings, those with ASD have been found to have more frequent symptoms such as constipation and pain compared with those without ASD [12]. These findings, in turn, potentially underscore a relationship between gut dysbiosis and autism, with several studies demonstrating various strains of Clostridium species to be over-represented in the fecal samples of patients with ASD compared with controls [13–15]. ASD patients with altered gut microbiota also demonstrate increased gut permeability when compared with controls [16], a phenomenon known as the leaky-gut state. In this state, an increased level of communication exists between the contents of the gut and the host body. This is particularly important when considering that the dysbiosis might be producing an unfavorable gut environment by disturbing the typical flora. For instance, short fatty acid chains and ammonia levels are increased in fecal samples of ASD patients [17]. This could represent poorer absorption of these bacterial products by the gut, but more likely indicates increased production of short chain fatty acids (SCFAs), ammonia, and other products by a dysbiotic gut flora. In that case, ASD patients with altered flora might be at risk of absorbing higher levels of bacterial by-products. This effect is probably superimposed with the leaky-gut phenomenon, predisposing this population to an elevated level of interaction between the gut and body—including the CNS. The increased permeability in the gastrointestinal mucosa also may contribute to systemic inflammation: lipopolysaccharide (LPS), an endotoxin which is found in many dysbiotic gut bacteria, has been shown to be elevated in the serum of autism patients, [18] resulting in the initiation of pro-inflammatory cascades. In addition, cytokines and interleukins produced locally in the gut can also circulate systemically. Interestingly, alterations in the BBB have also been detected in autism patients—selectin and claudin proteins, which are involved in tight junctions of brain endothelium, have been found to be decreased, for example [19, 20]. Taken together, these findings suggest a role for gut dysbiosis and the leaky-gut state in neuroinflammation, with the potential for causing altered CNS function and development. One proposed mechanism implicates SCFAs in mediating changes related to ASD. Propionic acid, one studied example of SFCAs, can cross the BBB and affect the parenchyma [21, 22]. In murine studies of propionic acid injected into the brain, changes associated with ASD were seen: neurochemical changes, neuroinflammation, oxidative stress, glutathione depletion, and altered phospholipid profiles.

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Further avenues exist linking the gut to the CNS. The study of germ-free mice has demonstrated changes in the brain including 5-HT receptors, neurotrophic factors like brain-derived neurotrophic factor, and N-methyl-D-aspartate receptors [6]. Although their mechanisms have not been fully outlined, these changes may be thought of as consequences of the pro-inflammatory state caused by the leaky gut and associated BBB permeability, circulating toxin, and inflammatory cascades. In addition, gut microbiota can produce a number of neurologically active compounds including histamine, gamma-aminobutyric acid, and dopamine [23]. These molecules may act locally within the enteric nervous system of the gut and indirectly affect the CNS via the feedback loop provided by the vagus nerve. Furthermore, these compounds can enter the circulation, cross the porous (BBB), and directly influence CNS function. Taken together, the clinical observation of gut symptomatology in ASD patients may be traced to biophysical changes peripherally and centrally which point to CNS dysfunction. Dysbiosis with leaky gut is integral in facilitating this pathway.

6.3

Neurodegenerative Disease—Parkinson’s Disease and Alzheimer’s Disease

Neurodegenerative disease refers to a variety of pathologies that ultimately cause impaired cognition, and in many cases dementia. PD, a motor disorder and neurodegenerative disease, is the second most common neurodegenerative disease in the developed world with a progressive incidence of 20 per 100,000 at 55 years of age to 120 per 100,000 at 70 years of age [24]. Clinically, PD is characterized by a resting tremor, muscle rigidity, gait instability, and bradykinesia—dementia often occurs sequentially. PD was discovered due to the loss of pigmented neurons in the substantia nigra, an area of particularly dopaminergic neurons. The cause of atrophy in this area is thought to be due to an aggregation of a-synuclein, characterizing PD into a group of synucleinopathies that also includes multiple system atrophy and Lewy body dementia. The accumulation of a-synuclein, which occurs intracellularly as Lewy body inclusions, is the consequence of misfolded proteins. It is proposed that oxidative stress and inflammation cause mitochondrial dysfunction and subsequent impaired dopamine metabolism [24]. For one reason or another, the neurons in the substantia nigra appear especially susceptible to a-synuclein aggregation [25]. The motor features readily apparent in PD are the result of these changes. Increasingly it is recognized that a number of symptoms may precede the motor symptoms and cognitive impairment stages of PD. This prodromal state of PD is thought to include rapid eye movement sleep behavior disorder, hyposmia, or anosmia, and gastrointestinal symptoms like constipation [26–28]. These findings correlate with autopsy studies that have identified incidental Lewy bodies in patients without the classic clinical presentation of PD. The Braak staging system

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proposed a sequence of a-synuclein aggregation beginning in the autonomic nervous system and olfactory bulbs with progression centrally to the brainstem and neocortex [29]. Thus, the earliest signs of PD are thought to occur because of a-synuclein accumulation in various areas of the body, with progression to motor and cognitive symptoms occurring only after progression to the substantia nigra and forebrain occurs. The frequency of gastrointestinal symptoms in PD patients has caught the attention of researchers in recent years. PD patients report higher rates of constipation and gastrointestinal discomfort, and have even been found to statistically significant variances in components of the gut microbiome [30]. Certain species have been found to vary consistently in PD. One group found the species Prevotellaceae to be reduced by 77% compared with control; furthermore, the abundance of Enterobacteriaceae species was positively correlated with clinical severity of gait instability [31, 32]. Recognition of these changes has led to the integration of the gut–brain–microbiome axis into the pathophysiology of PD. Recent studies have continued to support this proposition. Microscopic evaluation of gut samples from PD patients demonstrated increased levels of inflammatory cytokines and glial markers [33]. The presence of cytokines, which included tumor necrosis factor alpha (TNF-a) and interferon gamma (IFN-ϒ), may represent the impact of dysbiosis in the gut of patients with PD. This local inflammation likely has important effects on the integrity of the wall, with increased intestinal permeability in PD patients. Samples have demonstrated increased intestinal staining for E. coli, higher levels of oxidative indicators including nitrotyrosine, and elevated serum LPS binding protein [34]. Taken together, these observations appear to indicate that the gut in PD is compromised and may lead to pathologic changes. Additionally, gut dysbiosis may also allow for increased levels of neurofilament and a-synuclein, as has been seen in 72% of colon samples from PD patients compared with none in a control group [35]. From there, environmental stressors, including toxins or bacterial products, can cause the exocytosis of a-synuclein into the extracellular space. Neighboring neurons can subsequently undergo endocytosis of the a-synuclein. Retrograde transport of the material can occur within the neuron, causing its aggregation in a more central location [28]. Alternatively, systemic inflammatory changes may be to blame as well. Serum LPS binding proteins have been shown to be altered in PD populations, suggesting systemic exposure of the dysbiotic environment. Thus, alterations in the gut microbiome are directly linked to inflammation within the gut, followed by the initiation of pathophysiologic cascades that ultimately lead to the classical microscopic intracranial findings of PD. Once again, the study of germ-free mice has significantly aided the effort to support these claims. One group used a line of a-synuclein overexpressing (ASO) mice to examine the role of the microbiome [25]. The control ASO mice had drastic PD syndromes due to a-synuclein aggregation. Germ-free ASO mice, by contrast, exhibited far less a-synuclein accumulation in the substantia nigra and caudoputamen. Postnatal recolonization of germ-free ASO mice caused a return of a-synuclein accumulation and the dysfunctional phenotype, further inciting the gut

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microbiota as propagators of the disease. Perhaps most importantly, germ-free animals caused a halt of microglia maturation in the CNS. The importance of these findings cannot be overstated, as they appear to show the vital role of the gut– brain–microbiota axis and the conversion of peripheral to CNS pathological findings. The aforementioned pathway provides a role for the gut–brain–microbiota axis in the setting of PD. Although there are many details left unexplored, the basic framework has been developed. Interestingly, many parallels exist between the pathophysiology proposed for PD and that of autism described previously. This may be cited as good evidence for the conserved role of the gut–brain–microbiota axis in certain pathologies, a concept evidenced in another neurodegenerative disease—Alzheimer’s disease. AD is a very common neurodegenerative disease and is the leading cause of dementia. Two histopathological findings largely in the neocortex and hippocampus accompany AD [36]. The first are intracellular neurofibrillary tangles of hyperphosphorylated tau protein. The second are extracellular accumulations referred to as senile plaque, which are formed from accumulated beta sheets of amyloid protein. Similar to in PD, changes in AD are thought to be secondary to oxidative stresses and mitochondrial dysfunction of neurons—resulting in the pathological changes described. Various factors have been proposed to cause AD. Familial forms exist because of overexpression of amyloid proteins [37]. Other risk factors have been suggested to be head trauma, chronic infections, and even gender [37, 38]. Despite these known changes in AD, the precise pathophysiology remains unknown. In very recent years, a novel focus of research has shifted to the role of the gut in AD, with a handful of emerging studies purport to incite the gut microbiota. A study from 2016 found that antibiotic administration in mice led to changes in the gut microbiota, which in turn altered the accumulation of amyloid plaques [39]. Additional analysis noted differences in circulating cytokines and chemokines. The implications of this study are large, as changing components of the gut directly lowered the rate of amyloid accumulation. Correlative differences in inflammatory cytokines suggest local and systemic inflammation may be at least partially responsible for mediating these differences. A germ-free murine study from 2017 built upon this model by finding that mice lacking gut microbiota had less cerebral amyloid plaques. Both studies appear to clearly pave the way for the gut–brain– microbiota axis to contribute to AD pathology. Thus, in both PD and AD, strong evidence appears to support the role of intestinal dysbiosis in inducing changes responsible for the accumulation of abnormal proteins. Both states appear to rely on oxidative stress and inflammation, likely due to altered gut constituents. Although the precise mechanisms are still being illuminated, conversion of these peripheral findings to central pathology appears quite likely.

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Autoimmune Disease—Multiple Sclerosis

MS is an autoimmune inflammatory disorder affecting an estimated 2.5 million people worldwide with a male:female ratio of 1:1.5–2.5. [40, 41] MS is characterized by inflammation, demyelination, and gliosis of various areas of the CNS across different points in time, which can result in deficits of ambulation, vision, and more [41]. A number of risk factors have been proposed such as Epstein–Barr virus infection, cytomegalovirus infection, viral meningitis, and vitamin D deficiency. Family history also confers a predisposition for disease, meaning MS is likely the result of environmental and genetic factors. Although an autoimmune component is clear, the precise mechanism has not been uniformly established. Immune cells either intrinsic to or extrinsic to the CNS may be to blame for the pathophysiology of MS. A growing stock of evidence suggests that the extrinsic model, that is, peripheral immune cells infiltrating the CNS, may underlie MS. The bowel has long been implicated in autoimmune disease, ranging from inflammatory bowel disease to type I diabetes mellitus to rheumatoid arthritis [42]. A more narrow focus has begun to reveal the likely role of the gastrointestinal tract and its microbes in the pathophysiology of MS. Not least, alterations in the bacterial species of MS patients have been recently established. In one report, three groups were found to be significantly reduced in the group of MS patients—Faecalibacterium, Prevotella, and Anaerostipes species [43]. In the same study, Bifidobacterium and Clostridium species were elevated in MS patients, although not at a statistically significant level. In a study of MS patients, the largest of its kind, it was found that elevations in Archaea species—a kingdom separate from bacteria and eukaryotes—were associated with MS; on the other hand, known anti-inflammatory species from the Bacteroidetes and Firmicutes phyla were reduced in MS [44]. Taken together, these findings suggest that certain bacteria may accentuate autoimmune disease while others may be protective. The interface between the gastrointestinal microbes and the immune system has been alluded to previously but can be more precisely illuminated. Commensal bacteria of the gut both contain and produce components that can interact with the mucosa. These materials include but are not limited to short-chain fatty acids, tryptophan metabolites, and capsule components like polysaccharide A (PSA). Epithelial cells are able to interact with these materials via receptors, especially toll-like receptors (TLRs). The interaction of TLRs with gut materials can produce chemotactic signals for myeloid and lymphoid cells of the immune system [45]. Moreover, dendritic cells in the gut wall appear to play a role in directing inflammatory versus non-inflammatory responses when encountering foreign material. As a result, a mechanism for the gut microbiome directing immune cells begins to take shape. Gut bacteria have been consistently shown to induce inflammatory immune responses. It has been noted that germ-free mice have deficiencies in pro-inflammatory cell lines, especially Th17 cells [46]. Germ-free mice also have

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significant reductions in plasma cells, mucosal IgA production, and intestinal Peyer’s patches—all indicating that the microbiome is vital in stimulating the immune system [47]. The connection to MS emerges in light of the finding that immune cells from peripheral stimulus are found in the CNS. When germ-free mice were recolonized with segmented filamentous bacterium in the gut, responding Th17 cells were subsequently isolated in the CNS [48]. This demonstration highlights the crucial link between gut bacteria and inflammatory responses of the CNS. Murine models of experimental autoimmune encephalomyelitis (EAE) have shown that when recolonized with bacteria, previously germ-free mice develop demyelinating changes of the CNS that closely mimic those seen in MS, the main difference being that the causal antigen is artificially introduced in EAE by recolonization [49]. This finding has been reproduced in a number of studies, firmly suggesting that gut microbiota contribute to the induction of immune-mediated disease of the CNS [46, 48, 50]. Interestingly, germ-free mice are protected from EAE, even in a population of mice predisposed to the disease state [46]. Therefore, reintroduction of gut bacteria stimulates an intact peripheral immune system to confer changes centrally. Part of the centralization process also appears to involve the inclusion of B cells. To this point, most cellular responses discussed have been mediated by T cell responses or actions of the nonspecific innate immune system. In MS, however, B cells appear vital in provided auto-antibodies. This is modeled in experimental autoimmune encephalomyelitis by production of myelin oligodendrocyte glycoprotein, an auto-antibody toward myelin. Evidence that animals deficient in B cells —and thus the myelin oligodendrocyte glycoprotein auto-antibody—do not develop severe disease suggests that T cells alone cannot propagate the disease [46]. Instead, EAE likely represents the activation of B cells by T cell signaling, which confers the disease state. An important finding related to the PSA capsule of Bacteroides fragilis lends further support to this hypothesis. Specifically, the introduction of B. fragilis to the gut of mice destined to develop EAE resulted in a reduction in severity of the disease compared to a control group [50]. The proposed mechanism cited an increase in IL-10 producing T regulatory (Treg) cells, which have anti-inflammatory properties. The significance of these findings lies in the clear connection between gut microbiota, CNS disease, and secondary reduction in disease following colonization with another commensal organism. What can be concluded, then, is that gut microbiota likely stimulate T and B immune cells to proliferate—especially in a suspected dysbiotic state. Peripheral signals derived in the gut mucosa may be followed to the CNS via immune cells that incite damage on nervous tissue. Furthermore, different species and materials may have a protective effect against disease. These murine models offer vital insight into the likely role of the gut– brain–microbiota axis in the disease of MS. More specifically, the gut–brain–microbiota axis can mediate change by communicating through specialized changes of the immune system.

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Neuropsychiatric Disorders—Anxiety and Depression

Major depression disorder is the most prevalent psychiatric disorder. Just under 20% of the population will meet criteria for depression in their lifetime [51]. What’s more, nearly three in four individuals with depression also meet criteria for other psychiatric disorders—most frequently an anxiety-related disorder [51]. While sub-diagnoses exist within both depression and anxiety disorders, this section will focus broadly on these two topics without further specification. The pathophysiology of anxiety and depression has been well explored in the literature; however, the entire process remains incompletely understood. From a quite broad perspective, it has been generally accepted that neurotransmitter systems involving serotonin and noradrenaline appear altered in anxiety and depression [52]. This is supported by the fact that therapy for both depression and anxiety often utilizes serotonin reuptake inhibitors to increase its availability. Still, the alterations in neurotransmitter levels most likely occur as the consequences of biochemical pathology from other systems. That is, rather than the root cause of anxiety and depression, the changes in neurotransmitter levels are probably the result of other processes. A very likely contributor to this process is the hypothalamic–pituitary–adrenal (HPA) axis. It was reported as early as the 1950s that cortisol, which is the major product of the HPA axis, is elevated in the blood of depressed patients [53]. Thus, a central theory for depression and anxiety rests on the hyperactivity of this system. Corticotropin-releasing factor or corticotropin-releasing hormone (CRH) is synthesized and released from the hypothalamus onto the pituitary gland to allow adrenocorticotrophic hormone to enter systemic circulation; when adrenocorticotrophic hormone reaches the adrenal glands, the main product cortisol is released into the bloodstream. The hypothalamus, which initiates this cascade, receives neuronal projections from a number of areas including the brainstem, the limbic forebrain, and the lamina terminalis [54]. The integration of the HPA axis with the gut–brain–microbiota axis is substantial because it adds a method of communication between these organ systems. Previous discussions have noted the role of inflammation, the adaptive immune system, and neurotransmission as mediators of signals. Herein, the HPA axis adds the component of neuroendocrine communication. As demonstrated previously, the gut–brain–microbiota axis clearly acts as a bidirectional communication between the gut and central nervous system. It is then reasonable to conclude that the microbiota of the gut might be able to affect the regulation of the HPA axis. Support for this notion arrives from population-based studies that have found an increase in gastrointestinal disorders such as irritable bowel syndrome among patients with affective disorders—including anxiety and depression [55]. So these disorders join the ranks among the formerly discussed PD and ASD as CNS pathology that appears to have a disproportionate increase in gastrointestinal symptoms. As a result, anxiety and depression may reasonably be associated with alterations in the gut microbiome and gut function.

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Animal models of depression have further supported this connection. Firstly, dysbiosis has been associated with chronically depressed mice, [56] with altered colonic motility as well. In addition, central expression of CRH was found to be elevated, representing empirical evidence of integration of the HPA axis into the pathophysiology of depression. The elevation of CRH would indicate hyperactivity of the HPA axis, likely resulting in elevated serum cortisol. Germ-free mice have helped to define the role of gut microbiota in the development of anxiety and depression. In the absence of any gut microbes, animals regularly exhibit lower levels of anxiety-related behavior [57, 58]. Conversely, animals with gut microbes developed behaviors consistent with anxiety and decreased motor activity, which can model depression. The microbiota therefore is vital to initiating these neuropsychiatric disorders, possibly via the HPA axis. Indeed, it appears the gut microbiota actually shape the development of the HPA axis. When previously germ-free mice are reconstituted early in life with microbes, the HPA axis was reduced. However, if reconstituted at a late stage, the HPA axis remained hyperactive [58, 59]. The distinction between early and late reconstitution of microbes highlights the role of the gut–brain–microbiota axis in calibrating the HPA axis early on. This suggests that gut constituents at a particular phase or phases of life drive the HPA axis, and subsequently, the formation of depression and anxiety disorders. More than one species have been identified in animal studies as having protective properties. When Bifidobacterium infantis, a species commonly found in the gut flora of infants, was re-introduced to germ-free animals, depression behavior was reversed [60]. Oral ingestion of Lactobacillus strains resulted in lower anxiety and depression behavior in rats, in addition to lower stress-induced serum cortisol levels [61, 62]. In a human study, patients taking a probiotic containing Lactobacillus and Bifidobacterium species lowered scores on anxiety and depression scales, which correlated with decreased serum cortisol. In examining anxiety and depression, much emphasis is placed on the HPA axis. Disruptions in gut microbiota likely alter the HPA axis. This may be through inflammatory effects, metabolites, or even direct neurotransmission. Vagotomized rats in a depression model did not benefit from recolonization when compared with non-vagotomized animals, suggesting a central role for interaction of the microbiome and the neuroendocrine HPA axis [61]. The ultimate conclusion is that gut microbiota are able to induce CNS pathology by at least altering the HPA axis. The downstream mechanisms remain less clear; however, one can infer that the signal alterations may lead to the subsequent development of pathology.

6.6

Acute Pathology—Traumatic Brain Injury and Stroke

The previous sections focused on chronic pathologic disease states, but the gut– brain–microbiota axis also appears to be highly involved in mediating injury in acute pathologies as well. Traumatic brain injury (TBI) and stroke are at the

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forefront of the current literature focuses, not least because they are extremely common and burdensome conditions. An estimated 10 million cases of TBI occur worldwide annually, resulting in millions of emergency department visits and hundreds of thousands of hospitalizations [63, 64]. Acute stroke is also extremely common, with nearly a million US cases annually, and is the number one cause of chronic adult disability [65]. In both cases, TBI and stroke result in primary injury to the brain parenchyma. In this section, the ways in which secondary injury may occur will be explored within the context of the gut–brain–microbiota axis. An initial link between CNS injury in TBI and stroke is the effect of dysautonomia, or dysregulation of the autonomic nervous system. Dysautonomia is a phenomenon that manifests through a myriad of symptoms including episodes of tachycardia, hyperthermia, diaphoresis, hypertonicity, and/or decerebrate or decorticate posturing. The pathophysiology behind this process is thought to result from altered metabolism and release of key neurotransmitters and has been linked to TBI [66]. It is likely that the enteric nervous system conducts the dysautonomia to the gut as changes in sympathetic and parasympathetic input results in symptoms of bowel discomfort and chronic gastrointestinal pain [67]. It may be postulated that dysautonomia could alter the gut microbiome, causing a state of dysbiosis. Although this has not been shown in TBI models, SCI studies have demonstrated a correlation between dysautonomia and altered gut flora. Altered gut flora after SCI also produced worse neurologic outcomes compared with non-altered controls, implicating the gut–brain–microbiota axis in central neurologic recovery after trauma [68]. Other currently unknown mechanisms that alter the microbiome, such as neuroendocrine disruption or changes in vagal nerve signaling to the gut, may also be at play. Ultimately, CNS injury produced by trauma or stroke can be tied to dysbiosis and its subsequent effects. The cascade of effects caused by dysbiosis may once again start with altered gut permeability. Bacterial presence in the gut is well linked to intestinal mucosal integrity, as previously mentioned. Tight junction proteins undergo altered expression in the presence or absence of TLR activation [69]. These TLRs, a type of pattern recognition receptors, are thought to mediate the gut barrier integrity via baseline interactions with commensal bacteria. In a dysbiotic state, then, improper signaling may allow breakdown of this barrier. Evidence for this process has been found in a TBI animal model where gastrointestinal tissue demonstrated an increased presence of inflammatory markers, including TNF-a and IL-6, and upregulation of glycoproteins that function to recruit inflammatory cells [70]. In other words, TBI in rats resulted in protein expression to recruit immune cells and inflammatory signals in the gut, a possible result of altered mucosa integrity. The leaky gut may also allow toxic bacterial components, most notably LPS, to enter circulation. Recent work demonstrated that LPS mediates neuroinflammation after TBI by activating microglia in the CNS [71]. So as previously discussed, a pro-inflammatory state may confer damage to the CNS when circulating cytokines or bacterial components reach the intracranial circulation. Gut leakiness after CNS injury also exerts effects on the immune system. Animal models of stroke and TBI have supported this notion. An area of particular focus is

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the group of T cells referred to as Treg cells. Treg cells appear to primarily function as a fulcrum between pro-inflammatory and anti-inflammatory states. Treg cells are activated by interactions with normal gut bacteria, which results in several anti-inflammatory actions including secretion of IL-10 [72]. IL-10 production has been directly linked to a reduction in pro-inflammatory cell lines including Th1 and Th17 populations [69]. What’s more, IL-10 may exert neuroprotective effects centrally by suppressing microglia activation [73]. The mechanism for proliferation of Treg cells in the gut is thought to be driven largely through interactions with dendritic cells. By sampling the gut lumen contents, dendritic cells communicate the need for pro- or anti-inflammatory states. On the other hand, dysbiosis then may shift the balance of immune cells to favor an inflammatory state—which could hinder CNS healing or even cause further damage. Evidence for the role of the immune cells in secondary brain injury has been demonstrated in animal stroke models. After induced ischemic stroke, previously germ-free mice reconstituted with fecal contents of dysbiotic mice showed an increase in lesion volume when compared with control [74]. This finding strongly argues that intestinal bacteria stimulate an immune response that communicates with the CNS. Incredibly, the same stroke model used labeling to show that intestinal lymphocytes traveled to the brain. Further study has continued to support this notion and even hinted at an underlying mechanism. When post-ischemic-stroke mice are administered antibiotics, a reduction in cdT cells, a subset of effector T cells that produce the pro-inflammatory cytokine IL-17, and an increase in Treg cells were noted in the small intestine [75]. It can be inversely inferred that an imbalance in gut bacteria favors an inflammatory state created at least partially by cdT cells. In fact, mice deficient in cdT cells were found to have improved functional outcomes after SCI (Fig. 6.1) [76]. One consideration raised when considering the transposition of gut immune cells to the CNS is that of the BBB. In a healthy state, the BBB is vital for controlling vascular permeability and protecting the brain from unwanted influences including toxins or inflammatory factors. Following a TBI, the permeability of the BBB can increase up to four times its normal amount within just 6 h [67]. In the context of the gut–brain–microbiota axis, an increase in BBB permeability offers potentially crucial access from peripheral sources to the CNS. ICAM-1, which helps direct inflammatory cells, is expressed in the brain tissue of rats after TBI [77]. Upregulation of ICAM-1 would help to explain the presence of peripheral immune cells found in the CNS after injury, possibly providing a precise mechanism for secondary neuroinflammation after injury from TBI or stroke. In parallel, these findings illustrate the likely mechanism for which gut microbiota affect CNS healing after injury. Good evidence has been produced in stroke models, while TBI data is still growing or must be extrapolated from SCI models. Taken together, though, the information collected to date supports the notion that acute CNS injury has the capability to alter gut microbiota. In return, these changes appear to affect CNS healing. A leaky-gut phenomenon appears to promote inflammatory cytokine release and immune cell translocation to the brain. Thus, targets for reducing the morbidity of stroke and TBI may therefore focus on

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Fig. 6.1 CD4+ Regulatory T cells (Treg) serve as a fulcrum in the balance of pro-inflammatory and anti-inflammatory immune modulation. In the gut, microbiota are sampled or may translocate, resulting in an immune response. The CD103+ dendritic cells (CD103+DC), a type of antigen presenting cell of the intestinal mucosa, have been found to drive the proliferation of Treg cells while the microbiota is in a steady state. Subsequent activity by Treg cells results in suppression of an inflammatory response by multiple mechanisms. A central focus of this illustration is the Treg cell-mediated influence on cdT cells. cdT cells have the potential to cause either inflammatory or anti-inflammatory effects, but the influence of Treg cells while gut microbiota remain in steady state urges a reduced inflammatory state. Treg cells additionally produce IL-10, further suppressing Th1 and Th17 responses. In the presence of dysbiosis, interactions with dendritic cells and Treg cells result in a loss of inhibitory effects and, thus, the development of pro-inflammatory states

reducing inflammation, perhaps by modulating the population of gut microbes. More investigation of this promising topic, however, is required.

6.7

Summary

In this chapter, the extent of the gut–brain–microbiota axis has been explored within the context of brain pathology. This bidirectional communication between the gut and the brain is increasingly linked in various ways to disease states including ASD, PD, AD, MS, TBI, and stroke. Through these examples discussed

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Fig. 6.2 This figure demonstrates the proposed impact of dysbiotic gut microbiota on the integrity of gastrointestinal epithelial integrity and the central nervous system. When sampling dysbiotic flora, the local immune response results in inflammatory mediators including interferon (INF) and tumor necrosis factor (TNF) alpha. Systemic effects of this inflammatory process include a “leaky-gut” phenomenon at least partially due to tight junction downregulation. Synergistically, other products of dysbiotic flora such as short-chain fatty acids (SCFAs), lipopolysaccharide (LPS), and neurotransmitters may translocate. The pro-inflammatory signals and bacterial materials may then reach and affect the central nervous system

above, the communication pathways of the gut–brain–microbiota axis have been highlighted. It has been shown that various mechanisms underlie this relationship (Fig. 6.2). Neurologic disease has been consistently linked to gastrointestinal symptoms, which helped to uncover the frequent state of gut dysbiosis in these patients. The effects of altered gut microbial content can be traced to several effector functions on the CNS. One of the first consequences of dysbiosis seems to be an increase in intestinal permeability as demonstrated by increased serum levels of bacterial toxins and metabolites. These toxins and metabolites potentially have the capacity to directly influence the brain, but they also point to a further process. By increasing intestinal permeability, the gut is subjected to abnormal exposure to luminal contents. Because the gastrointestinal tract houses an immense part of the peripheral immune system, dysbiosis allows more communication between bacterial products and immune cells. Through a number of proposed mechanisms, a pro-inflammatory state becomes evident from circulating cytokines and translocated immune cells. Parallel findings have been noted in various disease states, stabilizing the foundations of these propositions.

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Although more investigation is required to fully illuminate the role of the gut– brain–microbiota axis, the basic mechanisms at play have begun to reveal themselves. With more bacteria in the lumen of the gut than cells in the human body, it is no wonder that the gut–brain–microbiota axis retains the potential to contribute to disease states. Furthermore, eventual therapeutic targets may lie within the details of these mechanisms.

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Chapter 7

Gut Microbiota and Renal Injury Lei Zhang, Wen Zhang, and Jing Nie

Abstract Renal injury, especially chronic kidney disease (CKD), is closely associated with gut microbiota. It is well known that renal injury development could cause enteric microbial compositional disruption. On the other hand, gut microbial composition, as well as their function, would directly influence the renal disease progression. Here, in the present chapter, we will summarize the crosstalk between intestinal microbiota and renal disease and discuss some potential therapeutic approaches based on this topic. Keywords Gut microbiota Metabolites

7.1


Chronic kidney disease
Short-chain fatty acids


Introduction

Chronic kidney disease (CKD) is a worldwide public health problem leading to poor outcomes and high financial burden. It is estimated that over 119 million Chinese people have CKD and further develop into end-stage renal failure (ESRD), a devastating condition that requires life-long dialysis or kidney transplantation [1]. Numerous epidemiological studies have indicated that the prevalence of CKD is increasing worldwide [2, 3]. As the population of patients with diabetes mellitus and obesity continues to grow, it is highly probable that this trend of increasing prevalence of CKD will only continue to worsen in the foreseeable future. In addition to decreased renal function, cardiovascular disease (CVD) is the most frequent cause of death in CKD patients. Despite the enormity of this problem, current therapeutic options for CKD in the clinical setting are scarce. New therapeutic interventions to delay the progression of CKD are critically needed. L. Zhang
W. Zhang
J. Nie (&) State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of Education), Division of Nephrology, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Ave., Guangzhou 510515, China e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 P. Chen (ed.), Gut Microbiota and Pathogenesis of Organ Injury, Advances in Experimental Medicine and Biology 1238, https://doi.org/10.1007/978-981-15-2385-4_7

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In the past decade, accumulating studies have shown that, compared with healthy people, the composition of intestinal flora in CKD patients has significantly changed [2, 3]. CKD-related dysbiosis and changes in the intestinal barrier encourage the increased translocation of living bacteria or bacterial products from the intestinal lumen into circulation, a process that could account for the persistent systemic inflammation in CKD/ESRD. Despite technical innovations, systemic inflammation caused by bacterial migration remains a serious problem to be solved. Therefore, studies have increasingly focused on the mechanisms of the kidney– intestinal axis, aiming to delay the progression of CKD and prevent ESRD complications through regulation of gut microbiota [4–8]. This chapter focuses on the potential roles of intestinal microbiota in the context of chronic kidney disease.

7.2

Impact of CKD/ESRD on the Intestinal Microbiota

In CKD patients, the homeostasis of the original intestinal flora is broken, which manifests as a decrease in probiotics and increase in toxigenic flora. Changes in the gut microbiome are thought to be different in different stages of CKD. Vaziri et al. [9] reported that the proportions of Cryptotermes brevis, Enterobacteriaceae, Halomonas, Moraxella, Polycystiaceae, Pseudomonas and Thiothrix were significantly increased, while those of Lactobacillaceae and Prevottiaceae were significantly decreased in stool samples of ESRD patients compared with healthy controls. In patients receiving hemodialysis, the number of intestinal anaerobic bacteria, especially enterobacteria and enterococci, is 100 times higher than in healthy people [10, 11]. The ratio of cellulose to protein is decreased in the intestinal tract of CKD patients, resulting in an increase in the proportion of Clostridium difficile and Bacteroides bacteria, which tend to produce toxic metabolites such as ammonia, amines, thiols and phenol, the main components of uremia toxins [8]. The intestinal flora imbalance in CKD patients is mainly due to the following reasons: (1) CKD patients usually have body fluid retention and urea accumulation; the microzymes of the intestinal flora hydrolyze the urea to produce ammonia, resulting in the uremic enterocolitis [12, 13]. (2) The intestinal epitheliums of CKD patients actively secrete a large amount of uric acid and oxalic acid into the intestinal cavity, leading to changes in the energy metabolism of the flora [14]. (3) Due to restrictions on potassium ion intake, CKD patients are limited in the amount of fruit and fresh vegetables they can consume, resulting in decreased cellulose intake. (4) In addition, the use of antibiotics and phosphorus-binding agents impairs the structure of intestinal flora.

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Impairment of the Gut Barrier in CKD

The intestinal epithelium is a major component of the gut barrier for separating microbial products in the gut lumen from the host circulatory system. The tight junction proteins between epithelial cells can prevent non-selective transport of substances across the barrier [15]. Intestinal Bifidobacteria promote the expression of tight junction proteins such as ZO-1, claudins, occludin and E-cadherin, to maintain the integrity of intestinal barrier [16]. In CKD patients, however, an imbalance in intestinal flora causes an increased proportion of pathogens and disruption of the epithelial layer ecosystem, which lead to increased intestinal permeability and impaired nutrient absorption [17]. Meanwhile, uremic toxins such as urea and ammonia are capable of directly damaging the gut barrier. In addition, intestinal wall edema, ischemia, electrolyte disorder and hypoalbuminemia can also lead to intestinal barrier dysfunction in CKD patients. Vaziri et al. demonstrated chronic inflammation extending throughout the gastrointestinal tract in hemodialysis patients [18]. Subsequent studies have found that CKD rats showed systemic oxidative stress and marked depletion of epithelial tight junction proteins such as claudin-1, occludin, and ZO-1 [19]. Systemic inflammation marked by activation of circulating leukocytes and elevation of plasma proinflammatory cytokines persists in CKD and has been suggested as a major catalyst for the progression of CKD as well as CVD in CKD [20, 21]. The major causes of systemic inflammation in CKD/ESRD patients include direct induction by uremic toxins, oxidative stress, catheter-related infections and biocompatibility between dialysis solution and membranes. Another cause not to be ignored is the translocation of living bacteria and endotoxins into systemic circulation in ESRD patients due to gut barrier impairment [22, 23]. Bacterial endotoxins are a powerful stimulus of inflammation activation via the Toll-like receptor 4 (TLR4) and NOD-like receptor protein 3 (NLRP3) inflammasome pathways. Endotoxins may also activate pattern recognition receptors (PRRs) in immune cells, triggering an inflammation cascade. Therefore, impairment of the intestinal barrier permits exposure of the mucosal immune system to pathogens, toxins and allergens, which leads to activation of inflammation pathways and release of proinflammatory cytokines. Persistent chronic inflammation and inflammatory cytokines could promote epithelial transition of tubular epithelial cells and fibroblast activation, and promote the progression of renal failure. Circulatory LPS can also activate vascular endothelial cells to release soluble TNF receptors and promote atherosclerosis [22– 24]. Continued inflammatory activation does not imply a stronger immunity to pathogens. In contrast, sustained immune activation induces immune tolerance, leading to a reduced immune response to pathogens and increased risk of severe infection in CKD patients. Therefore, the persistent chronic inflammatory state caused by intestinal barrier injury and intestinal flora migration is a factor for accelerated development of CKD; this calls for new therapeutic methods.

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SCFA, a Beneficial Product of Intestinal Flora

Short-chain fatty acids (SCFAs) are important products of intestinal flora and exert anti-inflammatory effects. The most abundant SCFAs are acetate, propionate and butyrate, produced by enteric bacterially mediated catabolism of dietary fiber. SCFAs are the preferred energy source for the colonic epithelium [25]. In addition, butyrate has been shown to promote reassembly of intestinal tight junction proteins and improve gut barrier function [26]. However, the abundance of SCFA-producing bacteria as well as serum levels of SCFA are significantly reduced in ESRD patients, and there is an inverse correlation between butyrate level and renal function [27]. It has been demonstrated that SCFA can exert anti-inflammatory effects through a variety of pathways. So far, researchers have suggested that SCFAs may operate in two manners: by binding G-protein membrane receptors (GPR41 and GPR43) to decrease cAMP production by inhibiting adenylate cyclase pathway, or by entering cells directly through transporter channels in the cellular membrane [28, 29] and working as histone deacetylase (HDAC) inhibitors to modulate epigenetic processes [30]. In acute renal injury, SCFA supplementation reduces cellular oxidative stress and promotes autophagy, thereby attenuating renal injury [31]. Gonzalez et al. reported that butyrate treatment increases AMPK phosphorylation in the intestines of 5/6th nephrectomy rats and promotes colonic mucin and tight junction protein expression to decrease LPS leakage and ameliorate inflammation [26]. In addition, SCFAs can act as a non-competitive inhibitor of histone deacetylases (HDACs) to modulate gene expression in immune cells and achieve immune tolerance [32]. Butyrate has been shown to inhibit histone deacetylases (HDACs) [33] and up-regulate FOXP3, which further promotes induction of peripheral Treg cells and reduction of inflammation [34]. Given the critical role of local and systemic inflammation in deterioration of CKD and arteriosclerosis, the anti-inflammatory effects of SCFAs are expected to delay the progression of CKD and reduce the risk of cardiovascular diseases in CKD patients.

7.5

Gut-Derived Uremic Toxins

CKD, especially ESRD, is characterized by the progressive accumulation of uremic toxins due to a decline in renal excretion. The precursors of uremic toxins are formed in the GI tract during protein fermentation by the microbiota [21]. Most uremic toxins are sulfidized or glycosylated and bound to albumin [35]. In a normally functioning kidney, the protein-bound solutes are removed through the active process of tubular secretion through the organic anion transport system. However, in patients receiving maintenance dialysis, dialysis does not adequately remove uremia toxins. As a result, the levels of these compounds in dialysis patients are extremely higher than those in normal people [36, 37].

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Among protein-bound solutes, indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are the most well studied (Fig. 7.1). Indole is generated by bacterial metabolism of tryptophan in the colon, which is further oxidized and sulfurized into IS in the liver. Gut flora can also convert tyrosine into 4-hydroxyphenylacetic acid, which is turned into p-methylphenol, mostly by decarboxylase of C. difficile; finally, p-methylphenol is converted into PCS [36, 37]. Serum levels of IS and PCS are reported to increase parallel to GFR declination. Their levels are in positive correlation with all-cause mortality and increased risk for cardiovascular events in CKD patients [38–40]. Mechanistically, IS can induce pro-inflammatory responses in endothelial cells through inducing oxidative stress and inhibiting their self-repairing processes [41, 42]. In vitro experiments showed that IS could induce NADPH oxidase and activate the MAPK/NF-jB pathway in vascular smooth muscle cells [43]. It has been reported that PCS stimulated endothelial microparticle release, a marker of endothelial damage. PCS could magnify oxidative stress in human vascular smooth muscle cells (HVSMCs) as well as in cardiomyocytes by up-regulating NADPH oxidase [44, 45]. In addition to vascular inflammation, IS and PCS are also involved in renal fibrosis processes. IS accelerates glomerular sclerosis and renal interstitial fibrosis by activating the RAS system and TGF-b/Smad3 pathway [46, 47]. PCS aggravates renal interstitial fibrosis by increasing inflammatory cytokine production and inducing epithelial to mesenchymal transition (EMT) of renal tubular epithelial cells. Watanabe et al. demonstrated that PCS promotes the production of reactive oxygen species (ROS) in renal tubular cells by enhancing NADPH oxidase activity, which further up-regulates the production of inflammatory cytokines and TGF-b1 [48]. Among the gut microbiota-produced metabolites, trimethylamine-N-oxide (TMAO) has entered the spotlight recently because of its tight connection with CVD [49–51]. A diet enriched in red meat, egg yolk, cheese or seafood contains high choline, lecithin, betaine and carnitine content. They can be metabolized by intestinal microbiota to produce trimethylamine (TMA), which in turn is oxidized to

Fig. 7.1 Crosstalk between kidney and gut microbiota

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TMAO by hepatic flavin-containing monooxygenases (FMOs) [52]. TMAO is predominantly excreted by the kidney, and its serum level therefore increases as eGFR declines. Concentrations of TMAO in dialysis patients are more than 5–10 fold higher than in non-dialysis CKD patients, and 30-fold higher than in healthy people. Accumulating clinical studies have demonstrated that elevated TMAO levels predict an increased risk of major adverse cardiovascular events in CKD patients [53]. A study of hemodialysis patients showed higher TMAO levels were associated with increased risks of cardiovascular events and all-cause death [54]. Seldin et al. found that TMAO could induce inflammatory marker expression in vascular endothelial cells, as well as activate mitogen-activated protein kinase (MAPK) and NF-jB signaling cascade [55]. Translocation of the NF-jB p65 subunit to the nucleus turns on the transcription of many target genes, such as inflammatory cytokines and the NLRP3 inflammasome [56, 57]. A previous study demonstrated that elevated TMAO levels portend poorer prognosis of kidney within non-CKD patients. Experiments in animal models showed that dietary choline or TMAO directly led to progressive renal tubulointerstitial fibrosis and dysfunction by up-regulating TGF-b production [58]. However, further mechanism studies are needed to determine how TMAO directly accelerates the progression of chronic kidney disease.

7.6

Modulations of Intestinal Flora Disorder in CKD/ ESRD

Since gut microbiota imbalance is associated with increased circulating levels of gut-derived uremic toxins, inflammation and oxidative stress, which are linked to cardiovascular disease and increased morbimortality of CKD patients, various nutritional strategies have been proposed to improve dysbiosis in CKD.

7.6.1

Dietary Interventions

The first approach is to optimize dietary components. Some research has focused on the use of dietary fibers. It has been shown that 56.4% of CKD patients had insufficient cellulose intake, and decreased soluble cellulose intake could lead to an increase in all-cause mortality in CKD patients [59]. Rossi et al. conducted a cohort study on CKD stage 4 and 5 patients, and found that the protein/cellulose ratio in patient diet was positively correlated with serum levels of IS and PCS [60]. Increasing the intake of soluble cellulose in diet is beneficial to the growth of Bacteroides, which promote the proliferation of glycolytic bacteria such as Bifidobacillus and Lactobacillus. The production of SCFAs by these bacteria can also play a beneficial role in reducing systemic inflammation [61]. Another animal

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study also showed that supplementation of fermentable dietary fibers could increase the expression of colonic tight junction proteins including ZO-1, occludin and claudin 7, as well as cecal SCFA concentration [62]. Therefore, in dietary guidance, CKD patients should be taught to eat coarse grains and cellulose-rich food in high-quality and low-protein diet. As mentioned above, TMAO mainly derives from the intestinal flora metabolites of red meat diet, and serum TMAO levels of CKD patients increase with the decline of renal function. Recent clinical studies revealed that TMA and TMAO production was substantially reduced in vegans/vegetarians [63]. Wang et al. demonstrated a significant correlation between serum TMAO level and red meat intake, and that discontinuation of dietary red meat reduced plasma TMAO within 4 weeks [63]. The PREDIMED study showed that a Mediterranean diet supplemented with extra-virgin olive oil or nuts could decrease the incidence of major cardiovascular events in a population at high cardiovascular risk [64]. Reducing the conversion of TMA to TMAO by inhibiting human FMO3 is not ideal, because direct FMO3 inhibition is usually accompanied by severe hepatic inflammation. Wang et al. treated mice with 3,3-dimethyl-1-butanol (DMB), an analog of choline, to feedback inhibit microbial TMA lyase, and thus raised a new approach to inhibit TMAO production [65].

7.6.2

Probiotics, Prebiotics and Synbiotics

Probiotics are defined as live microorganisms that maintain health and prevent disease of the host when administered in adequate amounts [66]. Bifidobacterium and Lactobacillus represent well-studied species that probably have some general benefits [67]. Several studies demonstrate that the administration of probiotics could significantly reduce the serum level of uremia toxins such as PCS, IS or dimethylamine nitrosamine in CKD patients [67–69]. In addition, probiotic supplementation could also decrease serum levels of endotoxin and pro-inflammatory cytokine IL-6 in peritoneal dialysis patients [70]. Mechanisms of the probiotics include competition with pathogenic bacteria for nutrients as well as inhibiting their adhesion, maintaining the integrity of the gut barrier, and modulation of immune response [70, 71]. Another group of microflora regulators are called prebiotics, mainly including inulin, fructooligosaccharides (FOS) and galactooligosaccharides (GOS), which are also found in some fruits, cereals, vegetables and in human milk [72]. Prebiotics serve as nutrients for microbial metabolism, which selectively promotes beneficial microorganisms [73]. Meijers et al. reported that prebiotic oligofructose inulin significantly reduced serum PCS concentrations in hemodialysis patients [74]. Several studies showed that, in animal models or CKD patients, a high amylose-resistant starch diet could increase amounts of Bifidobacteria and Lactobacillus, and decrease levels of PCS and IS [74]. Recently, an RCT study showed that supplementation of amylose-resistant starch, HAM-RS2, in CKD

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patients could increase the proportion of Faecalibacterium in the fecal microbiota of CKD patients, decrease serum urea, IL-6, TNFa and malondialdehyde, indicating an anti-inflammatory effect of prebiotic fibers on CKD patients [75]. However, the effect of probiotics or prebiotics alone on CKD patients remains controversial. A combination of prebiotics and probiotics called synbiotics is now considered necessary. The goal of this treatment is to selectively promote the growth of probiotic microorganisms. The combination of Bifidobacterium or Lactobacillus with fructooligosaccharides (FOS) has been commonly used in clinical studies [76]. Many studies report a decrease in serum levels of PCS, and some had amelioration of gastrointestinal symptom in hemodialysis or non-dialysis CKD patients [77, 78].

7.7

Therapeutic Drugs for Microbiota Regulation

At present, several drugs have been studied to correct dysbiosis-induced chronic inflammation by adsorbing intestinal toxins, promoting intestinal emptying or regulating TLR receptors. Phosphate binders are commonly used in ESRD patients. In addition to treating secondary hyperparathyroidism caused by hyperphosphatemia, several phosphate binders are believed to regulate intestinal flora of ESRD patients and promote the growth of probiotics. Ferric citrate complex is used as a dietary phosphate binder as well as an iron supplement. Lau et al. found that ferric citrate supplementation significantly changed gut microbiota in CKD patients, together with improved anemia, residual renal function and hypertension [79]. Sevelamer is an anion exchange resin with a backbone of multiple amines. Sevelamer has been reported to bind molecules such as LPS, indoles and phenols in vitro, as well as decrease serum levels of indoxyl sulfate and p-cresyl sulfate in hemodialysis patients [80]. In patients receiving peritoneal dialysis with type 2 diabetes mellitus, sevelamer treatment decreased serum PAI-1, CRP and IL-6 compared with the calcium carbonate treatment group [81]. Another randomized controlled trial showed that sevelamer treatment for 3 months significantly decreased serum levels of p-cresol in non-dialysis CKD patients [82]. As mentioned above, SCFAs are a product of intestinal flora with a protective effect on CVD events. Because sevelamer can also bind and remove SCFAs from the colon, the overall effect of this drug on intestinal flora remains to be explored. It should also be noted that sevelamer hydrochloride can lead to metabolic acidosis, so sevelamer carbonate is currently recommended [83]. AST-120 is a microsphere composed of porous carbon material, which can effectively absorb small molecules of intestinal toxins [84]. ESRD patients treated with AST-120 showed decreased levels of serum IS and PCS. An animal study confirmed that AST-120 not only directly absorbs toxins but also stabilizes the tight junction proteins of the intestinal epithelium, reduces endotoxin levels and relieves oxidative stress injury [85–87]. Some researches supported that AST-120 could ameliorates tubular injury in CKD patients by reducing proteinuria and oxidative

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stress generation, as well as effectively reducing the serum concentration of IS [88]. Adesso et al. revealed that AST-120 could decrease the inflammation and oxidative stress in the primary central nervous system induced by IS, and therefore ameliorates neurodegeneration in CKD patients [89]. AST-120 has been approved in several countries for improving uremia symptoms and delaying the initiation of dialysis in CKD patients. However, in a multinational RCT study, the EPPIC trials, AST-120 didn’t show significant advantages with regards to protecting residual renal function when compared to placebo in patients with moderate to severe CKD. Notably, the median durations of treatment for the EPPIC trials were 102.1 and 96.3 weeks, respectively, while the median time to primary end points in EPPIC-1 and EPPIC-2 were 189.0 and 170.3 weeks. Therefore, a longer observation period might be required to determine whether there is truly a significant difference between AST-120 and the placebo [90]. Intestinal flora disorders in CKD patients directly affect fecal formation and intestinal emptying, leading to increased absorption of harmful metabolites and accumulation of uremia toxins. Rubiprostone, a ClC-2 chloride channel agonist, can promote intestinal water secretion and fecal formation, and is used as laxative. Mishima et al. treated CKD rats with rubiprostone orally and found that fecal formation and intestinal emptying of these rats were improved, and renal interstitial fibrosis was decreased compared with the control group. They also found that rubiprostone could elevate the proportions of Lactobacillus and Prevotella in the intestinal flora, and decrease serum levels of IS and anti-aconitic acid [91].

7.8

Summary and Perspectives

There are significant changes in both the number and composition of intestinal flora in CKD patients. Proteins and other nitrogenous substances are metabolized by intestinal flora, generating toxic products, which become important components of uremic toxins in ESRD patients. Intestinal barrier dysfunction and increased permeability lead to increased amounts of toxins entering circulation to cause endotoxemia and aggravates systemic inflammation, which promotes renal function decline, insulin resistance, immune dysfunction, atherosclerosis and cardiovascular events in CKD patients [92]. Several clinical trials have proved that therapeutic approaches based on intestinal flora regulation, such as dietary guidance, and prebiotic and probiotic supplementation, could effectively delay CKD progression. Although significant challenges remain in terms of figuring out which patterns among the enormous diversity of microorganisms are linked to delayed progression of CKD, it is expected that microbiota modulation will become a promising therapeutic strategy in complement to traditional drugs and dialysis therapy for CKD patients.

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Acknowledgment This chapter was modified from a paper reported by our group in Journal of Clinical Nephrology (Lin Chuang Shen Zang Bing Za Zhi) (Zhang et al. 2016). The related contents are reused with permission.

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60. Rossi M, Johnson DW, Xu H et al (2015) Dietary protein-fiber ratio associates with circulating levels of indoxyl sulfate and p-cresyl sulfate in chronic kidney disease patients. Nutr Metab Cardiovasc Dis 25(9):860–865 61. Trompette A, Gollwitzer ES, Yadava K et al (2014) Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med 20(2):159–166 62. Hung TV, Suzuki T (2018) Dietary fermentable fibers attenuate chronic kidney disease in mice by protecting the intestinal barrier. J Nutr 148(4):552–561 63. Conlon MA, Bird AR (2014) The impact of diet and lifestyle on gut microbiota and human health. Nutrients 7(1):17–44 64. Stewart R (2018) Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts. N Engl J Med 379(14):1388 65. Wang Z, Roberts AB, Buffa JA et al (2015) Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 163(7):1585–1595 66. Hill C, Guarner F, Reid G et al (2014) Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol 11(8):506–514 67. Guarner F, Khan AG, Garisch J et al (2012) World Gastroenterology Organisation Global Guidelines: probiotics and prebiotics October 2011. J Clin Gastroenterol 46(6):468–481 68. Simenhoff ML, Dunn SR, Zollner GP et al (1996) Biomodulation of the toxic and nutritional effects of small bowel bacterial overgrowth in end-stage kidney disease using freeze-dried Lactobacillus acidophilus. Miner Electrolyte Metab 22(1–3):92–96 69. Guida B, Germano R, Trio R et al (2014) Effect of short-term synbiotic treatment on plasma p-cresol levels in patients with chronic renal failure: a randomized clinical trial. Nutr Metab Cardiovasc Dis 24(9):1043–1049 70. Wang IK, Wu YY, Yang YF et al (2015) The effect of probiotics on serum levels of cytokine and endotoxin in peritoneal dialysis patients: a randomised, double-blind, placebo-controlled trial. Benef Microbes 6(4):423–430 71. van Baarlen P, Troost F, van der Meer C et al (2011) Human mucosal in vivo transcriptome responses to three lactobacilli indicate how probiotics may modulate human cellular pathways. Proc Natl Acad Sci U S A 108(Suppl 1):4562–4569 72. Slavin J (2013) Fiber and prebiotics: mechanisms and health benefits. Nutrients 5(4):1417– 1435 73. Simpson HL, Campbell BJ (2015) Review article: dietary fibre-microbiota interactions. Aliment Pharmacol Ther 42(2):158–179 74. Meijers BK, De Preter V, Verbeke K, Vanrenterghem Y, Evenepoel P (2010) p-Cresyl sulfate serum concentrations in haemodialysis patients are reduced by the prebiotic oligofructose-enriched inulin. Nephrol Dial Transplant 25(1):219–224 75. Laffin MR, Tayebi KH, Park H et al (2019) Amylose resistant starch (HAM-RS2) supplementation increases the proportion of Faecalibacterium bacteria in end-stage renal disease patients: microbial analysis from a randomized placebo-controlled trial. Hemodial Int 23(3):343–347 76. Mafra D, Borges N, Alvarenga L et al (2019) Dietary components that may influence the disturbed gut microbiota in chronic kidney disease. Nutrients 11(3) 77. Nakabayashi I, Nakamura M, Kawakami K et al (2011) Effects of synbiotic treatment on serum level of p-cresol in haemodialysis patients: a preliminary study. Nephrol Dial Transplant 26(3):1094–1098 78. Cruz-Mora J, Martinez-Hernandez NE, Martin DCF et al (2014) Effects of a symbiotic on gut microbiota in Mexican patients with end-stage renal disease. J Ren Nutr 24(5):330–335 79. Lau WL, Vaziri ND, Nunes A et al (2018) The phosphate binder ferric citrate alters the gut microbiome in rats with chronic kidney disease. J Pharmacol Exp Ther 367(3):452–460 80. Lin CJ, Pan CF, Chuang CK et al (2017) Effects of sevelamer hydrochloride on uremic toxins serum indoxyl sulfate and P-cresyl sulfate in hemodialysis patients. J Clin Med Res 9(9):765– 770

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Chapter 8

Gut Microbiota and Heart, Vascular Injury Cheng Zeng and Hongmei Tan

Abstract The gut microbiota plays an important role in maintaining human health. Accumulating evidence has indicated an intimate relationship between gut microbiota and cardiovascular diseases (CVD) which has become the leading cause of death worldwide. The alteration of gut microbial composition (gut dysbiosis) has been proven to contribute to atherosclerosis, the basic pathological process of CVD. In addition, the metabolites of gut microbiota have been found to be closely related to the development of CVD. For example, short-chain fatty acids are widely acclaimed beneficial effect against CVD, whereas trimethylamine-N-oxide is considered as a contributing factor in the development of CVD. In this chapter, we mainly discuss the gut microbial metabolite-involved mechanisms of CVD focusing on atherosclerosis, hypertension, diabetes, obesity, and heart failure. Targeting gut microbiota and related metabolites are novel and promising strategies for the treatment of CVD.







Keywords Gut microbiota Gut microbial metabolites Cardiovascular diseases Atherosclerosis Hypertension Diabetes mellitus Obesity




8.1










Introduction

The human gut hosts a vast number of commensal microorganisms including bacteria, viruses, protozoa, achaea, and fungi. The complexity of this ecosystem is still far from being completely understood and analyzed, although important steps have been made in this direction. It is estimated that the cumulative genome of all these microorganisms consists of up to 100 trillion microbes and contains more than 150 times as many genes as the whole human genome [1]. Gut microbiota is dominated by two bacterial phyla, Bacteroidetes or Firmicutes, which constitute C. Zeng
H. Tan (&) Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 P. Chen (ed.), Gut Microbiota and Pathogenesis of Organ Injury, Advances in Experimental Medicine and Biology 1238, https://doi.org/10.1007/978-981-15-2385-4_8

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>90% of the taxa present in the human gut, and to a lesser extent by Actinobacteria, Cyanobacteria, Fusobacteria, Proteobacteria, and Verrucomicrobia [2], and these constantly adapt to lifestyle modifications [3]. Microorganisms benefit from a constant supply of human substrates. The human hosts benefit from microbial activities such as host metabolism, neurological development, energy homeostasis, instructing immune cell differentiation [4], vitamin synthesis, and digestion of carbohydrates as well as production of signaling molecules including short-chain fatty acids (SCFAs), bile acids (BAs), and so on [5]. The microbiota is capable of secreting or altering the production of molecules that affect host physiology and the microbial composition [6]. The homeostasis of gut microbiota is critical for maintaining human health. Over the past decade, studies have demonstrated that composition and extent of alterations of the gut microbiota (so-called “dysbiosis”) contributed to pathogenesis of various diseases including cardiovascular disease and cancers [7, 8]. Cardiovascular disease (CVD) is still the most common cause of death causing almost two times as many deaths as cancer across the worldwide [9]. In addition to genetic factors, other environmental factors such as nutrition and gut microbiota have also been recognized as the main contributor for developing CVD. Moreover, gut dysbiosis has been implicated as a risk factor for the development of diabetes and obesity, two major risk factors for CVD [10, 11]. Mountains of studies demonstrated that the gut microbiota affects the host via various distinct pathways, such as production of gut microbial metabolites. In this review, we discussed the roles of gut microbiota implicated in the development of CVD, mainly focusing on atherosclerosis, hypertension and the associated metabolic diseases, diabetes, and obesity. We further systematically overview the interplay between gut microbial metabolites and CVD, and summarize the recent advances of gut microbiota-targeted therapies for CVD.

8.2

The Interaction Between Host Metabolism and Gut Microbial Metabolites

Microbial metabolites are indispensable for the majority of the biological effects of the gut microbiota. Under physiological conditions, indigestible carbohydrates (for example, dietary fiber) and peptides/proteins can be actively fermented by commensal microbiota in the intestine. Gut microbiome metabolites that are associated with the onset of CVD include trimethylamine-N-oxide (TMAO), BAs, SCFAs, B vitamins, protocatechuic acid (PCA), 4-ethyl phenol sulfate (4-EPS), D-glycerob-D-manno-heptose-1,7-biphosphate (HBP), and other metabolites, such as phenylacetylglutamine, p-cresyl sulfate, indoxyl sulfate (IS), enterolactone, and hydrogen sulfide (H2S). Among these metabolites, TMAO, BAs, SCFAs, and H2S have been well studied in CVD.

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TMAO

Intestinal microbiota cleave trimethylamine containing compounds to produce trimethylamine (TMA), which is translocated to liver, oxidized by flavin monooxygenase 3 (FMO3) and further metabolized to TMAO. The precursors for gut microbiota to produce TMA include TMAO, choline, phosphatidylcholine, carnitine, c-butyrobetaine, betaine, crotonobetaine, and glycerophosphocholine, all of which are rich in red meat and fat [12, 13].

8.2.2

BAs

Primary BAs synthesized from cholesterol in the liver are chenodeoxycholic acid (CDCA) and cholic acid (CA) which may be conjugated with glycine or taurine, stored, and concentrated in gallbladder. The primary bile acids are produced in the liver via two pathways: the classical and the alternative pathway (80% vs. 20% of the bile acid pool). The classical pathway generates primary bile acids CDCA and CA, while the alternative pathway mainly generates CDCA; 12a-hydroxylase (CYP8B1) determined the ratio between them. The CYP7A1 gene encodes the enzyme cholesterol 7a-hydroxylase, which is the first and rate-limiting enzyme in the classical pathway of total bile-acid synthesis [14]. In rodents, there are additional primary bile acids UDCA and a/b-MCA. CDCA and UDCA are 6b-hydroxylated to product a- and b-MCAs by cytochrome P450 2C70 (CYP2C70) [15]. Primary BAs are metabolized by the gut microbiota-mediated deconjugation, dehydroxylation, dehydrogenation, and epimerization into secondary BAs, which are stored in the gallbladder and released into the duodenum to digest and enhance absorption of triglycerides, cholesterol, and lipid-soluble vitamins [16]. Secondary BAs include deoxycholic acid (DCA), hyocholic acid (HCA), hyodeoxycholic acid (HDCA), lithocholic acid (LCA), x-muricholic acid (xMCA), and murideoxycholic acid (MDCA) [15]. In the ileum, these bile acids are then reabsorbed and carried in the portal blood to the liver. This process is called enterohepatic circulation which preserves about 95% of the bile acid pool [17].

8.2.3

SCFAs

Dietary fibers, proteins and peptides which escape digestion by host enzymes in the upper gut, are metabolized by the microbiota in the cecum and colon [18] to produce three major SCFAs: acetic acid, propionic acid, and butyric acid; and two less abundant valeric acid and hexanoic acid [19]. The proposed biosynthesis of SCFAs in bacteria is from glycolysis of glucose to pyruvate, then to acetylcoA, and eventually to acetic acid, propionic acid, and butyric acid. These SCFAs either are

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used locally as fuel for colonic mucosal epithelial cells or enter the portal bloodstream to affect host health. Among the three major SCFAs, acetic acid, the most abundant SCFA in the colon comprising more than half of the total SCFA, can be generated by carbohydrate fermentation. Interestingly, major acetate-producing bacteria include Streptococcus spp., Prevotella spp., Clostridium spp. and Bifidobacterium spp., A. muciniphila, etc. [20]. The main propionate-producing bacteria are Bacteroides spp., Salmonella spp., Dialister spp., Veillonella spp., Roseburia inulinivorans, Coprococcus Catus, Blautia obeum, and so on [21]. And the main butyric acid-producing bacteria refer to Lachnospiraceae, Ruminococcaceae, and Acidaminococcaceae families [22]. More interestingly, dietary fiber can selectively increase abundance of SCFA-producing bacteria [23].

8.2.4

H2S

H2S is a colorless, flammable, water-soluble gas with the characteristic smell of rotten eggs [24]. Until recently, H2S is mostly associated with its toxic effects. However, research conducted over the last decade revealed that H2S serves biological signaling and function in numerous biological systems. Gut microbiota metabolizes carbohydrates, proteins, fat, and many other compounds from food uptake to produce H2S. Sulfate-reducing bacteria are the main H2S-generating bacteria that are widely distributed in mammalian colon [25]. The major genera for H2S production are Desulfovibrio, Desulfobacter, Desulfobulbus, and Desulfotomaculum [25]. These sulfate-reducing gut bacteria transfer a sulfate and an electron donor for the sulfate reduction to generate H2S. Therefore, a sulfate-rich diet may result in H2S production in the gut of humans and mice. Second source is an enzymatic reaction performed by either gut bacteria or colonic tissues. Several anaerobic bacterial strains Escherichia coli, Salmonella enterica, Clostridia, and Enterobacter aerogenes could catalyze cysteine to produce H2S by cysteine desulfhydrase. Moreover, sulfite reductase presented in some bacterial strains was also involved in generation of H2S. Finally, H2S is synthesized by mammalian tissues via cystathionine beta-synthase (CBS), cystathionine gamma-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST) responsible for metabolism of L-cysteine [25]. CSE seems to be a major source of the gut H2S generation [26].

8.3

Gut Microbiota and Atherosclerosis

Atherosclerosis is the main pathological basis for CVD, which is characterized by accumulation of cholesterol and recruitment of macrophages into artery walls and the consequent formation of atherosclerotic plaques. Emerging evidence has suggested an important role of gut microbiota in the progression of atherosclerosis [27]. By using shotgun sequencing of the gut metagenome in patients with or without

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symptomatic atherosclerosis, researchers have found that relative abundance of the genus Collinsella was higher in patients with symptomatic atherosclerosis, defined as stenotic atherosclerotic plaques in the carotid artery, leading to cerebrovascular disorders. In contrast, Roseburia and Eubacterium were enriched in healthy controls [28]. Moreover, Akkermansia muciniphila, a mucin-degrading bacterium belonging to a genus of Verrucomicrobia, has recently emerged as an important component of the gut microbial ecosystem and reversed western diet-induced increases in gut permeability to exert protective effects against atherosclerosis [29]. More importantly, bacterial DNA has been detected in atherosclerotic plaques, and the pyrosequencing result, suggesting that the bacteria in lesions may be derived from the gut and oral cavity that might thus serve as reservoirs of these potentially pathogenic microorganisms. On the other hand, germ-free (GF) conditions accelerated the atherosclerosis in ApoE−/− mice-fed standard low-cholesterol diet [30], and antibiotic therapy aimed at killing the gut bacteria also had no beneficial effect on cardiovascular events in human trials [31]. Thus, it is possible that modulation rather than clearance of the gut microbiota is a promising therapeutic strategy for atherosclerosis.

8.3.1

Gut Dysbiosis and Atherosclerosis

A large body of evidence suggests that infectious agents may contribute to atherosclerotic processes. This could occur by a direct infection of vessel wall cells and/or a distant infection by induction of cytokine and acute phase reactant proteins by infection at other sites. This notion is supported by evidence that bacterial DNA has been detected in atherosclerotic plaques. The pyrosequencing result revealed that the bacteria in lesions were predominantly derived from gut and oral cavity. A clinical study demonstrated that patients with symptomatic atherosclerosis (myocardial infarction or stroke) had a higher abundance of Anaeroglobus compared with healthy controls in the oral cavity. Several oral bacteria, including Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, have also been reported to be a pathogenic bacterium as increased lesions were observed in ApoE−/− and apolipoprotein E-deficient spontaneously hyperlipidemic (Apoe(shl)) mice by oral or intravenous infection [32, 33]. These results implicated that bacteria from the oral cavity might translocate to the vessel, where they might induce rupture of the atherosclerotic plaque. The gut is another source of microorganisms that could influence the development of atherosclerosis. Gut dysbiosis increased intestinal permeability by inhibiting the expression of tight junction proteins and subsequently resulted in the translocation of LPS, disposition of gut microbiota, into the blood [34]. LPS, as part of the outer membrane of Gram-negative bacteria, could recruit adaptor proteins such as myeloid differentiation of primary response protein MYD88 to the cytoplasmic domain of TLRs which further activated downstream signaling and resulted in production of proinflammatory cytokines and chemokines [35]. As such, LPS

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induces low-grade inflammation and promotes the progression of atherosclerosis [36]. In contrast, gavage with live Bacteroides vulgatus and Bacteroides dorei inhibited atherosclerotic plague formation in atherosclerosis-prone mice by strengthening tight junction formation and decreasing gut microbial LPS production [37], suggesting a novel therapeutic strategy for atherosclerosis by decreasing gut microbiota-derived LPS.

8.3.2

BAs and Atherosclerosis

BAs, as signaling molecules, not only regulate their own biosynthesis but also affect metabolic pathways involved in lipoprotein, glucose, drug, and energy metabolism by activation of nuclear receptors [38, 39] (Fig. 8.1). BA receptor, also known as farnesoid X receptor (FXR), is a dedicated nuclear receptor for bile acids. In liver, activation of FXR mediated triglyceride metabolism involving the production of VLDL and de novo lipogenesis and has also regulated steatosis and obesity in the small intestine [40].

Secondary BAs

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Fig. 8.1 BAs and possible molecular pathways linked to CVD. Gut bacteria are important in modifying BAs, which function as signaling molecules through the FXR, PXR, and TGR5. Activation of FXR and PXR not only promotes eNOS expression which induces NO release in endothelial cells but also regulates BAs and lipid metabolism in hepatic cells. In addition, TGR5 activation induces NO production via Akt activation and [Ca2+] increases in endothelial cells while inhibits inflammatory response via cAMP-mediated NF-jB inhibition in leukocytes

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However, conflicting data exist on the role of FXR on atherosclerosis progression. Compared with wild-type, FXR-deficient mice exhibit reduced expression of hepatic genes involved in reverse cholesterol transport (most notably for scavenger receptor B1), which lead to markedly reduction in plasma high-density lipoprotein (HDL) cholesterol ester clearance and profound hypercholesterolemia, suggesting that FXR is a critical regulator of cholesterol metabolism [41]. Conversely, activation of FXR reduced atherosclerotic plaque formation in apolipoprotein E (ApoE) or low-density lipoprotein receptor (LDLR)-deficient mice [42–44], while FXR knockout resulted in worse plasma lipid profile and larger atherosclerotic lesions in ApoE−/− mice [45]. These results suggest that FXR has protective role on atherosclerosis progression. In contrast, Guo and Zhang et al. reported that the FXR knockout decreased atherosclerotic lesion area in the aorta in ApoE−/− or LDLR−/− mice [46, 47], which suggests a nonprotective role for FXR. Therefore, the role of FXR on atherosclerosis need to be further understood in vivo and in vitro. The dysfunction of aortic vascular smooth muscle cells (VSMCs) and endothelial cells has been reported to promote plaque formation in atherosclerosis by inducing inflammatory response. Bacteria have the potential to directly regulate bile acid signaling in vasculature as VSMCs and endothelial cells also expressed FXR [47, 48]. Activation of FXR in VSMCs was shown to inhibit the inflammatory response and the migration of VSMCs. However, the role of endothelial-specific FXR on atherosclerosis progression seems to be controversial. A study in rabbits showed that FXR activation impaired endothelium-dependent relaxation due to a reduced sensitivity of smooth muscle to nitric oxide (NO) [49]. However, GW4064, an agonist of FXR, increased eNOS mRNA and protein expression and NO production in isolated endothelial cell, which induces vasodilatation [50]. Given that the role of microbial regulation of BAs and FXR in atherogenesis is not fully understood, additional investigation is warranted. Furthermore, most current data are based on animal models which may limit the translation ability to human subjects. G protein-coupled bile acid receptor 1 (GPBAR1; TGR5), another BA receptor, is responsive to BAs. Recent study has indicated that activation of TGR5 inhibited atherosclerosis, decreased intraplaque inflammation, and reduced plaque macrophage content which is a consequence of TGR5-induced cAMP signaling activation and the subsequent inhibition of NF-jB in macrophages [51]. In addition, taurolithocholic acid has a high affinity to TGR5 which significantly increased NO production and reduced inflammatory responses via activation of intracellular Akt and Ca2+ signaling in human umbilical vein endothelial cells [52]. Furthermore, pregnane X receptor (PXR) was also activated by BAs [53] and has been shown to accelerate development of atherosclerosis in PXR and ApoE double knockout mice [54]. This pro-atherosclerosis role of PXR attributes to the increase in CD36 expression and lipid uptake of macrophages [54] as well as the higher levels of atherogenic lipoproteins VLDL and LDL [55].

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TMA/TMAO and Atherosclerosis

Clinical studies indicated that TMAO level was associated with increased carotid intima-media thickness, risk of cardiovascular events, poor prognosis, death independent of traditional cardiac risk factors, lipid parameters, C-reactive protein, and even renal function [56]. In line with role of TMAO in CVD, circulating choline, betaine, and carnitine levels also have been shown associated with prevalence of CVD and can predict incident risk for major adverse cardiac events [13]. Zhu et al. showed that gut microbe-generating TMAO also directly contributes to platelet hyperreactivity, which is associated with cardiometabolic diseases and enhanced potential for thrombotic events [57]. In an animal study, dietary supplementation of mice with choline or TMAO promoted atherosclerosis formation, which was reduced by short-term broad-spectrum antibiotic, and in germ-free mice [58]. These findings suggest that circulating levels of microbiota-producing TMAO are important risk factors for the pathogenesis of CVD. Reversely, silencing of TMAO-producing enzyme FMO3 decreased circulating TMAO levels and attenuated atherosclerosis through enhancing basal metabolism and activating macrophage reverse cholesterol transport [59, 60]. It is reported that resveratrol, a natural phytoalexin, could attenuate TMAO-induced atherosclerosis by remodeling microbiota in ApoE−/− mice [58]. Moreover, a structural analog of choline, 3,3-dimethyl-1-butanol (DMB), and probiotic strains Lactobacillus plantarum ZDY04 are reported to inhibit TMAO production, and thus suppress atherosclerotic lesion development in mice fed a high-choline or L-carnitine diet [61, 62]. These studies indicated that pharmacological elimination or reduction of plasma TMAO is a potential therapeutic approach to reduce atherosclerotic cardiovascular events. Given the significant roles of TMAO-promoting CVD, a number of studies have been attempted to determine the underlying mechanisms (Fig. 8.2). Increasing intake of a TMAO precursor, choline, also accelerated the development of atherosclerosis. In choline-fed ApoE−/− mice, aortic macrophage number and positive scavenger receptor CD36 area as well as foam cell formation within aortic lesions were markedly increased, but not when intestinal microflora and TMAO production were suppressed by antibiotic treatment [8]. These results further support that gut microbial-generated TMAO accelerates atherosclerosis via inducing foam cell formation. However, in vitro study showed that different concentrations of TMAO treatment had no effect on acetylated LDL cholesterol loading or cholesterol efflux, and thus did not impact foam cell formation [63]. Therefore, the effect of gut microbial-producing TMAO on foam cell formation needs to be further investigated. TMAO can also contribute to atherosclerosis by inhibiting reverse cholesterol transport [12]. This mechanism may refer to changes in activity of cholesterol transporters in macrophages [12]. In addition, mRNA levels of key enzymes involved in BAs synthesis and transport in liver tissues were significantly reduced in mice supplemented with dietary TMAO [12], indicating that the pro-atherosclerotic role of TMAO is also associated with the alterations in BAs metabolism. TMAO was also shown to induce several atherosclerosis-promoting

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inflammatory responses in primary human aortic endothelial cells and vascular smooth muscle cells through activation of NF-jB or TXNIP/NLRP3 inflammasome [64–66]. These findings suggested that TMAO promoted inflammation-mediated atherosclerosis by inducing endothelial and monocyte dysfunction. Additionally, TMAO also increased stimulus-dependent platelet activation via inducing Ca2+ releases, resulting in the increased risks of thrombosis and plaque instability [57]. Although a number of studies have demonstrated an association between plasma levels of choline, TMAO, and atherosclerosis, the available data are still inconsistent. For example, increased TMAO level in circulation due to L-carnitine administration was surprisingly negatively correlated with aortic lesion size in ApoE−/− mice expressing human cholesteryl ester transfer protein [63]. Similarly, data show that digestion of dietary choline and betaine, as primary sources of TMAO, was not related with the progression of CVD [67, 68]. Therefore, the pro-atherosclerotic effects of TMAO as well as the validation of its therapeutic potential by targeting TMAO-producing bacteria or enzymes need to be further investigated in both animal and human models.

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Foam cell formation Fig. 8.2 TMAO and possible molecular pathways linked to CVD. Direct provision of TMA within the diet is phosphatidylcholine, choline, and L-carnitine. Activation of FXR induces FMO3 in the liver; this enzyme converts TMA to TMAO. TMAO induces foam cell formation via CD36 and suppresses reversed cholesterol transport by modulating the activity of cholesterol transporters in macrophages

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Gut Microbiota and Hypertension

Hypertension has been documented as the most important single risk factor for CVD [69]. Hypertension is associated with both genetic susceptibility and environmental factors. However, the precise cause of hypertension has not been elucidated to date [70]. As the role of gut microbiota in pathophysiology of a variety of disorders has been gradually recognized, many studies paid more attention to investigating relationships between gut microbiota and hypertension. It has been revealed that the germ-free (GF) mice, in which the intestinal bacteria are completely absent, showed relatively lower blood pressure (BP) compared to conventionally raised (CONVR) mice [71]. In addition, investigators have demonstrated that probiotics treatment can improve BP by meta-analyses in human clinical trials [72]. Especially, a recent study based on metagenomic analyses of the fecal samples of 41 healthy controls, 56 human subjects with pre-hypertension, and 99 patients with primary hypertension revealed a novel causal role of aberrant gut microbiota in contributing to the pathogenesis of hypertension. Elevated BP was observed to be transferrable through fecal transplantation from hypertensive human donors to germ-free mice, pointing out the significance of gut microbiota in pre-hypertension [73]. Further studies revealed that overgrowth of bacteria such as Prevotella, Klebsiella, and Streptococcus were abundantly distributed in hypertensive patients compared to healthy controls [73, 74]. In both spontaneously hypertensive rats and the chronic angiotensin II (AngII) infusion rat model, Yang et al. observed a significant decrease in microbial richness and diversity, while an increase in the ratio of Firmicutes/Bacteroidetes compared with controls [75]. Likewise, in AngII-induced hypertensive rats, compared with CONVR mice, GF mice have attenuated the BP increase and inhibited vascular dysfunction. Besides, transplant of dysbiotic cecal contents from obstructive sleep apnea (OSA)-induced hypertensive rats on high-fat diet into OSA recipient rats on normal chow diet resulted in hypertension [76]. These results may implicate a causal relationship between gut microbiota and hypertension, and suggest that manipulation of the microbiota may be a viable treatment for hypertension although the underlying mechanism needs to be further characterized.

8.4.1

SCFAs and Hypertension

A previous study of human populations living in China, Japan, and United Kingdom showed a direct association between urinary formate, a SCFA generated by microbial fermentation of dietary polysaccharides, and BP [77]. Moreover, by investigating the gut microbial composition of 60 hypertensive patients and 60 healthy controls, Yan et al. observed that F. prausnitzii and Roseburia (both R. intestinalis and R. hominis), as major SCFA producers in human colon, were abundantly distributed in healthy controls compared to hypertensive patients [74].

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A recent study found that high-fiber diet and acetate supplementation significantly decreased diastolic BP, cardiac fibrosis, and left ventricular hypertrophy compared with mineralocorticoid-excess mice fed a control diet [78]. These data demonstrated that gut microbiota-producing SCFAs in circulation played important role in hypertension. Fiber fermentation by gut microbiota generates SCFAs that are either absorbed by the gut or excreted in feces. In a study of 441 community-dwelling adults, investigators found that higher SCFA excretion was associated with evidence of gut dysbiosis and excess adiposity, and cardiometabolic risk factors [79]. These studies revealed that cardiometabolic dysregulation is due to less efficient SCFA absorption. The G protein-coupled receptors (GPCRs) pathways play a major role in SCFAs absorption and have been well documented to be associated with the progression of hypertension. At least four GPCRs including GPR41, GPR43, GPR109A, and Olfactory receptor 78 (Olfr78) have been reported to be regulated by SCFA [80]. Except GPR41 and Olfr78, other receptors in response to signals generated via gut microbes have not been characterized in hypertension [80]. Propionate produced an acute hypotensive response in mice through disruption of Olfr78 and GPR41 expression [81]. Interestingly, GPR41 contributed to the hypotensive effects of propionate, whereas Olfr78-mediated renin release to raise BP and to antagonize the hypotensive effects of propionate [81]. The fact that these receptors showed their apparently opposing effects on BP in response to SCFA stimulation indicated that the net effects of SCFAs may be complex as multiple pathways are involved in the mediation of SCFA signaling. Nevertheless, these findings revealed that SCFAs exert multiple beneficial effects on cardiovascular diseases (Fig. 8.3).

Fig. 8.3 SCFAs and possible molecular pathways linked to CVD. The dietary fiber is metabolized to SCFAs, such as acetate, butyrate, and propionate. These SCFAs activate GPR41 and Olfr78, and then inhibits CVD by decreasing blood pressure or stimulating hormone PYY and GLP-1 release

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H2S and Hypertension

H2S modulates a variety of physiological processes including cell protection, blood vessel relaxation, angiogenesis, lowing of BP, and heart rate [82, 83]. Investigators found that the H2S donor increased portal blood levels of thiosulfate and sulfane sulfur, and decreased mean arterial blood pressure (MABP) in a dose-dependent manner in spontaneously hypertensive rats, which lasted much longer than 90 min, and action could be inhibited by an antibiotic, neomycin [84]. This study implicated that gut-producing H2S may contribute to the control of BP and may be one of the links between gut microbiota and hypertension. Although the number of studies has reported that H2S has capacity to improve hypertension by multiple mechanisms including suppression of oxidative stress (OS) or inflammation, interaction with NO and CO, and ion channel-mediated relaxation of vascular smooth muscle [85], there are no direct evidence revealing that the H2S derived from gut microtia influences hypertension.

8.5

Gut Microbiota and Diabetes

Diabetes mellitus (DM) is a group of chronic diseases characterized by hyperglycemia and major risk factor for the development of CVD with a higher incidence of myocardial infarction in patients with DM than those without [86]. One of the injuries arising from diabetes is injury to vasculature, which is classified as either small vascular injury (microvascular disease) or injury to the large blood vessels of the body (macrovascular disease). Diabetic retinopathy may be the most common microvascular complication of diabetes. Among the diabetic patients, aerobic bacterial conjunctival flora were detected more frequently in those with diabetic retinopathy compared to those without retinopathy [87]. Further study demonstrated that predominant conjunctival organisms in type 2 diabetes (T2D) patients were Staphylococcus epidermidis and Staphylococcus aureus [88]. These works suggest that microbiota dysbiosis was associated with diabetic retinopathy. Recently, Beli et al. reported that intermittent fasting prevents diabetic retinopathy by restructuring the gut microbiota toward species producing tauroursodeoxycholic acid and subsequent retinal protection by TGR5 activation [89]. Although this study suggests that gut-derived microbiota was associated with progression of diabetic retinopathy in mice, more evidences that gut microbiota contributed to diabetic retinopathy need to be provided. Recently, studies revealed the gut microbiota functions as an important environmental factor in the development of diabetes including type 1 diabetes (T1D) and T2D. T2D is characterized by either insufficient production of insulin required to maintain normoglycemia in the face of insulin resistance or an inability of the body to utilize insulin produced. In 2010, Larsen et al. reported that the ratios of Bacteroidetes to Firmicutes as well as the ratios of Bacteroides-Prevotella group to

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C. coccoides-E. rectale group correlated positively and significantly with plasma glucose concentration in patients with T2D [90]. In addition, by analyzing the gut microbial DNA from 345 Chinese individuals by metagenome-wide association study (MGWAS) and a two-stage MGWAS based on deep shotgun sequencing, researchers found that patients with T2D were characterized as a decrease in the abundance of some universal butyrate-producing bacteria (Clostridiales sp. SS3/4, Eubacterium rectale, Faecalibacterium prausnitzii, etc.) and an increase in various opportunistic pathogens, as well as an enrichment of other microbial functions conferring sulfate reduction and oxidative stress resistance, further emphasizing that changes of gut microbiotas might be useful markers for classifying T2D [91]. Therapy of treatment-naïve T2D with metformin was recently found to alter the gut microbiome, which contributed to the therapeutic effects of this drug [92]. Moreover, researchers used shotgun sequencing to identify the fecal metagenome of 145 European women with normal, impaired, or diabetic glucose control and revealed that the abundances of four Lactobacillus species was higher, while five Clostridium species were lower in gut of T2D patient individuals compared to healthy controls [93]. In an cohort of Japanese T2D patients, the counts of Clostridium coccoides, Atopobium, and Prevotella were significantly reduced, while total Lactobacillus were increased in fecal samples of diabetic patients [94]. In addition to fecal samples, this study further revealed that gut bacteria were also detected in blood with significantly higher rate in diabetic patients than in control subjects, and most of these bacteria were Gram-positive [94]. Although T1D is an autoimmune disease that targets pancreatic islet beta cells, epigenetic and environmental factors have been shown to play an important role in this disease [95]. Patients with T1D showed a less diverse and less stable gut microbiome compared to healthy controls and gut dysbiosis have been observed in the patients [96, 97]. Abundance of butyrate-producing bacterium was decreased in children with T1D [98]. These evidences show that gut microbiota plays a significant role in the development for diabetes and also hinted that gut microbiota was related to complications of diabetes. More experiments need to be conducted whether gut microbiota contributes to microvascular and macrovascular complications of diabetes such as diabetic cardiomyopathy.

8.5.1

BAs and Diabetes

Over the past decades, a few studies have described alterations of the bile acid pool in T2D patients and animal models. One study showed an increased BA pool size in patients with uncontrolled T2D [99]. Subsequent studies demonstrated that the pool of the secondary bile acid DCA was elevated, whereas the CDCA pool decreased [100]. In addition, upregulation of BAs pool size by CYP7A1 overexpression improved insulin resistance and hepatic steatosis in high-fat-diet (HFD)-induced obesity mice [101]. These results indicate that modulation of BAs pools might be a potential therapeutic strategy for treating metabolic disorders.

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Indeed, BA sequestrants have been used in the treatment of T2D patients. In patients not adequately controlled by common antidiabetic therapeutics, the administration of colesevelam, a BA sequestrant, increased BA synthesis, particularly of CA, and decreased plasma glucose and hemoglobin by 0.7% in diabetics [102]. Schwartz et al. demonstrated that BA sequestrant may improve glucose control by improving whole-body insulin sensitivity in T2D patients [103]. Similar effect of BA sequestrant was confirmed in diet-induced obese mice [104]. In addition, Shang et al. reported that colesevelam induced the release of GLP-1 and thus improved insulin release in a diet-induced obesity rat model [105]. In addition to BA sequestrant, treatment with the semisynthetic BA derivative obeticholic acid (OCA), a high-affinity ligand of FXR, was able to improve insulin sensitivity in patients with nonalcoholic steatohepatitis (NASH) and T2D [106]. However, a multicentre, double-blind, randomized, placebo-controlled, phase IIIa study with OCA (FLINT) in 283 patients with NASH, with and without T2D, showed that insulin sensitivity and lipid profiles were deteriorated [107]. Therefore, the definite role of BAs in diabetes needs to be further investigated in clinical trials. A recent study further found that higher plasma bile acid levels improved glucose tolerance and high cholesterol levels after ileal interposition surgery in diet-induced obese rats [108]. Similar results that increased plasma bile acid levels were inversely correlated with 2-h post-meal glucose, and peak glucagon-like peptide-1 (GLP-1) was observed in patients after gastric bypass surgery [109].

8.5.2

SCFAs and Diabetes

In The Environmental Determinants of Diabetes in the Young (TEDDY) study, by analyzing microbiomes in children who were from 3 months to up to 5 years of age, the expression of microbial genes involved in the biosynthesis of SCFAs was lower in children who developed T1D than in those who did not [110]. In addition to T1D, Zhao et al. reported that giving high-fiber diets to patients with T2D for 12 weeks significantly increased acetate- and butyrate-producing microbial subpopulations and decreased hemoglobin A1c levels and improved glucose tolerance [23]. Sanna et al. further expanded this field by using bidirectional mendelian randomization (MR) analyses to assess causality, that is, the relationship between host genetics on microbial expression of SCFAs in the gut and its subsequent impact on glycemic indices. They found that host-genetic-driven increase in gut production of the SCFA butyrate was associated with improved insulin response by an oral glucose tolerance test, whereas abnormalities in the production or absorption of another SCFA, propionate, were causally related to an increased risk of T2D [111]. These works together indicated that gut microbiota-producing SCFAs are related closely with progression of diabetes. The ability to secrete insulin depends on the functioning and mass of pancreatic b-cells. SCFA receptors GPR41 and GPR43 were expressed in pancreatic b-cells of mice and humans [112, 113]. GPR43-knockout mice shown a marginally

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significant defect in insulin secretion during hyperglycemic clamps [114], demonstrating that SCFAs increase glucose-stimulated insulin secretion via GPR43. Consistent with this finding, GPR43 knockout was related with b-cell dysfunction and increased b-cell mass in obesity mice [112]. Moreover, SCFA-activated GPR41 signaling have the capacity to mediating pancreatic b cell insulin secretion in fed and fasting states, as GPR41 knockout or overexpression in mice resulted in impairments in glucose control [113]. In a human study, inulin-propionate ester delivered in colon was associated with improved b-cell function that was independent of changes in GLP-1 levels [115]. Further in vitro study showed propionate promoted glucose-stimulated insulin secretion and maintained b cell mass by inhibiting cell apoptosis [115]. These results all revealed that SCFAs-GPR signaling has important role on regulation of insulin secretion and blood glucose homeostasis. With respect to glucose metabolism, SCFAs suppress appetite by increasing the release of satiety hormones and stimulating vagal afferent chemoreceptors, increasing energy expenditure by upregulating thermogenesisrelated proteins in the liver and adipose tissue [1]. Given that SFCAs were produced from the fermentation of these indigestible carbohydrates such as fiber, a diet strategy was to enhance the dietary fiber to colonic microorganisms for preventing and improving metabolic disorders including diabetes [23].

8.5.3

H2S and Diabetes

H2S is a major product of protein fermentation via gut microbiota. The potential role of H2S in the pathogenesis of diabetes was somewhat conflicted. Study in vitro from Yang and colleagues has demonstrated that H2S treatment led to apoptosis in rat insulinoma INS-1E cells, while pharmacological inhibition of CSE, a key enzyme of H2S production, prevents streptozotocin-induced INS-1E cell death [116]. Consistent with in vitro data, excess H2S suppressed pancreatic islet function, and therefore contributed to T2D progression in vivo [116, 117]. Moreover, H2S impaired glucose uptake and glycogen storage in hepatocytes [118]. These results indicated that H2S has pro-diabetic role. In contrast, there was some evidence showing that H2S has an antidiabetic role. For example, H2S has a protective role in mouse islets and in MIN6 cells exposed to high glucose or fatty acids by downregulating thioredoxin-interacting protein expression [119, 120]. This role of H2S also was confirmed to prevent the onset of T2D in mice study [119]. Especially, data from humans showed that patients with T2D have low plasma concentrations of H2S compared with healthy controls [121]. Although several studies have begun to characterize the potential role of H2S in the pathogenesis of T2D, subsequent studies need to be conducted to bring clarity and mechanistic insight into H2S anti- or pro-diabetic role and show whether H2S generated from gut microbiota took part in the progression of diabetes.

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TMAO and Diabetes

Some evidences show that TMAO may affect glucose metabolism and high TMAO may be closely related to diabetes. Previous studies have suggested that plasma TMAO were increased [122] and remained predictive of both major adverse cardiac events and mortality risks in T2D patients [123]. A study in HFD-fed mice showed that dietary TMAO exacerbated impaired glucose tolerance, which may be involved in glycogen synthesis, gluconeogenesis, and glucose transport in liver [124]. In contrast, Mcentyre et al. found that diabetic patients treated with metformin showed decreased glucose but increased plasma TMAO compared to untreated ones [125]. Another study showed that plasma TMAO concentration was high variable in obese diabetic patients, which suggested TMAO may be a low predictive or diagnostic value [125]. In animal models, the level of hepatic TMAO and choline was decreased in diabetic mice, while administration of TMA attenuated endoplasmic reticulum stress in STZ-induced diabetic rats [126], which implies the protective role of TMAO in diabetes [127]. Given above contradictional results, precise evidences need to be demonstrated the role of TMAO in diabetes and whether gut microbiota regulated progression of diabetes by its metabolites TMA/TMAO. All results demonstrated that gut microbiota is intimately related to progression of diabetes. Given the pathologic hallmark of diabetes involves the vasculature leading to both microvascular and macrovascular complications, and chronicity of hyperglycemia is associated with long-term damage and failure of various organ systems mainly affecting the eyes, kidneys, and the heart, there is a great possibility that gut microbiota regulated cardiovascular complications of diabetes, which need to be further studied in vivo and in vitro.

8.6

Gut Microbiota and Obesity

Obesity is becoming a global epidemic in both children and adults. It is associated with increased risk of cardiovascular disease and premature death. The Bogalusa and Pathobiological Determinants of Atherosclerosis in Youth pathology studies have shown a strong association between overweight and the increased presence of atherosclerotic lesions in both the aorta and coronary arteries [128]. Obesity is quite important in the pathogenesis of hypertension. Although the mechanism of this relationship is not completely understood, epidemiologic studies also show a strong relationship between obesity and other cardiovascular diseases for both adults and children. Thus, once gut microbiota affected obesity, there appeared a strong possibility that gut microbiota-mediated obesity contributed cardiovascular complications of obesity. Indeed, the increase in the prevalence of obesity in many parts of the world is clearly driven by changes in exposure to environmental factors [129]. Recently, many studies raise the possibility that the gut microbiota plays a

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important role in regulating host energy metabolism and may contribute toward the development of obesity. In 1983, Wostmann et al. first observed that adult male GF rats need more energy to maintain their body mass than conventional ones [130]. Recent studies showed that GF mice are leaner than their CONVR counterparts and do not trigger diet-induced obesity [131]. Colonization of GF mice with a normal microbiota increases the amount of body fat and inhibits insulin sensitivity [132], suggesting that gut microbiota may be associated with the regulation of body fat. Indeed, sequence-based studies in rodents have showed an increase in ratio of Firmicutes and Bacteroidetes and a decrease in the diversity of the microbiota in the gut [133]. Some studies report a similar increase in the ratio of Firmicutes and Bacteroides, as well as a decrease in the gut biodiversity of obese humans, but there are studies showing contradictory results in obese compared with lean humans [134]. In addition, beneficial microbiotas including Bifidobacteriumbv and anti-inflammatory Faecalibacterium, and butyrate-producing Ruminococcaceae were significantly decreased, while Bacillus and potential opportunistic pathogens were increased in patients with obesity compare to healthy controls [135]. Especially, at the phylum level, Proteobacteria have potential pathogenic features [136], and its abundance was higher in patients with obesity compared with healthy controls or patients with overweight [135]. Therefore, gut dysbiosis contributes to obesity while prebiotic agents, such as Ganoderma lucidum, have potent to prevent obesity [137].

8.6.1

SCFAs and Obesity

By analyzing 16S ribosomal RNA sequencing from 205 women, data have revealed that the abundance of the SCFA-producing bacterial families Odoribacteraceae and Clostridiaceae were inversely correlated with BMI in obese pregnant women [138]. Indeed, SCFAs activated GPR43 and thus decreased release of inflammatory cytokines in the intestines [139], which may also increase hypothalamic sensitivity to leptin, an important regulator of obesity [140, 141]. In addition, SCFAs have an important role in sustaining energy homeostasis. Butyrate has been reported to inhibit histone deacetylases (HDACs) [142] and therefore induce histone hypermethylation of genes involved in fatty acid oxidation [143]. Similarly, there are some effects of each SCFA on various gut peptides which would have a net effect of slowing digestion and nutrient intestinal transit, promoting satiety, and increasing plasma insulin. G protein mediated secretion of the satiety-stimulating hormone peptide YY (PYY) and GLP-1 as well as rates of lipolysis and lipogenesis in fat cells were upregulated in the gut after butyric acid or propionate administration [144, 145]. Butyrate and acetate have been reported to improve diet-induced obesity; propionate has capacity to decrease food intake while increase locomotor activity [146]. Based on these rodent data, colonic administration of SCFA may also have beneficial effects on human substrate and energy metabolism. However, there is a conflicting literature; Perry et al. revealed that an increased acetate

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turnover promotes the development of obesity and insulin resistance [147], indicating that each SCFA may have a diverse effect on pathogenesis of obesity. Human data indicating the in vivo effect of SCFA on obesity are scarce. The most abundant SCFA (acetate) via acute infusions in the distal of the colon enhanced fat oxidation and circulating levels of the PYY in overweight men, indicating an improved metabolic profile [148]. Moreover, in a randomized crossover trial that aimed to investigate the role of gut-derived SCFA by rectally administered physiologically relevant SCFA mixtures, Emanuel et al. found that SCFA mixtures upregulated not only fasting fat oxidation and resting energy expenditure but also fasting and postprandial PYY concentrations [149], providing evidence that SCFAs have important clinical implications on food intake regulation and control of body weight.

8.6.2

BAs and Obesity

BAs have been reported to affect the regulation of energy expenditure and development of obesity by action of its receptors, TGR5 and FXR. Watanabe et al. demonstrated that dietary CA administration reversed HFD-induced obesity and fat accumulation by activating TGR5-mediated intracellular thyroid hormone and thus increased thermogenesis in brown adipose tissue [150]. Subsequent studies have confirmed that TGR5 increases energy expenditure of brown adipose tissue and muscle, and release of increasing glucagon-like peptide (GLP)-1 in intestinal L cells and a cells in the pancreas [151]. Similarly, INT-777, a specific TGR5 agonist, has been reported to ameliorate hepatic steatosis and adiposity and improve insulin sensitivity in mice with high-fat-diet-induced obesity [152]. Another receptor, FXR, was also expressed in intestinal L cells where it inhibits GLP-1 synthesis [153]. Liver-specific FXR/small heterodimer partner SHP double knockout improved glucose/fatty acid homeostasis and suppressed body weight gain and adiposity in aged mice, suggesting that intrahepatic FXR activation may also regulate whole-body energy [154]. In addition, hepatic FXR inhibited steatosis [155] while intestine-selective FXR contributed to obesity [156, 157], suggesting that the role of FXR on obesity seems to depend on its location. Thus, the precise role of FXR needs to be further investigated in vivo and in vitro. A human study demonstrated a promoting effect of bile acids on energy expenditure and showed that CDCA increased whole-body energy expenditure and activated brown adipose tissue in 12 healthy women [158]. Paradoxically, most studies found increased total bile acid levels in humans with obesity [159]. Gut microbiota plays an important role in progression of obesity. Obesity is associated with vascular remodeling, inflammation, oxidative stress, insulin resistance, and endothelial dysfunction, which all lead to maladaptive structural and functional alterations of the heart such as left ventricle remodeling and diastolic dysfunction, sometimes termed obesity-associated cardiomyopathy, and through a period of asymptomatic subclinical disease may ultimately result in clinically overt

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CVD. Therefore, there are reasons to speculate that gut microbiota may be associated with cardiovascular complication of obesity even though detail evidence should be supplied.

8.7

Gut Microbiota and Heart Failure

Heart failure (HF) is growing to a modern epidemic and a main cause of mortality and morbidity worldwide despite advances in therapy; it still carries an ominous prognosis and a significant socioeconomic burden. The gut has also been implicated in the progression of heart failure because a decreased cardiac output and/or splanchnic venous impaired perfusion to the intestines and thus lead to intestinal barrier dysfunction and increased circulating endotoxins that can contribute to the underlying inflammation [160]. In addition to intestinal wall ischemia, intestinal wall edema caused by elevated systemic congestion with HF also increased bacterial translocation and circulating endotoxins. Once endotoxins such as LPS enter the mesenteric lymph nodes or the systemic circulation through the intestine, they have potentially leading to further HF exacerbations [161]. Indeed, higher concentrations of bacterial DNA in circulation have been detected in patients with CVD compared with healthy subjects [162]. The concentration of bacterial DNA has reported to be considerable impact on the onset of cardiovascular events [163]. Recently, a study in human showed that intestinal overgrowth of pathogenic bacteria and Candida species was associated with intestinal permeability and clinical disease severity in patient with chronic heart failure (CHF) [164]. In another study, HF patients had a significantly decreased diversity of gut microbiota and a depletion of key intestinal bacterial groups [165]. These data indicated that improvement of intestinal barrier function may be an effective therapy for HF. As mentioned above, there were clear evidences showing that TMAO levels have been linked to poor prognosis in patients with HF [8, 13, 166, 167]. In transverse aortic constriction(TAC)-induced HF mice, TMAO- or cholinesupplemented diets induced myocardial fibrosis and accelerated adverse ventricular remodeling compared with the control diet [168]. Recently, TMAO treatment induced cardiac hypertrophy and cardiac fibrosis, which was inhibited by pharmacological inhibition of Smad3 in SD rats [169]. In contrast, reducing TMAO synthesis by antibiotics improved TAC-induced cardiac fibrosis [169]. This role of TMAO on pro-fibrosis by transforming growth factor-b Smad3 pathway is also observed in kidney tissue of mice fed with chlorine or TMAO [170]. These animal model studies suggest that beyond association studies and adverse prognosis data in humans, the TMAO pathway may directly induce adverse ventricular remodeling and HF phenotype. Arial fibrillation, a common kind of arrhythmia, is associated with an increased risk of worsening HF [171]. A clinical study demonstrated that TMAO predicts the risk of atrial fibrillation and positively correlates with the occurred atrial fibrillation [172]. Further study in animal model revealed that TMAO facilitated the

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progression of atrial fibrillation by activation of cardiac autonomic nervous system [173]. In addition to microbiota-derived TMAO, increased circulation LPS was derived from gut microbiota and associated with major adverse cardiovascular event occurrence in patients with atrial fibrillation [174]. The precise relationship between gut microbiome and atrial fibrillation needs further study, both clinically and basically. Myocardial infarction is one of the most common causes leading to HF. Lam et al. demonstrated that antibiotic vancomycin altered abundance of individual groups of intestinal microbiota and resulted in reduced myocardial infarcts and improved recovery of postischemic mechanical function compared to untreated controls by changing circulating leptin levels in Dahl S rats [175]. Other low-molecular-weight metabolites, such as phenylalanine, tryptophan, and tyrosine, produced by intestinal microbiota and carried to the systemic circulation, also affect the severity of myocardial infarction [176]. These works suggested that a direct link between the gut microbiota and the severity of myocardial infarction in rats. Further study reveals that the richness of gut microbiota and the abundance of Synergistetes phylum, Spirochaetes phylum, Lachnospiraceae family, Syntrophomonadaceae family, and Tissierella Soehngenia genus was higher and associated with intestinal barrier impairment in acute myocardial infarction rat [177]. In myocardial infarction patients, the researchers found that after ST-segment elevations, the abundance and diversity of circulatory microbiota were increased and more than 12% of the blood bacteria were dominated by intestinal microbiota and contributed to cardiovascular events post-myocardial infarction [178]. Therefore, the intervention of gut microbial composition to improve myocardial infarction may be a new method of myocardial infarction treatment. Probiotic administration (Lactobacillus rhamnosus GR-1) inhibited left ventricular hypertrophy and improved left ventricular ejection fraction and fractional shortening in myocardial infarction rats [179]. Recently, Tang et al. found that dietary SCFA supplementation can improve survival of antibiotic-treated mice after myocardial infarction and suggested that microbiota-derived SCFAs play an important role in maintaining repair capacity after myocardial infarction [180]. In addition, HIV infection is associated with increased risk of coronary heart disease beyond that explained by traditional risk factors. Several studies have reported that altered composition of microbiota in HIV infection is associated with increased systemic inflammation, suggesting a potential association between altered microbiota and coronary heart disease in HIV infection. Recently, Haissman et al. reported that although there was no difference in plasma TMAO when comparing HIV-infected persons and uninfected controls, TMAO was elevated in HIV-infected persons with myocardial perfusion defects [181].

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Therapeutic Potential of Gut Microbiota in CVD

Although many types of medicines are available in the clinic to treat CVD, currently, it is still the leading cause of death worldwide. In recent years, the gut microbiota was regarded as important regulator in the development of CVD and aroused interest in the development of microbiota-targeted therapies by regulating the composition of gut microbiota community and/or gut microbial metabolites (Fig. 8.4).

8.8.1

Antibiotic, Probiotic, and Prebiotic Treatment in CVD

Antibiotic treatment was usually regarded as a experimental strategy to study how the gut microbiome influences various disease states in animal models. Recently, several randomized, placebo-controlled trials have investigated whether antibiotic

2. Antibiotic treatment, probiotic and prebiotic

Antibiotic

1. Fiber-rich diet

Lactobacillus spp. etc Reshape microbiota

4. Inhibitors targeting signalings involving gut microbial metabolites

3. Fecal microbiota transplantation

DMB etc Donor fecal sample

Fig. 8.4 Targeting gut microbiota and related metabolites are promising strategies for the treatment of CVD. Some strategies have therapeutic actions on CVD by reshaping the gut microbiota. The most frequently used approaches to manipulate the gut microbiota include antibiotic treatment, probiotic, prebiotic, diet intervention, fecal microbiota transplantation, and inhibitors targeting signaling involving in production of gut microbial metabolites

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treatment has beneficial effects on CVD. However, data from these clinic trials showed no benefit in reducing mortality or cardiovascular events in patients with coronary artery diseases [31]. The disappointing results are attributed to short treatment duration, bacterial resistance, or unselective targeting of protective bacteria. However, long-term treatment with antibiotics might not be sensible because antibiotic administration during early life is associated with childhood obesity in humans and mice [182, 183]. Therefore, antibiotic treatment should focus on preservation of the beneficial microbiota and duration of treatment. Probiotics are beneficial live microorganisms to improve health by re-establishing an appropriate balance in the intestinal microenvironment. Focusing on the variable hypocholesterolemic effects of probiotics, scientists have researched the mechanisms by which probiotics impact hypercholesterolemia in vitro and in vivo. Numerous studies have revealed the effect of probiotics on decreasing serum LDL cholesterol and total cholesterol levels, which are main risk of CVD [184]. Further research studies demonstrated that fermented milk containing wild-type Lactobacillus strains has hypocholesterolemic effects [185]. In 2000, a double-blind randomized study of 70 overweight and obese adults showed that consumption of probiotic yogurt containing S. thermophiles and Enterococcus faecium for 8 weeks significantly reduced 8.4% of LDL cholesterol which was associated with a reduced risk of CVD by 20–30% [186]. In addition, Kekkonen et al. further found that probiotic Lactobacillus rhamnosus GG could decrease sphingomyelins [187], a major predictor of heart disease. In a recent study, Lactobacillus reuteri was reported to induce insulin secretion in obese glucose-intolerant patients [188]. A meta-analysis of nine randomized, controlled trials found that daily consumption of  1011 CFU probiotic for 8 weeks significantly decreased BP [72]. Studies in experimental animals have also revealed beneficial effects of probiotic administration on CVD. These probiotics include VSL#3, L. rhamnosus GG, L. acidophilus ATCC 4358, and A. muciniphila, etc. [189]. Another strategy to regulate intestinal microbiota is the use of prebiotics. Prebiotics are nondigestible carbohydrates that beneficially affect host health by selectively stimulating the growth and/or activity of the health-promoting gut microbiota [190, 191]. Typical prebiotics are food indigestible fibers such as oligosaccharides or complex saccharides [192]. Oligofructose supplementation for 3 months has been reported to improve glucose tolerance and lose weight in patient with obesity [193]. Although administration of antibiotics or prebiotics improves gut permeability and glucose intolerance in genetically obese and diet-induced leptin-resistant mice [194], the prebiotic treatment did not show similar strong effects in women with obesity. Therefore, prebiotic administration for treating CVD needs to be further confirmed, particularly through clinical trial.

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Fecal Microbiota Transplantation in CVD Treatment

Fecal microbiota transplantation (FMT) is a therapeutic intervention in which the intestinal microbiota is transferred from a healthy donor to the patient, with the goal to displace intestinal pathogens by introducing or restoring a stable microbial community in the gut. In the past few decades, FMT was reportedly used as a therapeutic approach for antibiotic resistance in human subject infected with Clostridium difficile [195]. Recently, the application of FMT has been broadened and tested in clinical trials to improve cardiometabolic disorders [196]. Vrieze et al. demonstrated that insulin sensitivity in overweight patients with metabolic syndrome was improved about 176% after being transplanted with microbiota from lean healthy controls for 6 weeks [196]. The FMT increases overall gut microbial richness and especially abundance of butyrate-producing bacteria in treated patients. However, improvement of insulin sensitivity by FMT was unabiding as no difference was observed at 18 weeks. However, clinical application of FMT is currently limited because the treatment may induce transfer of endotoxins or infectious agents from the donors to the treated patients, thus increasing the risk of infection following FMT therapy [197]. Thus, instead of fecal contents, transplantation of only a defined group of bacteria may be advisable for FMT. Nevertheless, future studies are needed to optimize FMT in cardiometabolic disorders.

8.8.3

Reshaping the Population of Gut Bacteria by Dietary Intervention and Other Therapies

The dietary interventions could be a major relational factor in rapidly shaping gut microbiota and, hence, a dietary approach to nutritional interventions had been proved to be an effective strategy for treating CVD. Fiber-rich diets have been reported to decrease BP, cardiac hypertrophy, and fibrosis through increasing richness of acetate-producing microbiota [78]. In addition, Xiao et al. demonstrated that dietary intervention with whole grains, traditional Chinese medicinal foods, and prebiotics led to improvement in insulin sensitivity, lipid profiles, and BP which was accompanied with the reduction of opportunistic pathogen of the Enterobacteriaceae and Desulfovibrionaceae and increment in the family gut barrier-protecting bacteria Bifidobacteriaceae [198]. Modulation of gut microbiota composition through nutritional intervention represents a promising therapeutic approach. Furthermore, the metabolites of gut bacteria and their associated enzymes were also recognized as potential therapeutic targets of CVD. For example, a structural analog of choline, DMB, inhibited choline diet-enhanced endogenous macrophage foam cell formation and atherosclerotic lesion development in ApoE−/ − mice [61]. Therefore, additional research to delineate the precise mechanisms by

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which gut dysbiosis increases CVD risk and the novel therapeutic strategy that restores the homeostasis of gut microbiome in the host are likely to emerge.

8.9

Conclusion

The pathophysiology of CVD is complex, multifactorial, and, in many respects, poorly understood. Nevertheless, growing body of evidence suggests that gut microbiota plays a significant role in the development of CVD. Based on metabonomics and metagenomic sequencing analysis, scientists have demonstrated

Table 8.1 Gut metabolites and CVD Gut metabolites

Gut metabolite-related receptor

CVD

Detrimental or beneficial function

References

BAs

FXR FXR FXR FXR FXR TGR5 TGR5

Atherosclerosis Atherosclerosis T2D Obesity Obesity Atherosclerosis Diabetic retinopathy Obesity Atherosclerosis Atherosclerosis Atherosclerosis Diabetes Diabetes Heart failure Atrial fibrillation Hypertension T2D hypertension T2D Obesity Myocardial infarction Hypertension Diabetes Diabetes

Beneficial Detrimental Beneficial Beneficial Detrimental Beneficial Beneficial

[42–45] [46, 47] [106] [155] [156, 157] [49, 51] [89]

Beneficial Detrimental Detrimental Beneficial Detrimental Beneficial Detrimental Detrimental

[149] [54] [8, 57–62] [63] [124, 125] [126] [168] [173]

Beneficial Beneficial Beneficial Beneficial Beneficial Beneficial

[81] [113, 115] [102] [112, 114] [139] [175]

Beneficial Detrimental Beneficial

[82–84] [116–118] [119, 120]

TGR5 PXR TMA/ TMAO

SCFAs

H2S

GPR41 GPR41 Olfr78 GPR43 GPR43

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that gut microbiota impacts host health and disease by production of bacterial metabolites. The detrimental metabolites, such as TMA/TMAO, may sustain and aggravate an ongoing process of CVD, while some beneficial metabolites, such as SFCAs, may slow progression of CVD (Table 8.1). There is great promise of finding new approaches to treat CVD by using gut microbial metabolites such as supplement with beneficial gut microbiota metabolites or blocking the production of detrimental microbial metabolites. Although intervention of metabolites has been investigated in animal models, well-designed large-scale clinical studies needed to validate the feasibility of this approach.

8.10

Sources of Funding

This work was supported by the National Natural Science Foundation of China (No. 81873514 and 81570394).

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Chapter 9

Gut Microbiota and Endocrine Disorder Rui Li, Yifan Li, Cui Li, Dongying Zheng, and Peng Chen

Abstract The gut microbiome contains trillions of commensal microorganisms that maintain a symbiotic relationship with the host, and its profound effects on gastrointestinal diseases have been widely described. Recently, gut microbiota have emerged as important factors in endocrine system diseases. Disruption of the gut microbiota affects neuroendocrine homeostasis and promotes peripheral endocrine system diseases, including obesity, diabetes, and hyperuricemia. This chapter provides a comprehensive overview of the biological mechanisms of gut microbiota that participate in endocrine system pathologies and discusses potential novel therapies for these diseases. Keywords Gut microbiota

9.1


Neuroendocrine disorder
Diabetes
Obesity

Gut Microbiota

Virtually, all multicellular organisms maintain an intimate relationship with microbes, and humans are no exception. A large number of bacteria, archaea, viruses, and unicellular eukaryotes coexist with the human body. The field of microbiota research has boomed over the last decade, resulting in the publication of a vast array of reports that describe both the composition of intestinal microbiota and their wide-ranging impact on host physiology and pathology [1–4]. Microbes live on our skin and in the genitourinary, gastrointestinal, and respiratory tracts, colonizing virtually every surface on the human body. The gastrointestinal tract (GIT) is the most heavily microbe-colonized organ [5], and recent studies suggest that over 35,000 bacterial species reside therein. Of the strict anaerobes, facultative anaerobes, and aerobes in the human GIT, the most important are Gram-positive bacteria of the phyla Firmicutes and Actinobacteria, followed by R. Li
Y. Li
C. Li
D. Zheng
P. Chen (&) Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, No. 1838 Guangzhou Ave., Guangzhou 510515, China e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 P. Chen (ed.), Gut Microbiota and Pathogenesis of Organ Injury, Advances in Experimental Medicine and Biology 1238, https://doi.org/10.1007/978-981-15-2385-4_9

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the genera Clostridium, Bifidobacterium, Lactobacillus, Ruminococcus, and Streptococcus and Gram-negative bacteria belonging to the genera Bacteroides, Prevotella, and Akkermansia [6, 7]. These microorganisms are critical to healthy intestinal development in the host. Metabolic abnormalities, endocrine disorders, and other factors negatively impact the intestinal system, disrupting microorganisms and their secretions and causing immune system, endocrine, and urinary diseases [8–11].

9.2

Endocrine Systems

The endocrine system consists of the endocrine organs, including hypophysis, thyroid, parathyroid, adrenal gland, gonad, pancreas, and clusters of endocrine cells or tissues located in other organs, such as adipose tissue, pancreatic islets, and reproductive tissue. Endocrine glands and tissue cells secrete biologically active substances called hormones, which are released into the blood or lymphatic systems and circulate throughout the body. The endocrine system oversees the growth, development, metabolism, and reproduction of the whole organism.

9.2.1

Neuroendocrine System

A broad range of hormones are produced by the central endocrine glands, including the pineal gland, hypothalamus, and pituitary gland that comprise the neuroendocrine system. Pituitary gland The pituitary gland is a small structure at the base of the hypothalamus; its activity is regulated by projections from cell bodies located in the paraventricular nucleus (PVN). The pituitary is divided into anterior, intermediate, and posterior lobes. It secretes several different hormones, such as growth hormone, thyroid stimulating hormone, adrenocorticotropic hormone, gonadotropin, oxytocin, prolactin, and black cell-stimulating hormone, and also stores and releases antidiuretic hormone secreted by the hypothalamus. These hormones are important for metabolism, growth, development, and reproduction [7, 12–14]. Pineal gland The pineal gland is a small neuroendocrine organ that secretes melatonin. Pineal activity is strongly driven by external light information relayed through the retinohypothalamic tract and sympathetic nervous system. Melatonin has many targets throughout the body, and its receptors are located in the brain and peripheral organs like the heart, liver, adrenal glands, testes, and ovaries [15–17].

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Peripheral Endocrine System

Thyroid gland The thyroid is the largest endocrine gland in adults, containing triiodothyronine (T3) and thyroxine that regulate metabolism, growth rate, and other related biological processes and systems [18–20]. Adrenal glands The adrenal glands rest atop the kidneys and consist of an outer cortex that secretes corticosteroids and an inner medulla that produces the catecholamines epinephrine and norepinephrine. In addition to hormonal input from the pituitary gland, the adrenal gland receives neural input from the suprachiasmatic nucleus (SCN) via a projection through the PVN from the intermediolateral column of the spinal cord. Adrenal glands are critical to maintaining normal physiological function [21–23]. Adipose tissue Adipose tissue has recently come to the forefront as an important peripheral endocrine tissue. Adipocytes secrete chemical messengers such as leptin, adiponectin, tumor necrosis factor a (TNF-a), angiotensinogen, and inflammatory cytokines. These molecules affect insulin sensitivity, blood pressure, endothelial function, and inflammatory responses, all of which participate in many important pathophysiological processes [12, 24–26]. Pancreatic islets Pancreatic islets are clusters of cells scattered between pancreatic acinar cells and account for between 1 and 2% of total pancreatic volume. Pancreatic islet cells secrete glucagon, insulin, and pancreatic polypeptides (PP). Insulin is the only hormone in the body that lowers blood sugar and promotes the synthesis of glycogen, fat, and protein, and its primary physiological function is to regulate metabolic processes. Insulin can promote the uptake and utilization of glucose in tissues, cells and glycogen synthesis and can inhibit gluconeogenesis and reduce blood glucose. As for lipid metabolism, insulin is capable of promoting fatty acid synthesis and fat storage as well as reducing fat decomposition. It also facilitates amino acid to transfer into cells and modulates protein synthesis therein. Overall, insulin controls energy storage and use [27–29]. Glucagon facilitates glycogen decomposition and gluconeogenesis in the liver that significantly increases blood glucose. It also promotes fat decomposition and increases ketone body production [30, 31]. Protein intake stimulates PP secretion; fat and sugar do so as well, but to a lesser degree. PP can inhibit the secretion of pancreatic juice and bile after meals and the secretion of gastric acid caused by pentagastrin and participates in a wide range of processes in the GIT.

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Consequences of Endocrine Disorders

There are dozens of endocrine diseases, and each organ malfunctions in distinctive ways. Common endocrine-related metabolic diseases include hypopituitarism, thyroid disorders, adrenal cortex diseases, diabetes, obesity, thyroid diseases, and hyperuricemia. Thyroid diseases Thyroid diseases are medical conditions resulting from impairments of thyroid function. Different thyroid diseases include Hashimoto’s thyroiditis (HT), hyperthyroidism, and hypothyroidism. Hyperthyroidism is the most common of these, such as Graves’ disease and Plummer’s disease [22, 32]. Adrenocortical diseases Adrenocortical diseases include Cushing’s syndrome and primary chronic adrenocortical dysfunction. Cushing’s syndrome is caused by the excessive production of glucocorticoids (mainly cortisol) by the adrenal glands, and reasons for which can vary. The main clinical manifestations are full-moon face, sanguinity, concentric obesity, purple lines in the skin, acne, diabetes, hypertension, and osteoporosis [33, 34]. Primary chronic adrenal cortical dysfunction, known as Addison’s disease, is caused by insufficient adrenal cortical hormone secretion due to the destruction of the bilateral adrenal glands by autoimmune pathology, tuberculosis, fungal infection, tumor, and leukemia, among others [35, 36]. Secondary chronic adrenocortical dysfunction is caused by insufficient adrenocortical hormone (ACTH) resulting from hypothalamic–pituitary axis pathologies [37]. Autoimmune diabetes Autoimmune diabetes, also called type 1 diabetes, is caused by autoimmune destruction mediated by pancreatic islet T cells. It is characterized by the development of islet inflammation and an increased presence of islet B cell autoantibodies. Type 2 diabetes mellitus and obesity Conversely, patients with type 2 diabetes mellitus (T2DM) produce normal or even excessive amounts of insulin but demonstrate significant insulin resistance [38–40]. Obesity due to an imbalance between energy intake and expenditure is an important cause of certain endocrine pathologies and T2DM. Some also have implicated socioeconomic factors in the development of obesity, such as poor diet and a sedentary lifestyle [41–43]. Hyperuricemia and urarthritis Uric acid (UA) is a terminal metabolite of human purine compounds, and purine metabolism disorders can lead to hyperuricemia. Uarthritis, or arthritis associated with gout, is a heterogeneous disease caused by monosodium urate (MSU) deposition directly related to hyperuricemia. Severe uarthritis is accompanied by joint destruction and renal function damage. Clinical studies have shown

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that hyperuricemia associates with chronic interstitial nephritis, UA urinary calculi, diabetes, and other endocrine disorders [44–46].

9.3

Gut Microbiota and the Endocrine System

Studies over recent years have shown that the gut microbiome can influence host endocrine functions via a range of bacteria-derived metabolites (Fig. 9.1).

9.3.1

Gut Microbiota and Neuroendocrine System Diseases

The gut–brain axis refers to the communication between the gut and central nervous system (CNS) that regulates different physiological processes via the endocrine system [47, 48]. Gut microbiota are significant players in the gut–brain axis. Changes in the microbial community can lead to the production of different hormones, metabolites, and immune factors in the GIT [49, 50]. Gut microbiota interferes with vitally important hypothalamus, pituitary gland, and pineal gland homeostasis through its interaction with the host neuroendocrine system [50–53]. The mechanisms through which gut microbiota influences neuroendocrine function and, consequently, host behavior have yet to be fully deciphered. Increasing evidence suggests, however, that gut microbiota activity is facilitated by

Fig. 9.1 Gut microbiota metabolites affect endocrine function in the host

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direct production of neuroendocrine metabolites, such as short-chain fatty acids (SCFAs), neurotransmitters, GIT hormones, precursors to neuroactive compounds such as tryptophan and kynurenine, and, indirectly, modulation of inflammatory responses, immune responses, and hormonal secretion [54–59]. Short-Chain Fatty Acids The microbiome converts indigestible carbohydrates into SCFAs. SCFAs include formic acid, isobutyrate, propionate, acetic acid, isovalerate, and butyrate [60]. Increasing evidence suggests that SCFAs can directly influence brain function and behavior [61]. Butyric acid and propionic acid can modulate the synthesis of dopamine and norepinephrine by increasing the expression of tyrosine hydroxylase genes [62]. Propionic acid can regulate serotonin neurotransmission and reduce levels of ɣ-aminobutyric acid (GABA), serotonin, and dopamine in the body [63]. Interestingly, SCFAs have also been shown to affect the maturation and function of microglia, the macrophages of the CNS. Mice born and raised in a sterile environment show microglial defects that were reversed after long-term SCFA treatment [64]. Because gut microbial-mediated SCFAs can bind to enteroendocrine cell (EEC) receptors FFAR1 and FFAR3, stimulating the secretion of related peptides and hormones, mice deficient for the SCFA receptor FFAR2 recapitulated the microglia defects observed under germ-free conditions. These findings suggest that bacteria can regulate microglia maturation and function, whereas microglia impairment can be rectified to a certain extent by complex SCFAs [65, 66]. Dietary regulation of SCFAs also alleviated blood–brain barrier defects in sterile mice, which may be related to circuits that regulate CNS and hypothalamus function [67, 68]. Neurotransmitters and tryptophan metabolism Studies have shown that gut bacteria can produce several neurotransmitters in addition to SCFAs, such as dopamine, norepinephrine, and GABA; these molecules influence hypothalamus function and act in the main neuroendocrine axis of the host [69–72]. Microbial glutamate and GABA signaling also exert certain neuro-endocrinological effects [73]. Gut microbiota can decarboxylate levodopa to dopamine via tyrosine decarboxylases. A large number of intestinal bacteria tyrosine decarboxylases were observed at the proximal end of the small intestine, where levodopa is absorbed in Parkinson’s disease patients, which had a significant impact on levodopa levels in rat plasma. This result demonstrates that an abundance of bacterial tyrosine decarboxylase in the proximal small intestine could explain the increased dosages required during levodopa treatment in Parkinson’s disease patients [74]. Human intestinally derived strains of Lactobacillus and Bifidobacterium have been shown to produce GABA, a main inhibitory neurotransmitter in the CNS that is also associated with depression and anxiety [75, 76]. Serotonin (5-HT) is another important neurotransmitter involved in CNS adaptation responses to tryptophan metabolism [70, 77]. The gut microbiota might metabolize tryptophan to increase plasma levels of 5-HT. Streptococcus, Enterococcus, and Escherichia coli also produce 5-HT [78]. In the context of microbial-derived

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neurotransmitters and brain functions, further investigation is needed to delineate the direct or indirect effects of microbiota-induced changes in peripheral neurotransmitter levels on neuroendocrine functions and mechanisms and the blood– brain barrier. Enteroendocrine cells and enteroendocrine signaling EECs are widely distributed in the GIT and they can regulate two-way communication between the intestinal tract and the brain. Hormones and peptides secreted by EECs act on receptors in the vagus afferent pathway and influence different neurophysiological functions of the host [79, 80]. The main hormones secreted by EECs are cholecystokinin (CCK), peptide YY (PYY), and glucagon-like peptide-1 (GLP-1), which regulate the catabolism of fat, protein and carbohydrates [81, 82]. Studies have shown that germ-free mice have fewer EECs and lower levels of PYY, GLP-1, and CCK than conventionally colonized mice [81, 83, 84]. Enteral E. coli protein infusion can increase plasma PYY and GLP-1 levels, possibly due to casein hydrolytic protease B (ClpB) produced by E. coli [66]. Peptides such as ghrelin, GLP-1, PYY and CCK secreted by the gut significantly impact energy balance and homeostasis by inducing satiety and meal termination [85]. Gut peptides can also bind with homologous receptors on immune cells and vagus nerve endings to achieve indirect entero-brain communication, influencing the expression of endocrine peptides and regulating anxiety and depression. The concentration of intestinal peptides is regulated by signals from the intestinal microflora and by gut microbiota composition [86]. Vagus nerve The vagus nerve is a key mediator of cross-communication between gut and brain and it is a major player in homeostasis, sensing the milieu intérieur and modulating nervous and endocrine system activity to maintain gastrointestinal health. Gut microbiota can control the production and release of neurotransmitters by interacting with the CNS through the vagus nerve. Diet-driven unfavorable microbiota composition or imbalances can lead to an increase of pro-inflammatory byproducts, such as lipopolysaccharides (LPS). A chronic increase of circulating LPS has been associated with impairments in the gut–brain axis and vagus-mediated satiety signaling. Evidence suggests that correcting imbalances in microbiota composition in rats fed with high-fat diet (HFD) prevents vagal remodeling [87]. Mice that underwent vasectomies demonstrated that effects of Lactobacillus rhamnosus administration on mice behavior were dependent on the presence of the nerve. Chronic treatment with L. rhamnosus (JB-1) was shown to induce region-dependent alterations in GABA(B1b) mRNA in the brain, along with increases in the cingulate and prelimbic cortical regions and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. (JB-1) administration also reduced GABA (Aa2) mRNA expression in the prefrontal cortex and amygdala, but increased mRNA expression thereof in the hippocampus. Importantly, (JB-1) was

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Fig. 9.2 The gut–brain axis is associated with neuroendocrine function

associated with reduced levels of stress-induced corticosterone and anxiety- and depression-related behavior [83, 88]. Together, these findings highlight the importance of the gut–brain axis in neuroendocrine system functioning and suggest that gut microbiota could be used to assist in the treatment of neuroendocrine diseases such as anxiety and depression (Fig. 9.2).

9.3.2

Gut Microbiota and Peripheral Endocrine System Diseases

Gut microbiota is also closely related to the peripheral endocrine system, and microbial metabolites are reported to be involved in peripheral endocrine disease processes (Fig. 9.3). Relationship between gut microbiota and thyroid diseases The functional link between the gut and thyroid has long since been confirmed. T3 is theorized to impact the development and differentiation of intestinal mucosa and execute intestinal neuromotor function [89]. The gastrointestinal system participates in the enterohepatic recycling and metabolism of thyroid hormones [90, 91]. Autoimmune thyroid disease is the most common organ-specific autoimmune disease, affecting about 5% of the world’s population, with HT as the most prevalent [92, 93]. Although the factors that underlie the genesis of HT have yet to be completely elucidated, studies have established that its pathology derives from the interaction of a predisposing genotype with endogenous and environmental triggers [32]. Peripheral thyroid homeostasis may be sensitive to microbiota changes, and there is also evidence that the genesis and progression of autoimmune

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Fig. 9.3 Gut microbiota interferes with peripheral endocrine system diseases through multiple pathways

thyroid disorders may be significantly affected by changing intestinal microbial composition or overt dysbiosis [94]. The abundance of Prevotella and Dialister in the guts of HT patients is decreased, while elevated genera in these patients include Escherichia-Shigella and Parasutterella. The number of E. coli in the intestinal tract of HT patients is also increased. Gut microbiota can alter the development of primary and secondary lymphoid organs and the activation and differentiation of B cells associated with autoimmune thyroid diseases [95, 96]. At present, the link between microbiota and autoimmune thyroid disease is under scrutiny but has yet to be fully elucidated [97]. Studies have shown that hypothyroidism patients have a greater chance of developing bacterial overgrowth in the small intestine that can contribute to the impairment of gastrointestinal neuromuscular function [98]. Researchers analyzed fecal samples of hyperthyroid patients and discovered a significant decrease in Bifidobacterium and Lactobacillus and an increase in Enterococcus in these patients compared with the control group [94, 99]. The impact of gut microbiota on thyroid disease is not well studied and should be further explored and verified as to molecular mechanisms and clinical presentations. The relationship of gut microbiota with obesity, insulin resistance, and diabetes Changes in lifestyle and increased intake of calorie-rich foods are significant contributors to the global obesity epidemic [100]. When energy intake exceeds energy expenditure over the long term, adipose tissue cannot store the excess triglycerides, leading to increased lipid content in non-adipose tissues such as the liver and skeletal muscle. Excessive lipids lead to lipid peroxidation, impaired metabolic lipid function, and heterotopic lipid accumulation. As the ability to store lipid decreases, adipose tissue inflammation develops, resulting in increased production and secretion of pro-inflammatory adipokines that lead to the development of peripheral and hepatic insulin resistance implicated in T2DM and nonalcoholic fatty liver disease (NAFLD) [101–104].

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Studies have implicated gut microbiota composition in the development of obesity which consider it as an environmental factor that contributes to obesity and its comorbidities, such as insulin resistance, diabetes, and cardiovascular disease [55, 105]. Gut microbiota have emerged as important regulators of energy and substrate metabolism. Abnormalities in gut microbiota composition and function can result in energy metabolism imbalances, including effects on adipose tissue, muscle, and liver metabolism [106, 107]. The gut microbiome is also associated with the development of chronic obesity-related inflammation, and gut microbiota metabolites such as SCFAs and succinic acid are vital to the prevention and treatment of obesity and its complications [108, 109]. A. Firmicutes/Bacteroidetes ratio The phyla Firmicutes and Bacteroidetes are the predominant members of gut microbiota. The product of Firmicutes butyrate is a principal energy source used by enterocytes, and the Bacteroidetes products acetate and propionate are flushed to the liver for lipogenesis and gluconeogenesis [110]. Various studies have reported changes to the intestinal Firmicutes/Bacteroidetes ratio associated with obesity. Ley et al. showed gut microbiota alterations in genetically obese (ob/ob) mice, observing an increase in Firmicutes and a decrease in Bacteroidetes [111]. However, whether the pathology of obesity is also associated with alterations to the Firmicutes/Bacteroidetes ratio in human obese patients remains a matter of debate [112–116]. Studies suggest that Firmicutes and Clostridium species are significantly reduced in the gut microbiota of diabetics and that increases of the Bacteroides/Firmicutes and Pseudobacillus/E. coli ratios were positively correlated with higher blood glucose levels irrespective of the patient’s weight [117]. Lambeth et al. found significantly increased b-Proteobacteria in patients with T2DM along with reductions of Bifidobacterium, Firmicutes, and Fusobacterium. Ratios of Bacteroides/Firmicutes and Brevibacterium/Clostridium sphaeroides were positively correlated with blood glucose levels, demonstrating that changes in the gut microbiota were closely related to reductions in glucose tolerance [118]. B. SCFAs and T2DM Researchers reported that gut microbiota acts as a mediator, rather than an initiator, of the physiological and pathological progression of obesity and T2DM [119]. SCFAs are formed by microbial fermentation and then absorbed and transferred to various tissues. The majority of them are used as an energy resource in peripheral tissues, although they also demonstrate certain specificities. While acetate and propionate are preferentially flushed to the liver and regulate cholesterol synthesis, butyrate preferentially enters enterocytes and is used for energy producing [120, 121]. Acetates enter the lipogenesis pathway, whereas propionate participates in the gluconeogenesis. All of these molecules contribute to adipogenesis [122, 123]. SCFAs are also ligands for G-protein-coupled receptors FFAR2 and FFAR3, the activation of which affects functions related to satiety and insulin sensitivity [124].

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Activation of FFAR2 in adipocytes stimulates them to release leptin [125]. It has also been reported that activating FFAR2 in EECs triggers the secretion of PYY [126], and SCFA-mediated FFAR3 activation can also elevate PYY serum levels [127]. Both leptin and PYY are appetite suppressors [128]. Acetate and propionate can also suppress appetite by enhancing the secretion of GLP-1, which stimulates the production of insulin in pancreatic b-cells and promotes insulin sensitivity and satiety [129, 130]. Receptor-knockout experiments in obese and insulin-resistant mice have demonstrated that SCFAs can increase glucose-stimulated insulin secretion via GPR43 [125, 131]. In line with this finding, another study found that the depletion of GPR43 in mice with diet-induced obesity was associated with deteriorated b-cell function and increased b-cell mass [132]. SCFA–GPR41 signaling appears to be of particular importance in controlling pancreatic b-cell insulin secretion in satiety and fasting states, as GPR41 knockout or overexpression in mice resulted in impairments in glucose control but did not affect insulin sensitivity [133]. Clinical studies have shown that dietary fibers could promote SCFA-producing bacteria growth. When fiber-promoted SCFA producers were present in greater diversity and abundance, participants had more significant improvements in hemoglobin A1c levels, partly via increased GLP-1 production. Thus, targeted restoration of these SCFA producers may present a novel ecological approach for managing T2DM [39]. C. Gut microbiota influences intestinal immunomodulatory cells to regulate autoimmune diabetes As mentioned above, gut microbiota mediate the relationship between intestinal immune cells (IICs) and endocrine diseases. IICs participate in the pathogenesis of gut microbiota and endocrine diseases, especially vital T lymphocytes, including Th1, Th2, Th17, and Tregs [134]. T cells differentiate to Th1 cells after exposure to IL-12 through the STAT4 pathway and to Th2 cells after exposure to IL-4 through the STAT6 pathway [135]. The main products secreted by Th1 cells are IL-2 and IFN-c; those of Th2 are IL-4 and IL-10. Notably, Bacteroidetes and its secretions, such as polysaccharide A, induce IL-12 expression, while commensal A4 bacteria from Lachnospiraceae may inhibit intestinal Th2 cell responses [136]. IFN-c participates in macrophage activation leading to cytotoxic activity that ultimately destroys islet b-cells. IL-12 binds to IL-12 receptors on islet b cells to activate the pro-inflammatory cytokines IL-1b, TNF-a, and INF-c; these, in turn, contribute to islet b cell apoptosis via the STAT4 pathway [137]. IL-4, the main product of Th2 cells, can help improve insulin sensitivity and glucose tolerance. IL-10 binds to IL-10 receptors on cell surface, and it has been shown that when IL-10 binds to these receptors on macrophages, it inhibits phagocytotic activity, while when IL-10 binds to glucose transporter receptors on skeletal muscle cells, it reduces inflammation and protects glycometabolic pathways [138, 139]. Scientists have found that Bacteroidetes and segmented filamentous bacteria induce a striking increase in Th17 responses in the small intestine [140]. Th17 cells mainly secrete IL-17, including IL-17A and IL-17F, thereby inducing

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pro-inflammatory cytokines and chemokines. An increase in Th17 cells correlates with a concomitant increase in Th1 cells and can contribute to the development of DM by transferring thereof into Th1-like cells. Inhibition of Th17 cells has been shown to reduce islet-specific inflammatory T cell infiltration [141]. Another group of scientists found that benign intestinal symbiotic microbiota such as Schaedler flora can induce Treg cell differentiation and inhibit Th1 and Th17 cell responses. Short-chain fatty acids (SCFAs) can also promote the development of Tregs by activating GPR43. In some animal models, the combined production of CD4+, CD25+, FoxP3+, and Tregs can mitigate the destruction of pancreatic islets and protect against autoimmune DM [142]. D. Gut microbiota participate in bile acid metabolism Bile acids, the functional components of bile, are synthesized in hepatocytes from cholesterol. After conjugating to glycine and taurine, bile acids are secreted into the duodenum from the gallbladder after a meal [143]. About 95% of intestinal bile acids are actively reabsorbed by enterocytes in the terminal ileum, while 5% of bile acids escape from enterohepatic circulation and arrive in the large bowel where they are transformed into secondary bile acids under the action of intestinal flora [144– 146]. Small intestinal bile acids act as biological detergents for the solvation, digestion, and absorption of consumed lipids and lipophilic vitamins [147]. Bile acids are also crucial signaling molecules that regulate lipid, glucose, and energy metabolism via interaction with different intracellular ligand-activated nuclear receptors [147– 149]. Gut microbiota may trigger changes in weight and lipid metabolism through mechanisms mediated by the farnesoid-X-receptor (FXR) and cell surface-located G-protein-coupled bile acid receptor TGR5. According to a recent finding, gut microbiota facilitates high-fat-diet-induced obesity by modifying the bile acid profile and altering FXR signaling. FXR may also induce an obese phenotype by affecting the composition of gut microbiota [150, 151]. Bile salt hydrolase (BSH) in the human microbiome specifically catalyzes the hydrolysis of conjugated bile salts that are subsequently transformed into free bile acids. BSH is crucial for signaling pathways mediated by bile acids that regulate glucose metabolism and lipid absorption [152]. Joyce et al. demonstrated that gut microbiota could secrete BSH to influence adiposity and cholesterol levels in the host via processes that include lipid metabolism and transport, signaling pathways, hormone production, peripheral circadian rhythms, gut homeostasis and barrier function [153]. Li et al. indicated that Tempol treatment could alter the composition of intestinal flora and result in lower BSH activity in mice. Specifically, the administration of Tempol was associated with the transformation from Firmicutes to Bacteroidetes at the phylum level and decreases in Lactobacillus. Reduction in BSH activity could potentially be directly linked to higher levels of taurine-conjugated bile acids, including tauro b-muricholic acid (T b-MCA), taurocholic acid (TCA), and taurochenodexycholic acid (TCDCA) in the intestine. An increase in taurine-conjugated bile acids contributes to the inhibition of the FXR signaling pathway, through which Tempol may alleviate obesity and insulin resistance in mice [119].

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Recent clinical metagenomic and metabolomic analyses showed that samples from individuals with newly diagnosed T2DM naively treated with metformin for 3 d demonstrated a decrease in Bacteroides fragilis and an increase in the bile acid glycoursodeoxycholic acid (GUDCA) in the gut. These changes were accompanied by the inhibition of FXR signaling. B. fragilis administration augmented HFD-induced glucose intolerance, and also diminished the metabolic benefits of metformin. Furthermore, GUDCA was identified as an intestinal FXR antagonist and was proven to be benefit for metabolic disorder in animals. Thus, metformin acts in part through a B. fragilis–GUDCA–intestinal FXR axis to improve metabolic dysfunction, including hyperglycemia [154]. Relationship between gut microbiota and hyperuricemia Gut microbiota are commonly believed to participate in UA metabolism. Recent evidence indicates that gut microbiota may be associated with increasing levels of UA and the development of hyperuricemia. Intestinal flora in individuals with gout have been found to be quite different from those in healthy individuals, with higher levels of Bacteroides caccaeand and Bacteroides xylanisolvens and lower levels of Faecalibacterium prausnitzii and Bifidobacterium pseudocatenulatum [155]. Hyperuricemia treatment has also been associated with changes in gut microbiota. Treatment with allopurinol and benzbromarone was shown to decrease levels of UA and was observed to alter gut microbiota in rats at the phylum and genera levels, with increasing abundances of Bifidobacterium and Collinsella and reductions of Adlercreutzia and Anaerostipes, Yu et al. suggested that the mechanisms by which allopurinol and benzbromarone decrease UA may be correlated with gut microbiota changes [156]. Garcia-Arroyo et al. showed that the administration of probiotic bacteria could accelerate UA secretion and reduce concentrations of serum UA, suggesting another possible treatment for hyperuricemia [157].

9.4

Conclusions and Potential Therapies

A great deal of research has produced strong evidence that gut microbiota and their metabolites are important for the stability of the endocrine system and the progression of diseases such as diabetes, hyperthyroidism, and hyperuricemia. Recent research also indicates that fecal bacteria transplantation (FBT) and probiotic intervention hold promise for the treatment of these endocrine diseases. Specifically, endocrine disorders, such as obesity and diabetes, can be addressed by adding normal, beneficial bacteria, or microbial metabolites to patients’ diets. Probiotics have demonstrated its anti-inflammatory, hypoglycemic, insulinotropic, antioxidative, and satietogenic properties and could be employed in the treatment of T2DM and obesity. Most available probiotics contain bifidobacteria, lactic acid bacteria (LAB), dairy propionibacteria, yeasts (Saccharomyces boulardii), Bacillus, and the Gram-negative E. coli strain Nissle [158]. Probiotic administration

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has been associated with immune response modulation, improved lactose tolerance, prevention of diarrhea, anti-inflammatory effects, and even restorations of obesity-linked gut dysbiosis. Probiotic supplementation may also help reduce hyperphagia and improve control over weight gain, fat mass loss, and glucose tolerance [159]. Probiotics have been shown to increase the production of tight junction and adherens junction proteins, arresting gut permeability and inhibiting the passage of LPS into systemic circulation, and thereby decreasing metabolic endotoxemia. Probiotics have been investigated as a beneficial dietary supplement, positively contributing to endocrine system homeostasis. Interestingly, a growing body of research suggests that it is not the probiotics or other microbiota themselves that ameliorate endocrine pathologies, but rather the post-biologics produced by these gut microbiota. Whichever may be the case, a causal relationship between gut microbiota metabolites and endocrine disorders has yet to be fully elucidated. The function of certain metabolites, such as succinic acid and ethanol, is particularly unclear. However, manipulating microbial substrates can increase the complement of beneficial intestinal flora metabolites, and the focus on screening and identification thereof may yield new strategies for the prevention or adjuvant treatment of metabolic diseases in the future.

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Chapter 10

Gut Microbiota and Immune Responses Lijun Dong, Jingwen Xie, Youyi Wang, and Daming Zuo

Abstract The gut microbiota consists of a dynamic multispecies community living within a particular niche in a mutual synergy with the host organism. Recent findings have revealed roles for the gut microbiota in the modulation of host immunity and the development and progression of immune-mediated diseases. Besides, growing evidence supports the concept that some metabolites mainly originated from gut microbiota are linked to the immune regulation implicated in systemic inflammatory and autoimmune disorders. In this chapter, we describe the recent advances in our understanding of how host–microbiota interactions shape the immune system, how they affect the pathogenesis of immune-associated diseases and the impact of these mechanisms in the efficacy of disease therapy. Keywords Gut microbiota

10.1


Immune system
T cells
B cells
Macrophage

Introduction

Human microbiota consists of a remarkable diversity of organisms, involving bacteria, fungi, archaea, protozoans, and viruses, which seem to be more numerous than host cells [1]. Million years of symbiosis between the microorganisms and L. Dong The Fifth Affiliated Hospital, Southern Medical University, Guangzhou 510900, China L. Dong
J. Xie
Y. Wang Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China Y. Wang
D. Zuo (&) School of Laboratory Medicine and Biotechnology, Institute of Molecular Immunology, Southern Medical University, Guangzhou 510515, China e-mail: [email protected] D. Zuo Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China © Springer Nature Singapore Pte Ltd. 2020 P. Chen (ed.), Gut Microbiota and Pathogenesis of Organ Injury, Advances in Experimental Medicine and Biology 1238, https://doi.org/10.1007/978-981-15-2385-4_10

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host has resulted in a mutualistic relationship in which both the microbiota and the host benefit each other. Commensal microbiota acquires niches and nutrients to survive and grow from their host and, in turn, the microbiota contributes to various host physiological and pathophysiological processes. The resident microbes digest plant structural carbohydrates into the metabolites that the host can use for energy and nutrition. Besides, the microbes produce vitamins for disease prevention. The microbiota also plays an essential role in the maintenance of the intestinal barrier, which is crucial for homeostasis and functionality of the gut. It is generally accepted that the gut microbiota colonization is in close relationship with the establishment of intestinal mucosal immunity. The commensal microbiota modulates the maturation of the mucosal immune system, whereas the pathogenic microbiota initiates immunity dysfunction, leading to disease development. Indeed, there is increasing evidence support that gut microbiome can communicate with peripheral immune cells and influence the systemic immune system works. Alternatively, the immune system has adapted to work together with microbiota, and thus control and shape the composition of the microbiota. In this chapter, we provide an overview of the current understanding of the interplay between the gut microbiota and immunity in health and disease.

10.2

Role of Gut Microbiota in Immune System Development and Differentiation

The effect of microbiota on the development and maturation of the host immune system was explored on germ-free (GF) mice which display an underdeveloped immune system associated with dramatically reduction in size and number of secondary immune organs including Peyer’s patches and cryptopatches, altered crypt structure, and limited mucus production from goblet cells [2–5]. Additionally, deficient IgA production, over-activation of anti-inflammatory Th2 cytokines, and decreased expression of pattern recognition receptors (PRRs), like the toll-like receptors (TLRs), are observed in GF animals [6].

10.2.1 Gut Bacteria Numerous studies have revealed the complex connection between gut bacteria and immunity. Initial research had suggested that the crosstalk occurred mainly in the gut lamina propria, where a toxic gut microbial signal maintains a homeostatic immune equilibrium [7]. Recent studies have reported that bacteria–immune interaction also happens at remote extraintestinal sites [8]. Normally, the gut microbial community is predominantly comprised of the two phyla Firmicutes and Bacteroidetes, followed by the phyla Actinobacteria and

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Verrucomicrobia. A growing body of evidence suggests that gut bacteria are essential for the normal development and function of lymphoid organs and lymphocytes [9–11]. GF animals display extensive deficits in the development of gut-associated lymphoid tissues (GALT) [5]. Notably, GF animals exhibit impaired development and maturation of isolated lymphoid follicles (ILFs) [12]. Specific members of the commensal bacteria, such as B. fragilis and B. subtilis, promote GALT development through a subset of stress responses [13]. Regulatory T cells (Tregs) are most abundant in the colonic mucosa and play a vital role in the maintenance of immune homeostasis. The induction of colonic Tregs requires commensal bacteria with specialized properties in both inflammatory and noninflammatory conditions in the gut [14, 15]. Mazmanian et al. reported that monocolonization of mouse gut with B. fragilis leads to systemic immunological maturity of GF mice and increases the splenic CD4+ fraction to that seen in specific-pathogen-free (SPF) mice [9]. Treatment of mice with B. infantis led to a reduction in intestinal inflammation and an increase in the number of Tregs [16]. Additionally, colonization of GF mice with specific bacterial species is sufficient to instruct CD25+FoxP3+ Tregs differentiation and modulate disease phenotype [10]. Of note, each Bacteroides strain has been shown to induce significant increases in the proportions of Tregs among CD4+ T cells in the colon lamina propria from GF mice [11]. Prominent human symbiont B. fragilis prevents animals from experimental colitis through expanding Tregs, and this beneficial effect depends on a single microbial molecule (polysaccharide A, PSA) [10, 17]. Alternatively, B. fragilis-produced PSA directs the expansion and differentiation of CD4+ T cells, leading to a Th1 response shifting the Th2 immune response of GF mice [9, 18]. Interestingly, oral inoculation of mice with a defined mix of Clostridium strains also boosts colonic Tregs, resulting in resistance to colitis and systemic IgE responses [14]. Integrated microbiome and metabolome analyses reveal that bacterial metabolites mediate communication between the commensal bacteria and the immune system [19, 20]. Butyrate and propionate, two abundant short-chain fatty acids produced by the commensal bacteria, can induce extrathymic Treg induction by their histone deacetylation (HDAC) inhibitory activity and subsequently increased Foxp3 gene transcription [21, 22]. IL-17-expressing CD4+ cells (Th17 cells) constitute a remarkable proportion of lymphocytes presented in the intestinal lamina propria [23, 24]. Colonization of mice with the segmented filamentous bacterium (SFB) strongly induces intestinal Th17 cells in the lamina propria, which play a crucial role in host defense against intestinal pathogens and promote systemic autoimmunity [23, 25–27]. Microbiota low in Firmicutes promotes expression of Th17-related genes and differentiation of Th17 cells in mice, and administration of bacterial isolates from the F. phylum significantly eliminates the heightened Th17 responses in vitro [28]. Mao et al. found that sequential activation of IL22+ innate lymphoid cells (ILCs) followed by Th17 cells and Tregs occurs in the gut as a response to the gut microbiota [29]. Intriguingly, intestinal dysbiosis alters immune homeostasis in the gut, resulting in an enhancement in Tregs and a decrease in IL17-positive cd T cells [30]. Oral administration with

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L. casei significantly protects mice from colorectal cancer, with the modulation of Tregs to a Th17-biased immune response [31]. The immune balance of Th1/Th2 cells is crucial for immune regulation. Several studies have shown that the gut bacteria and its metabolites affect the balance of Th1/Th2 cells in the intestinal tract [32–34]. B. fragilis could promote the expression of proinflammatory cytokines, thereby enhancing the differentiation of Th1 cells by the activation of the IL-12/STAT4 pathway and major histocompatibility complex II (MHC II) expression [9, 18]. Commensal A4 bacteria, a member of the Lachnospiraceae family, which produce an immunodominant microbiota CBir1 antigen, inhibit lamina propria Th2-cell development [34]. Gut bacteria exert a dramatic, systemic effect on the activation and differentiation of B cells via direct and indirect mechanisms [13, 35, 36]. Children who colonized with E. coli and bifidobacteria early in life exhibits more circulating CD27+ memory B cells in the circulation later than infants not colonized by these bacteria [37]. Early B cell development also occurs in the mouse intestinal lamina propria (LP), where the associated V(D)J recombination/receptor editing processes are driven by interactions with antigens from commensal bacteria [13, 35]. The combination of B. fragilis and B. subtilis resulted in the development of the preimmune Ab repertoire, as indicated by a significant increase in somatic diversification of V(D)J genes [13]. Additionally, the resident bacterial metabolites short-chain fatty acids (SCFAs) modulates the metabolism status in B cells, thereby enhancing the antibody production in the host [36]. The intestinal lamina propria includes antigen-presenting cells with features of dendritic cells (DCs) and macrophages, collectively referred to as mononuclear phagocytes (MNPs), integrating microbial signals to maintain gastrointestinal homeostasis and direct adaptive immunity [38]. It has been reported that intestinal microbial colonization drives the continuous replenishment of macrophages in the intestinal mucosa by monocytes that express C–C chemokine receptor type 2 (CCR2) [39]. CX3CR1+ MNPs, derived from CCR2+Ly6Chi peripheral blood monocytes, are the most abundant intestinal macrophages in the healthy intestine [39]. The local accumulation CX3CR1+ MNPs depends on the enteric flora since a limited amount of CX3CR1+ cells was observed in the LP of GF animals [40]. CX3CR1+ MNPs ensure the maintenance of immune tolerance by facilitating the differentiation of Treg cells [41]. Stimuli from microbial commensals increase the secretion of BMP2 by macrophages, thereby controlling the gastrointestinal motility [42]. Intestinal macrophages also play a crucial role in the maintenance of mucosal T cells, with commensal bacteria-driven production of IL1b by mucosal macrophage having been shown to associate with the development of the Th17 cells [43]. Foligne et al. have determined that DCs internalize L. rhamnosus, thus maintaining an immature phenotype. Moreover, the L. rhamnosus-treated DCs can prime Tregs activity in the gut [44]. Collectively, these data make it clear that the gut bacteria are essential for the education of both the innate and adaptive immune systems (Fig. 10.1).

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Fig. 10.1 The interaction between gut microbiota and immune system development.Disorders of the proportion and quantity of intestinal commensal bacteria and pathogens can lead to dysbiosis under pathological conditions. Dysbiosis enhances gut permeability and leads to bacterial and toxins translocation. Pattern recognition receptors (PRRs) expressed on activated immune cells (DC) are able to recognize pathogen-associated molecular patterns (PAMPs) expressed on bacterium, thereafter, influencing the CD4+ T cell differentiation into subsets such as Th1, Th2, Th17, and Tregs. Furthermore, the concomitant action of Tregs creates a state of immunosuppression. B cells in the lamina propria of the intestine exert immune function by secreting antibodies after antigen stimulation

10.2.2 Gut Virus Numerous studies have demonstrated the association between the host and viruses in the gut that is more similar to host–bacteria interactions and contains both beneficial and detrimental effects for the host [45–47]. Reovirus enteric infection can result in loss of tolerance to dietary antigens by influencing intestinal immune homeostasis [46, 48]. In an animal model, the differentiation of peripheral regulatory T cells via IFN-I and increased dietary antigen-specific Th1 responses through the transcription factor IFN regulatory factor 1 (IRF1) were blocked by reovirus infection [46]. In addition, patients with celiac disease exhibit elevated production of type I interferon (IFN-I), including IFN-a and IFN-b, by intestinal DCs that promote Th1 responses in the gut that is consistent with the side effect of antiviral therapy [48]. Notably, patients with celiac disease also have higher anti-reovirus antibody titers, correlated with a higher level of IRF1 in the small intestinal mucosa [46]. The gut is a major site of HIV replication and HIV-specific immune response, which leads to aggressive depletion of lamina propria CD4+ T cells during acute infection [49]. Enteric adenoviruses and anelloviruses are markedly increased in HIV-positive patients with low peripheral CD4+ T cell counts, indicating that gut commensal virus was associated with HIV infection [47]. A recent study

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demonstrated that murine norovirus infects tuft cells, leading to induce type 2 immune responses and promote the virus infection [50].

10.2.3 Gut Fungus The fungal community, also named as mycobiota, inhabits on various barrier surfaces of the host, which range from the skin, lung, oral cavity, and the vagina to the best-known site, the gastrointestinal tract [51]. Evidence supports that fungi can also interact with gut immune cells to maintain intestinal well-being [52, 53]. The dimorphic fungus C. albicans is the majority member of the gut mycobiota and is associated with gut immunological homeostasis [52, 54]. Of note, C. albicans stimulates Th17 cells in the mouse intestine irrelevant of the preexisting gut mycobiome composition [55, 56]. Circulating C. albicans-specific Th17 cells are observed in the peripheral blood of healthy individuals [57]. In addition to recognizing intestinal bacteria, CX3CR1+ MNPs express several antifungal C-type lectin receptors (e.g., dectin-1, dectin-2, and Mincle) and can phagocyte intestinal yeast and filamentous fungi [58]. In the gut, CX3CR1+ MNPs prime antigen-specific Th17 responses to C. albicans via the activation of Syk signaling [52]. Besides, the induction of antifungal antibodies is partially dependent on CX3CR1+ MNPs, which is associated with intestinal inflammation [52]. Interestingly, C. albicans-specific Th17 cells could cross-reactive to other fungal species, like Aspergillus fumigatus [59]. Antifungal antibodies against C. albicans detectable in the serum of patients with colitis co-occur with antibodies recognizing several other mycobiota members belonging to the Saccharomycetaceae family, such as C. parapsilosis, S. cerevisiae, and P. kudriavzevii [52]. These results show that gut mycobiota initiates trained immunity and suggests that mycobiota participates in the intestinal immune homeostasis. However, current studies are limited by the use of few model fungal strains.

10.3

Role of Gut Microbiota in the Regulation of Immune Responses

The immune system is responsible for recognizing, responding, and adapting to countless foreign and self-molecular and is therefore important during conditions of both health and disease. It is well known that the microbiome helps to regulate immune responses, and, in turn, the immune system shapes the composition of the microbiota. GF animals showed limited immune resistance to infection and increased mortality compared with conventionally colonized animals when challenged with pathogenic microorganisms. Management of commensal microbiota affects the outcome of enteric pathogen infection through its modulation of host

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immune responses to infection [60, 61]. GF animals show reduced antigen-specific systemic immune responses to S. typhimurium, suggesting that enteric pathogens might develop strategies to counter both the immune system and the microbiota during the infectious process [61]. It is conceivable that GF mice have significantly different serum chemokines and cytokine profiles at baseline compared to conventionally raised mice [62]. Additionally, a marked reduction in the levels of secretory IgA in the gut was observed in GF mice [63]. Indeed, gut microbiota dysbiosis is associated with abnormal immune responses, accompanied by aberrant expression of inflammatory cytokines [64]. Gut microbiota contributes to the homeostatic production of pro-IL1b by intestinal phagocytes in a MyD88-dependent manner, thereby priming these cells to respond rapidly to pathogenic bacterial infections by conversion of pro-IL1b to mature IL1b through the NLRC4 inflammasome [65]. Intriguingly, oral administration of F. prausnitzii or supernatant from F. prausnitzii cultures enhanced the production of IL10 by peripheral blood mononuclear cells, reduced the production of TNF in the colon, and ameliorated intestinal disease in mice [66]. Interestingly, treatment of colitis mice with the probiotic cocktail (a mixture of bacteria consisting of four strains of L. casei, L. plantarum, L. acidophilus, and L. delbrueckii) increased the production of IL10 and the percentage of TGFb-expressing T cells [67]. Depletion of TGF-b-bearing CD4+ T cells from mice treated with probiotic bacteria before the transfer of lamina propria cells abolished the protective capacity of these cells [67]. The proinflammatory gut microbiota from caspase1−/− mice accelerates the atherogenesis in the mice model of atherosclerosis and increases the systemic inflammation, accompanied by enhanced proinflammatory cytokines and increased blood leukocyte numbers, implying a relationship between microbiota composition, inflammation, and atherosclerosis [68]. The gut resident microbiota composition profoundly influences the adaptive immune responses to influenza virus infection through the proper activation of inflammasomes, and antibiotic treatment predisposes the mice to high viral replication in the lung [69]. In the gastrointestinal tract, the association of commensal fungi with the innate immune receptor dectin-1 could prevent inflammation in the context of acute mucosal injury [58]. In murine experimental autoimmune encephalomyelitis (EAE) model, modifying certain gut microbiota components affects immune cell priming in the periphery, leading to dysregulation of immune responses and neuroinflammatory processes in the central nervous system (CNS) [70, 71]. Wilck et al. showed that a salt challenge in healthy individuals influences the abundance of intestinal Lactobacilli, accompanied by increased frequencies of proinflammatory Th17 cells in the blood, resulting in aggravation of experimental neuroinflammation [72]. Multiple bacterial species present in the gut produce metabolites, such as short-chain fatty acids (SCFAs), vitamin A, and butyrate, contributing to the orchestration of host immune response [19, 71]. Gut microbiota-produced SCFAs inhibit nuclear factor-jB (NF-jB) signaling and limit the production of TNF in neutrophils and peripheral blood mononuclear cells [73, 74]. Recognition of SCFA by innate immune cells for the regulation of inflammation in response also showed

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the models of arthritis and allergy [75]. Additionally, administration of the SCFA during EAE ameliorates disease symptoms by increasing Treg cell frequencies in the small intestine, thereby leading to a more anti-inflammatory environment in the gut [71, 76]. Gut bacteria control the production of the vitamin A metabolite retinoic acid to weaken the immune system and increase the risk of infectious diseases [77, 78]. Klebanoff et al. reported that vitamin A controls the homeostasis of pre-DC (precursor of DC)-derived splenic DCs and contributes to the regulatory specialization of mucosal DCs in the gut [78]. Butyrate was shown to markedly promote anti-inflammatory IL10 production in DCs and macrophages, implicating its regulatory role in immune functions [79]. It is noteworthy to mention that IL-10 augments the generation of functional Tregs likely mediated via the STAT3 and Foxo1 pathway [80]. The induction of Tregs in the gastrointestinal tract environment contributes to the maintenance of a mutualistic relationship with the microbiota and the systemic control of host immune responses [16].

10.4

Gut Microbiota and Immune Diseases

The interactions between the host and its gut microbiota are crucial for the maintenance of tissue homeostasis. It is unsurprising that abnormal interactions have emerged as a pivotal driver of various chronic disease states. Indeed, gut dysbiosis and the consequent development of pathogenic populations within the gut microbiota and its metabolites may contribute to a wide variety of pathologies, even in sites distant from the gut, ranging from bowel inflammation to systemic autoimmune disorders and cancer (Table 10.1).

10.4.1 Autoimmune Disorders The etiology of autoimmune disorders is multifactorial, including a mixture of genetic susceptibility and environmental factors. Among the environmental factors that gained attention during the last few decades, the imbalanced gut microbiota has been suggested to involve in the maintenance of healthy human physiology and the development of systemic autoimmune orders [81].

10.4.2 Inflammatory Bowel Diseases Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative disease (UC), is a group of chronic inflammatory disorders that affect the gastrointestinal tract and extraintestinal organs. Gut microbes were proven to be an essential factor in intestinal inflammation in IBD [82, 83]. HLA-B27 transgenic

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Table 10.1 Studies investigating intestinal microbiota in patients Disease subjects Alteration in microbiota Autoimmune disorders IBD mice H. hepaticus IBD mice F. varium IBD patients F. prausnitzii UC mice B. fragilis and its polysaccharide A UC mice Clostridium UC mice B. fragilis T1D mice L. johnsonii N6.2 and some Streptococcal species T1D mice Lactobacillaceae T1D mice Segmented filamentous bacteria T1D mice A. muciniphila SLE mice Clostridia SLE mice Segmented filamentous bacteria SLE mice Lactobacilli SLE mice Synergistetes RA mice RA mice

P. gingivalis Segmented filamentous bacteria Immunodeficiency disorders CVID patient Firmicutes AIDs patients Proteobacteria, Prevotella Cancers CRC patients Fusobacterium CRC mice B. fragilis Colon cancer B. fragilis patients and mice Colorectal cancer Lactobacilli liver tumor mice Melanoma mice pancreatic cancer Epithelial tumors

Clostridium species Bifidobacterium Bifidobacterium A. muciniphila

Immune-related target IL-10 Inflammatory cells Inflammatory cytokines Tregs Tregs IL-10 Th17 cells

References 87 90 68 17 14 17 110,111

CD103+ DCs Th17 cells

112 26

Immune tolerance Th17/Th1 balance IL-17

109 127 129

IL-6 IL-6 and anti-dsDNA titer IL-17 Tfh cells

8 127

Tregs Active T cells, DCs

15 150

Antibody IL-10 CTLA4 Th17-biased immune response NKT cells PD-L1 T cells CCR9+CXCR3+CD4+ T cells

140 141

164 17,165 179 31 170 180 171 181

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rats, which spontaneously generate chronic colitis, do not develop the inflammatory intestinal disease when they are kept in a GF environment [84]. Uniformly, spontaneous IBD in IL-10 deficient mice associated with the infection with H. hepaticus [85]. The next-generation sequencing analysis showed that Enterobacteriaceae, Pasteurellacaea, Veillonellaceae, and Fusobacteriaceae are revealed to be increased in IBD, while the abundances of Erysipelotrichales, Bacteroidales, and Clostridiales are negatively correlated with disease status [86]. Garrett et al. found that Enterobacteriaceae act in concert with the gut microbiota to cause IBD [87]. F. varium and its metabolite, butyric acid, are able to cause UC-like lesions in mice [88]. Alternatively, there are also studies that determine the specific groups of gut microbiota that may play a protective role against IBD [28, 66, 89]. Compared with healthy controls, the gut microbiota of patients with CD exhibited a markedly reduced diversity of Firmicutes [89], and similar findings were observed in CD patients with monozygotic twins discordant [90]. Indeed, GF mice colonized with microbiota from UC patients low in Firmicutes showed increased sensitivity to colitis compared with mice transferred with synthetic ecosystems rich in Firmicutes [28]. F. prausnitzii displays anti-inflammatory properties and is underrepresented in IBD patients [66]. Indeed, CD patients with low abundances of F. prausnitzii in the mucosa are more prone to have relapse after surgery [91]. It was also confirmed that certain intestinal symbiotic bacteria and their metabolites could promote the immune balance among Th cells in mammals, thereby preventing the development of IBD [17, 92, 93]. Human symbiont B. fragilis and its polysaccharide A (PSA) can inhibit the infiltration of neutrophils in the intestinal tract of experimental animals with IBD by stimulating Treg cells to produce IL-10, thereby preventing mice from developing colitis [17]. Oral inoculation of Clostridium during the early life may alleviate colitis in mice, where the action of the bacteria is facilitated by inducing Tregs [14]. Notably, preliminary data suggest that an elevated load of Candida species in the gut may be associated with the pathogenic feature of CD, indicating a role of the gut mycobiota in the pathogenesis of IBD pathogenesis [94]. Fecal microbiota transplantation (FMT) is a safe and highly effective treatment for colitis caused by C. difficile infection (CDI) [95]. The therapeutic success of FMT in CDI-induced colitis is attributed to the restoration of the gut microbial homeostasis in patients with dysbiosis [96]. It should be noted that CDI-induced colitis is associated with reduced microbial diversity (Bacteroidetes and Firmicutes), which is similar to what is seen in IBD patients [97]. In multiple mouse models, F. prausnitzii, Clostridia strain, and B. fragilis could attenuate the severity of colitis [17, 66, 93]. In the future, FMT will be likely substituted by the use of defined microbe or their metabolites in the treatment of IBD.

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10.4.3 Type 1 Diabetes Type 1 diabetes (T1D) is caused by autoimmune destruction of insulin-producing beta cells and is believed to involve both genetic and environmental factors. Altered permeability of the gut barrier with microbial dysbiosis has been implicated in the pathogenesis of T1D [98, 99]. A markedly decrease in alpha diversity of the gut microbiome in infants genetically predisposed to T1D during the time window between seroconversion and T1D diagnosis [100]. Comparison of new-onset T1D patients and control subjects suggests that functional changes in the stool metaproteome may be associated with islet autoimmunity [98]. Earlier studies determined that non-obese diabetic (NOD) mice maintained under GF conditions have an increased incidence of diabetes [101, 102]. A recent study showed that GF NOD mice colonized with human gut microbiome are able to delay the onset and reduce the incidence of diabetes [103]. Together, these data suggest that intestinal microbiota is involved in the development of T1D. Of note, NOD mice deficient for MyD88, a canonical adaptor for inflammatory signaling pathways downstream of members of the Toll-like receptor (TLR) and interleukin-1 (IL-1) receptor families, are protected against diabetes, but this effect was diminished in the absence of commensal bacteria [104]. Transfer of gut microbiota from diabetes-protected MyD88−/− NOD mice altered the mucosal immunity and further significantly delayed the development of autoimmune diabetes [105]. Moreover, NOD mice cohoused with dysbiotic inflammasome-deficient mice display lower diabetes incidence compared to noncohoused NOD mice [106], indicating that inflammation modulates the intestinal immune system and inflammation control may be important in T1D management. Many studies have shown that modulation of specific gut microbiota has a significant impact on gut mucosal and the pathogenesis of T1D [26, 107]. Colonization of NOD mice with SFB can induce a substantial population of Th17 cells in the lamina propria and prevent diabetes development [26]. Besides, oral administration of L. johnsonii N6.2 and some Streptococcal species suppresses anti-islet autoimmunity and prevents diabetes development in a spontaneous rat diabetes model by gut flora-mediated Th17 differentiation [108, 109]. Dolpady et al. reported that modification of the gut microbiota profile by oral treatment with Lactobacillaceae-enriched probiotic also affects the inflammasome activation and of tolerogenic CD103(+) DCs differentiation in the gut, therefore changing the intestinal microenvironment and preventing T1D [110]. Notably, the transfer of A. muciniphila to NOD mice promotes mucus production and significantly lowers the incidence of T1D, accompanied by a reduction in serum bacterial endotoxin levels and islet TLR expression [107]. Additionally, emerging evidence indicates that gut microbial metabolites are possible modulators of diabetes [111–114]. Gut microbiota acts as a regulator of glycaemic control in diabetic autoimmunity, and altered microbial metabolism may contribute to the pathogenesis of T1D [111]. Indeed, the beneficial effect of A. muciniphila on protection against the development of T1D is mediated by evoking metabolic and immunologic signaling to

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facilitate immune tolerance in the gut [107]. Dexi is considered as a candidate gene for human T1D risk [115, 116]. Disruption of Dexi in the NOD mouse depletes gut microbial metabolites and enhances serum levels of IgA and IgM, resulting in accelerated spontaneous autoimmune diabetes [116]. The gut microbiota-derived metabolites, aryl hydrocarbon receptor (AHR) ligands and butyrate, increase the IL-22 production by pancreatic ILCs, thereby preventing autoimmune diabetes in the NOD mice [113]. Strikingly, feeding NOD mice with a combined acetate- and butyrate-yielding diet protects against insulitis, mainly through decreasing the frequency of autoreactive T cells by acetate and boosting Treg cells by butyrate [114]. Collectively, alteration of the gut microbiome or metabolite profile might represent an effective approach for diabetes management.

10.4.4 Systemic Lupus Erythematosus Compared to healthy controls, a depletion of the Lactobacillus population, an enrichment in members of the family Lachnospiraceae, and an increase in overall diversity have been described in the systemic lupus erythematosus (SLE) mouse model, MRL/lpr mice [117]. In an NZB/W F1 murine model, the composition of the gut microbiota was dependent on the disease onset, showing a higher diversity and increased the representation of several bacterial species as lupus progressed from the predisease stage to the diseased stage [118]. Oral antibiotics are known to trigger lupus flares in human, suggesting a crucial role for commensal bacteria in SLE patients [117, 119]. Hevia et al. found a significantly lower Firmicutes/ Bacteroidetes ratio in SLE individuals than in healthy subjects [120]. Consistently, depletion of Firmicutes and enrichment of Bacteroidetes in SLE patients from China were also observed [121]. In contrast, Luo et al. reported that SLE patients with active disease possessed distinct relative abundances of particular Bacterial species, with an increase in Gram-negative bacteria, but the Firmicutes/ Bacteroidetes ratio was no different from that found in a healthy human cohort [118]. The inconsistency conclusion may be due to differences in the study design (active vs. inactive patients; female patients group vs. female and male patients group; patients receiving immune therapies vs. patients not receiving immune therapies). The human gut microbiota provides a major source for antigenic variation, which may trigger autoimmunity via cross-reactivity in genetically susceptible individuals. Greiling et al. reported that human Ro60 autoantigen-specific CD4 memory T cell clones from lupus patients were induced by commensal Ro60-containing bacteria. Moreover, monocolonization with a bacterial Ro60 ortholog enhances systemic lupus-like disease in a lupus mouse model [122]. A key feature of SLE is T cell activation, which facilitates the formation of self-antigen/antibody immune complexes [123]. In vitro studies revealed that microbiota isolated from SLE patient stool samples promoted highly lymphocyte activation and Th17 differentiation compared to healthy control microbiota [124]. Also, fecal microbiome from SLE mice could lead to an obvious increase of

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anti-dsDNA antibodies and promote the immune response in recipient mice [125]. A mixture of two Clostridia strains significantly reduced the Th17/Th1 balance, whereas B. bifidum supplementation prevented CD4+ lymphocyte over-activation in SLE [124]. SFB strongly induces intestinal Th17 cells in the lamina propria [23, 25], and gut colonization with SFB promotes antinuclear antibodies production in mice mediated by IL-17 receptor signaling [126]. Similarly, restoration of lactobacilli levels by recolonization, antibiotic, or retinoid acid therapy ameliorated lupus symptoms and survival in lupus-prone mice by decreasing IL-17-producing cells and IL-6 secretion in the gut [8]. Intriguingly, reduced amounts of intestinal Synergistetes in SLE microbiota are linked with increased anti-dsDNA titer and IL-6 serum levels but a reduced quantity of natural protective anti-phosphorylcholine IgM antibodies [124]. It is noteworthy that the microbial components may influence levels of host hormones and play a role in disease development. Colonization of female BWF1 mice with gut microbiota from male BWF1 mice suppresses the SLE disease severity by enhancing tolerogenic CD103+ DC activity, which reinforces the role of microbiota in the sexual bias of SLE disease development [127].

10.4.5 Rheumatoid Arthritis Rheumatoid arthritis (RA) is a chronic and systemic autoimmune disease characterized by destructive alterations to the multiple joints. It results from a complex interaction between genetic and environmental factors, leading to a breakdown of immune tolerance and synovial inflammation [128]. The association of gut microbiota in RA development is supported by the observation that mice models, which spontaneously develop arthritis in a conventional environment, but do not develop arthritis under a GF condition [27, 129]. Moreover, a stronger reduction in gut microbial diversity was observed in RA patients compared to healthy controls, which is associated with the disease duration and autoantibodies levels [130]. RA patients under treatment with anti-TNF-a antibody present a partial restoration of beneficial microbiota [131]. Mice susceptible to collagen-induced arthritis (CIA) showed abundant Lactobacillus as the dominant genus prior to arthritis development. L. casei protects against the RA progression by suppressing the Th1-type cellular and humoral immune responses in arthritic inflammation [132, 133]. By contrast, L. rhamnosus and L. reuteri administration failed to attenuate the RA disease in patients suggesting that different Lactobacillus species may act differently on the development of arthritis [134, 135]. Of note, GF-free mice administrated with the commensal microbiota from CIA-susceptible mice showed a higher incidence of arthritis than those conventionalized with the microbiota from CIA-resistant mice. It was shown that the concentration of serum IL-17 and the frequency of CD8+ T cells and Th17 cells in the spleen were significantly higher in the former group, indicating that gut microbiome influences the arthritis susceptibility through regulation of systemic immune response [136]. Consistency,

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P. gingivalis administration significantly aggravated the arthritis induced by collagen in DBA mice with elevated sera IL-17 levels and a significant alteration in the gut microbiome [137]. Besides, administration of a single gut-residing species, SFB, into GF animals reinstates the lamina propria Th17 cell compartment and triggers autoimmune arthritis, which is associated with the differentiation and migration of Peyer’s patch T follicular helper (Tfh) cells [27, 138]. A recent study demonstrates that the high level of kaempferol in the gut regulates the intestinal flora and microbial metabolism, which are potentially responsible for the anti-arthritis effects of kaempferol [139]. RA patients receiving anti-TNF-a etanercept exhibit an enrichment of Cyanobacteria in the gut [131]. It should be noted that Cyanobacteria produce secondary metabolites with multiple bioactivities, like anti-inflammatory and immunosuppressant activities [140]. It is possible that metabolites produced by Cyanobacteria benefit RA patients. Intriguingly, ES-62, a phosphorylcholine (PC)-containing glycoprotein secreted by the filarial nematode A. viteae, has been able to modulate the gut-associated immune responses [141, 142]. Doonan et al. reported that subcutaneous administration ES-62 protects against joint disease in the CIA, which is related to the normalization of gut microbiota and prevention of loss of intestinal barrier integrity [141].

10.4.6 Immunodeficiency Disorders Immunodeficiency is a state in which the host immune system fails to fight against infection and disease. The cases of immunodeficiency disorders can either be primary by heritage or secondary due to extrinsic factors. Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency characterized by recurrent infections and low antibody levels. CVID patients have reduced gut bacterial alpha diversity compared to healthy subjects, and the decreased diversity is related to elevated plasma levels of endotoxins and weakened systemic T cell activation [143]. Indeed, the functional impairment of CD4+ T cells in CVID patients is restricted to bacteria-specific CD4+ T cells. Notably, endotoxemia was associated with significantly increased expression of programmed death 1 (PD-1) on CD4+ T cells, indicating that CD4+ T cell exhaustion and functional impairment observed in CVID patients is related to bacterial translocation [144]. CVID patients have a lower proportion of Treg cells compared to healthy controls in their peripheral blood. The hallmark of CVID is hypogammaglobulinemia, which suggests that the IgA production is also impaired. Interestingly, the diversified IgA contributes to maintain the diversity and stability of healthy microbiota, in turn, facilitates the expansion of Tregs [15]. Disruption of this feedback loop in CVID patients through IgA deficiency and microbiota disorder can thereby have a profound effect on Treg cells. Human immunodeficiency virus (HIV) infection is a viral infection that progressively destroys certain immune cells and further lead to acquired immunodeficiency syndrome (AIDS). Gastrointestinal disease is a serious complication of

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AIDS, indicating that dysbiosis is common among patients with AIDS [145]. Indeed, HIV infection-associated dysbiosis is characterized by reduced levels of a-diversity and Bacteroidetes as well as increased levels of Proteobacteria [146– 148]. Most importantly, the alterations of gut microbiota correlate with the route of HIV transmission [146]. Indeed, the gut microbial dysbiosis is associated with many immunological properties, including CD4+ T cell activation and inflammatory regulation, all of which have been related to the disease progression [147–149]. Interventions to reverse gut dysbiosis could be a new approach for improving immune reconstitution of individuals with HIV infection.

10.4.7 Cancer A growing body of evidence suggests a crucial role for gut microbes in the etiology of cancer, including both local and distant cancers [150]. Previously, the researchers paid much attention to identify specific microbiota that may directly promote or protect against gastrointestinal malignancies. Indeed, the capacity of gut microbes to induce systemic inflammation and immune homeostasis indicates that the commensal microbiota may also be associated with the development of cancers in tissues outside of the gastrointestinal tract. H. pylori is an important bacterium colonized in the human stomach, which provokes the chronic inflammatory state and is believed to account for the occurrence of gastric cancer [151]. Interestingly, several studies show that chronic infection with H. pylori appeared associated with moderately increased risk of colorectal cancer (CRC), particularly among African-Americans [152–154]. A recent study showed that antibodies to four H. pylori proteins were most often present among the different ethnic groups with CRC. VacA, an H. pylori protein, in particular, has a strong association with increased risk of CRC among the African-American patients. Most importantly, high levels of antibodies against VacA linked to the incidence of CRC in both African-Americans and Asian-Americans [154]. It is of interest to determine whether the types and amounts of gut microbiota people harbored based on the genetic origin or heritage, and further studies are warranted. Notably, studies have provided evidence that other species of gut bacteria may play a role in the colonic carcinogenesis [155–159]. E. coli expressing the polyketide synthase (pks+) enhance tumorigenesis in preclinical CRC models [158]. Genomic analysis of the gut microbiome of human CRC patients reveals a major enrichment of Fusobacterium species, such as F. nucleatum, in this cancer [155]. In vitro studies showed that F. nucleatum enhances the CRC cell proliferation [160]. Moreover, F. nucleatum modulates the tumor immune environment by promoting M2 polarization of macrophages and suppressing the function of tumor-infiltrating lymphocytes, thereby affecting the carcinogenesis of CRC [161]. Enterotoxigenic B. fragilis (ETBF) that can secrete B. fragilis toxin is thought to possibly promote early CRC carcinogenesis through affecting the mucosal immune responses [156]. In contrast, Lee et al. revealed that

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B. fragilis treatment prevents colon tumorigenesis in a mice model of colitisassociated CRC. The decreased tumorigenesis by B. fragilis administration is accompanied by an inhibited expression of C-C chemokine receptor 5 (CCR5) [157]. Indeed, B. fragilis exhibits a preventive effect against intestinal inflammatory diseases in the animal model with colitis [17, 162]. The contradictory function of B. fragilis observed in the development of CRC might due to the imbalanced composition of intestinal microbiota and that intestinal inflammation during the process of CRC. It is worthy to mention that restricting the bloom of Enterobacteriaceae suppresses intestinal inflammation and decreases the incidence of colonic tumors in mouse models of colitis-induced CRC [163]. Apart from the stomach and colorectal cancers, associations of the gut microbiome with the cancers in tissues outside of the gastrointestinal tract (e.g., liver, pancreas, prostate, breast, and others) have also been well documented [150, 164, 165]. The liver has long been known to communicate with the intestine via the portal vein and expose to the substances derived from the gut microbiota [165]. Alteration of gut microbiota modulates the secreted levels of deoxycholic acid (DCA), which can provoke the senescence-associated secretory phenotype in hepatic stellate cells (HSCs) and facilitate hepatocellular carcinoma development in mice [166]. Ma et al. found that colonization with a commensal Clostridium species, which are involved in the conversion of primary to secondary bile acids, inhibits the accumulation of hepatic NKT cells and increases the liver tumor metastasis [167]. Hence, future investigations are warranted to determine the potential effect of these factors on the immunosurveillance of liver cancers. Alteration of gut microbiota is associated with increased risk of pancreatic cancer since removing bacteria from the gut and pancreas reduced the pancreatic cancer growth [168]. Mechanistic studies showed that the abundant gut microbiome drives an immune suppression program in pancreatic cancer [168]. Of note, the capacity of gut microbiome to influence systemic hormone levels may be important in the diseases such as prostate cancer and breast cancer that is dually affected by estrogen and androgen levels [169, 170]. Together, these studies point out the crucial role of gut microbiota in modulating carcinogenesis at distant sites through systemic effects. Accumulating evidence supports that the gut microbiota can influence the effectiveness of cancer immunotherapy [171, 172]. GF mice and mice that are treated with antibiotics both show a diminished response to immunotherapy by CpG oligonucleotides and chemotherapy owing to the impaired function of myeloid-derived cells in the tumor microenvironment [171]. Indeed, some probiotic supplements have shown a potential antineoplastic activity. For example, the culture supernatant from L. casei exhibits a strong tumor-suppressive effect on colon cancer cells, which is mediated by the activation of the JNK pathway [173]. It has also been reported that Lactobacilli is able to induce a Th17-biased immune response for antitumor activity [31]. Treatment with the immune checkpoint inhibitors exhibits dramatic effects on improving survival rates for people with cancer [172]. Preclinical and clinical studies hint a link between the composition of gut microbiome composition and antitumor efficacy of immune checkpoint inhibitors

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[174]. Unfolded protein response (UPR) is a cellular process that helps to keep protein populations stable by clearing away those that cell stress has caused to fold incorrectly. Li et al. found that UPR activity was lower in people with melanoma whose cancer responds to immune checkpoint inhibitors and pinpointed the UPR as an important link between the gut microbiota and antitumor immunity [175]. Experimental data from animal models demonstrate that gut microbiotas, such as Bacteroides species, Bifidobacteria species, and A. muciniphila, are able to potentiate the anticancer effect of checkpoint blockade therapies, including anti-CTLA-4 and anti-PD-1 antibodies [176–179]. A greater understanding of the communications of commensal bacteria with each other and the host immune system will allow us to improve the patient responses to cancer immune therapy through manipulating the human gut microbiome.

10.5

Concluding Remarks

The importance of the innate immune sensing of commensal microorganisms was recognized merely a decade ago. Since then, multiple levels of interaction between the microbiota and the cells of the immune system have been uncovered. This area of research has led to the integration of the microbiota as an intrinsic regulator of both local and systemic immunities. A comprehensive characterization of the microorganisms and metabolites that are sensed by the host immune system and their effects on the transcriptional and post-transcriptional landscape of the host will greatly expand our understanding about the molecular etiology of microbiotadriven tissue and organ disorders. Importantly, our deepening knowledge about the interactions between the host immune system and the gut microbiota will ultimately result in the development of therapeutic approaches for multiple diseases. However, the various candidates among these complex interactions (e.g., microbiota species, microbial metabolites, host factors, and molecular signaling pathways) as well as the diet influence remain to be determined. In fact, the microbiome is amenable to rapid change through dietary interventions that could be tailored by the host genetic background, microbiome, and metabolome, as well as nutrient intake and habitual food consumption. Identifying the association of gut microbiome alteration with immune response modulation and defining the change of metabolic pathway are necessary for the development of safer strategies for strength host immunity. The future of immunotherapy might combine direct drug-based immune modulation with microbiome and metabolome modification to collectively improve therapeutic outcomes.

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Chapter 11

Gut Microbiota and Multiple Organ Dysfunction Syndrome (MODS) Peng Chen and Timothy Billiar

Abstract Multiple organ dysfunction syndrome (MODS), also referred to as external challenge-induced multiple organ injury, is characterized by dysfunction of two or more organs during infection or following shock or trauma. The pathogenesis of MODS is multifactorial and involves systemic inflammation and cell stress responses including cell death; sepsis is defined as an infection with MODS. Gut microbiota contributes significantly to organ dysfunction and to the pathobiology of sepsis. However, the relationship between the development of sepsis and the composition of gut microbiota is equivocal and is only now starting to be elucidated. Recent studies by our group and others reveal that enteric microbial composition and function are disrupted during sepsis, and that microbial products can either promote or alleviate the progression of sepsis. Here, we summarize the current research on the functional link between gut microbiota and sepsis, and argue the point that gut microbiota is a potential therapeutic target in the management of sepsis. Keywords Gut microbiota

11.1


MODS
Sepsis

Sepsis

Sepsis is one of the leading public health problems worldwide and is caused by a dysregulated host immune response during infection, leading to multiple organ dysfunction syndrome (MODS) [1, 2]. Overall, the patient mortality from sepsis is P. Chen Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, N.No.1838 Guangzhou Ave., Guangzhou 510515, China e-mail: [email protected] T. Billiar (&) Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 P. Chen (ed.), Gut Microbiota and Pathogenesis of Organ Injury, Advances in Experimental Medicine and Biology 1238, https://doi.org/10.1007/978-981-15-2385-4_11

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approximately 20–30% and it is the principle cause of death in intensive care units (ICU) [3–5]. In 2016, the definition of sepsis was updated and now incorporates infection, dysregulated immune response, and organ dysfunction as contributing factors. Specifically, the combination of an infection and a sequential organ failure assessment (SOFA) score of  2 is recognized as sepsis [6]. A SOFA score is calculated from the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2), and using plasma bilirubin and creatinine concentrations and blood pressure readings, among other parameters. The detail information about SOFA score could refer to reference 6. When sepsis is complicated by a low mean arterial pressure (2 mmol/L), the condition is defined as septic shock. The cardiovascular, neurologic, and hematologic systems, with liver, kidney, and lung, encompass the respective systems and organs disrupted in sepsis. During the initial stages of sepsis, the lungs are usually first affected, resulting in decreased respiratory function, as characterized by reduced PaO2/FiO2. Furthermore, sepsis involves the liver, with its dysfunction evidenced by increase in plasma bilirubin and aminotransferases. In addition, coagulation disturbances are often observed and are associated with diminished platelet numbers. This effect is partially due to microthrombi formation leading to malperfusion at the level of microcirculation. Vascular dysfunction and capillary leaks lead to drops in blood pressure that are resistant to vasopressor treatments. Renal dysfunction, as measured by elevated creatinine, is one of the major causes of adverse outcomes and often requires organ replacement therapy. Finally, impairment of central nervous system function is estimated by the Glasgow Coma Score. Sepsis induced MODS is identified by dysfunction of two or more organs, complications and high mortality [1]. Thus, the pathogenesis of sepsis is complex and involves dysregulated host immune responses, and damage to normal organs, tissues, and cells. For example, uncontrolled infection precedes systemic inflammation from cytokine over-production by macrophages and other immune cells, that is, “cytokine storm” [7, 8]. Depressed immune defenses render the host susceptible to secondary microbial infections and further propagate organ dysfunction [9]. Overall, the dysregulated immune responses in sepsis are complicated and are the topics of ongoing investigation.

11.2

Gut Microbiota and Sepsis

Knowledge about the link between gut microbiota and sepsis is limited. Traditionally, it was considered that sepsis augmented intestinal permeability and promoted translocation of gut microbiota to the circulatory system and peripheral organs, amplifying inflammation and organ injury [10–12]. However, the specific mechanisms by which sepsis enhances gut permeability remain unclear, and few data are available to link intestinal microbial composition and/or functional

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alterations to sepsis. Investigating this intriguing hypothesis, we and others are the first to establish a direct link between sepsis and enteric microbial eubiosis [13]. In the clinic, we found that sepsis patients show enteric dysbiosis compared with healthy subjects. Thus, the microbial composition between the two groups was different; alpha-diversity metrics (Chao1 index, Observed species, Shannon index, and Simpson index) were decreased in patients with sepsis as compared with healthy subjects. Moreover, specific strains such as Bacteroidetes, Proteobacteria, and Actinobacteria were enriched, whereas Firmicutes was reduced in patients with sepsis. However, most patients with sepsis were treated with antibiotics, so it is reasonable to question whether the microbial disruptions resulted from sepsis or were due to antibiotics. As we could not withdraw antibiotics from patients, we confirmed our results in animal models. We established murine sepsis models by cecum ligation punch (CLP) and by Streptococcus pneumoniae administration; both models caused obvious alterations in gut microbial composition. These data indicate that sepsis may directly lead to enteric dysbiosis. Microbial functions were also disrupted during sepsis development. By employing metabolomic and proteomic analysis techniques, we reveal that metabolites and proteins generated from intestinal microbiota were different between healthy individuals and patients with sepsis. For example, dimethyl trisulfide and ceramide (d18:0/25:0) were elevated, and cytosine and 6-tridecene were decreased in septic feces. Using bioinformatics to classify our proteomic data, gene ontology enrichment analysis indicated that microbial proteins belong to the biological processes pathway, and that cellular components and molecular functions were likely changed in patients with sepsis. Hence, these results directly signify that microbial functions were influenced during sepsis development. Disturbed eubiosis could directly promote organ damage during sepsis. We performed fecal microbiota transplantation (FMT) experiments and found that mice given feces from patients with sepsis versus that from healthy subjects had more severe liver injury and inflammation. Thus, the altered gut microbiota observed in sepsis was not only the consequence, as there was increased sepsis-related organ injury. Overall, our clinical and experimental pilot data have systematically uncovered the association between sepsis and enteric eubiosis at both the compositional and functional levels for microbiota. However, further mechanistic studies are required to extend this novel investigative direction in intensive care medicine. Besides our work, other groups also found similar microbial phenotypes. In ICU patients, it is reported that gut microbial composition at the phyla level showed dynamic changes after their admission to ICU. Specifically, Bacteroidetes to Firmicutes (B/F ratio) in deceased patients tended to increase, whereas the B/F ratio was stable in survivors. Although this was a small-scale study in only 12 patients, the data suggest a new direction by which gut microbiota may serve as a predictor of ICU mortality [14]. Large-scale clinical trials are urgently required to confirm this hypothesis. Zaborin et al. showed that alpha-diversity (Chao1 index) was decreased in ICU patients compared with healthy subjects [15]. More importantly, they found that the intestinal microbial community in prolonged critical illness was dramatically

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changed, as characterized by ultra-low-diversity bacterial communities. They further demonstrated that the “commensal lifestyle” of bacteria could be shifted to a “pathogenic style”, strengthening the hypothesis that gut microbiota plays a key role during sepsis progression. Besides clinical observations, basic research from animal models also unmasks essential roles for gut microbiota in intensive care diseases. It is reported that germ-free mice were more sensitive to Pseudomonas aeruginosa-induced pneumonia, and this phenotype may have resulted from altered gut epithelial cell apoptosis [16]. Similarly, Schuijt et al. disclosed that antibiotic-treated mice were more sensitive to pneumococcal pneumonia, and furthermore, the protective effects of the gut microbiota were possibly mediated by modulation of alveolar macrophage function [17]. Although these studies clearly suggest that the gut microbiota is important for sepsis and/or pneumonia, the actual mechanisms are largely unknown. Using a CLP-induced sepsis model to investigate the novel mechanism of gut microbial action in sepsis progression [18, 19], we found that the metabolic profile was different between sepsis-sensitive mice (mice who died either before or around 24 h after CLP) and sepsis-resistant mice (mice who survived until 7 days after CLP). Our findings were noteworthy, as fecal and plasma granisetron levels were significantly greater in sepsis-resistant mice than in sepsis-sensitive mice. Moreover, we also found that granisetron-mitigated CLP-induced lung and liver damage via reduction of cytokine/chemokine over-expression in macrophages. This molecular mechanism may involve the Toll-like receptor 4 (TLR4)-signaling pathway, because the protective effect of granisetron was blocked in TLR4 knockout mice. Additionally, granisetron may affect inflammasome activation in macrophages. Thus, the anti-inflammatory effects of granisetron may be complex. To translate this basic study to the clinic, we are now performing a clinical trial to determine whether granisetron can be used as a novel treatment strategy for patients with sepsis. Although the fundamental mechanisms by which the gut microbiota influences sepsis remain unclear, we can conclude that several key inflammatory pathways are involved. First, gut microbial strains can exert pathogenic changes during sepsis development [20]; for example, Escherichia coli, the classic gram-negative bacterium, augments host infection and inflammation through lipopolysaccharide toxicity. Similarly, other commensal bacteria may also become pathogenic, likely due to disrupted host immune systems. Secondly, gut commensal microbiota could modulate gut barrier integrity. Interactions between microbiota and intestinal epithelial cells (IECs) are complex. Bacteria-derived products such as short-chain fatty acids may act directly on IECs and strengthen the gut barrier. Notably, microbiota may also modulate goblet cells function, which influences mucus production [1]. However, inflammatory responses due to changes in gut microbiota are recognized as a main regulatory pathway during interactions between the gut microbiota and gut barrier. Inflammatory

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factors, such as immune cell activation, and cytokine/chemokine generation, disrupt gut barrier integrity. Augmented gut leakiness could amplify systemic inflammation via the release of microbiota and/or microbial products from the intestine into the circulatory system and peripheral organs; this mechanism is a key pathophysiologic process contributing to organ deterioration during sepsis. Thirdly, intestinal immunologic responses modulated by microbiota may impact the gut barrier, and influence immune reactions and inflammation in the periphery. Gut microbiota may modulate adaptive immune cells like Treg, Th17, B cells, and innate immune cells, such as macrophages and neutrophils. In fact, microbial-generated lipids may activate intestinal natural killer T cells, which could migrate to the liver and cause hepatocyte apoptosis and subsequent liver damage [21]. There are few direct clues about whether intestinal-derived immune cells can migrate into the circulatory system and promote sepsis progression; therefore, additional investigations should focus on this topic. Targeting gut microbiota is increasingly recognized as a novel and effective approach for sepsis management, and this approach translates from basic research to clinical practice. Rodent studies revealed that a high-fiber diet could increase survival during CLP-induced sepsis, and this sepsis-resistant phenotype was accompanied by reduced systemic pro-inflammatory cytokine production and decreased organ inflammation [22]. The authors further demonstrated that a high-fiber diet could modulate gut microbial composition, as characterized by enrichment of Lachnospiraceae and Akkermansia, which is known as a new “probiotic” and could provide beneficial effects to the host. Promising clinical data by Shimizu et al. found that synbiotics (Bifidobacterium breve strain Yakult, Lactobacillus casei strain Shirota, and galactooligosaccharides) significantly reduced enteritis and ventilator-associated pneumonia, without affecting mortality in patients with sepsis [23]. One study confirmed that probiotics could provide protection to ICU patients against intestinal inflammation [24], and a meta-analysis revealed that probiotics and synbiotics may be beneficial for postoperative sepsis [25]. Besides specific strain therapies, whole microbiome interventions, such as FMT, were also considered as a potential treatment approach. For example, FMT was an efficient method for curing ICU patients with Clostridium difficile infection [26]. Moreover, some case reports suggest that FMT could treat severe diarrhea in ICU patients [27], but definitive data are urgently required to provide guidance to clinicians and intensive care units for successful FMT administration. Importantly, the FMT approach has both advantages and disadvantages. As a full spectrum treatment, it may improve the whole microbial environment in the intestine and may be more effective than a single strain for maintaining a healthy gut. However, current reports about FMT use in the ICU mainly focus on sepsis in patients with intestinal abnormalities. Little information is available about whether FMT may improve extra-intestinal organ injuries, although basic research has demonstrated that the gut microbiome could affect multiple organ damage. Future clinical studies are needed to expand FMT

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application to the pathophysiology of other organs. Moreover, donor selection is complicated, and there are no common criteria for donor selection in this situation. Thus, the outcome of FMT depends largely on the interaction between donor feces and the recipient gut. Because of the complicated pathogenesis of sepsis, FMT therapy may not be appropriate with all patients with sepsis, and more detailed clinical practice knowledge is required [28].

11.3

Conclusion

Although increasing attention has been paid to the link between gut microbiota and sepsis pathogenesis (Fig. 11.1), mechanistic insights are still limited. The types of microbiota and microbial products which impact the host to influence sepsis development and progression, as well as the molecular pathways which mediate it, are still largely unknown. Nonetheless, focusing on the gut microbiota as a therapeutic target is a promising strategy for the future treatment of sepsis. Basic research scientists and clinicians should combine their efforts to fill this knowledge gap in intensive care medicine.

Organs injury

Gut microbiota Modulate organs injury

Generate protecve products, e.g. SCFAs, granisetron Disrupt gut barrier Exert “pathogenic”effects ……

Disrupt enteric eubiosis Alpha-diversity↓Metabolites, Bacteroidetes↑ proteins Acnobacteria↑ disrupon ……

Sepsis development Fig. 11.1 The bidirectional crosstalk between gut microbiota and organ injury during sepsis

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