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Microbiome in Gastrointestinal Cancer Jun Yu Editor 123 Microbiome in Gastrointestinal Cancer Jun Yu Editor Microbiome in Gastrointestinal Cancer Editor Jun Yu Department of Medicine & Therapeutics The Chinese University of Hong Kong Hong Kong, China ISBN 978-981-19-4491-8 ISBN 978-981-19-4492-5 (eBook) https://doi.org/10.1007/978-981-19-4492-5 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 This work is subject to copyright. All rights are solely and exclusively licensed 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. 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The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Jun Yu 2 Gut Microbiome in Health and Gastrointestinal Cancer . . . . . . . . . . 5 Harry Cheuk-Hay Lau 3 Microbiome in Colorectal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 Pingmei Huang and Chi Chun Wong 4 Microbiome in Gastric Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 Elke Burgermeister and Matthias P. Ebert 5 Microbiota and Liver Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 Chun-Ying Wu and Ching-Hung Tseng 6 Non-bacteria Microbiome (Virus, Fungi, and Archaea) in Gastrointestinal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 Olabisi Oluwabukola Coker 7 The Role of Microbiome in Nonalcoholic Fatty Liver Disease . . . . . . 107 Hye Won Lee 8 Diet and Gut Microbiome in Gastrointestinal Cancer . . . . . . . . . . . . 119 Jia Yang and Jun Yu 9 Diet Modulates Gut Microbiome and Metabolites in Non-alcoholic Fatty Liver Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131 Yasi Pan and Xiang Zhang 10 Host–Microbiome Interactions in Gastrointestinal Cancers . . . . . . . 147 Jun Sun 11 Gut Microbiome and Immune Responses in Gastrointestinal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 Robyn Laube and Ken Liu v vi Contents 12 Animal Models in the Study of Microbiome in Gastrointestinal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 Xinning Wang and Hong Wei 13 Machine Learning on Microbiome Research in Gastrointestinal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 Henley Cheung and Yufeng Lin 14 Gut Microbiota Modulation: Probiotics and Prebiotics in GI Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201 Phillip Lung Wai Au-Doung, Ryan Hei Chan, William Ka Kei Wu, and Qing Li 15 Gut Microbiota Impacts on the Efficacy of Anticancer Treatment of Colorectal Cancer . . . . . . . . . . . . . . . . . . . . 237 Jie Hong and Jing-Yuan Fang 16 Targeting Gut Microbiota in Colorectal Cancer . . . . . . . . . . . . . . . . . 251 Sunny H. Wong 17 Microbiota in Cancer Immunotherapy: The Next Milestone of Immuno-oncology? . . . . . . . . . . . . . . . . . . . . . . 269 Nick Lung-Ngai Ting and Jun Yu 18 Gut Microbiota in Coronavirus Disease 2019 . . . . . . . . . . . . . . . . . . . 289 Harry Cheuk-Hay Lau and Jun Yu Chapter 1 Introduction Jun Yu Keywords Gastrointestinal cancer · Gut microbiome · Basic research · Clinical research Gastrointestinal cancers account for over a third of new cancer cases globally, and represent a major public health burden. Colorectal cancer (CRC), gastric cancer (GC), and liver cancer are the most common gastrointestinal cancers in most parts of the world. Accumulating evidence has documented a rising trend in gastrointestinal cancers over the past 5–10 years, and thus is a serious health threat to humans. Multiple international genetic and transcriptomic sequencing projects over the past decade have established the role of genetic and epigenetic determinants of cancer. Nevertheless, environmental factors, such as smoking, diet, alcohol consumption, obesity, and more, are proposed to play predominant roles in the development of sporadic gastrointestinal cancers. In this context, a unique feature of gastrointestinal cancers, such as CRC and GC, is their close proximity to our gut microbiota. Gut microbiota consists of a collection of trillions of microorganisms encompassing bacteria, viruses, fungi, and archaea. Our gut microbes could interact with host cells in a variety of ways to modulate cancer initiation and progression. Over the past decade, the investigation of gut microbiome in GI carcinogenesis has flourished—facilitated by major technological advances. First, metagenomic sequencing efforts have enabled rapid and comprehensive profiling of the gut microbiota, which clearly demonstrated that the gut microbiota is dysregulated in gastrointestinal cancers including CRC, GC, and liver cancer. On the other hand, molecular and cell biology studies have resulted in great strides in our understanding of the functional role and mechanism of action of gut microbiota in gastrointestinal cancers. Accumulating evidence indicates that gut microbiota can be harnessed for cancer prevention as well as to modulate the efficacy of chemotherapy and J. Yu (*) Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 1 J. Yu (ed.), Microbiome in Gastrointestinal Cancer, https://doi.org/10.1007/978-981-19-4492-5_1 2 J. Yu immunotherapy. Against this backdrop, we believe that it is timely to propose this series “Microbiome in Gastrointestinal Cancer” to cover state-of-the-art topics cov- ering these major areas, including (1) characterization of the dysregulated microbiome in gastrointestinal cancers (Chaps. 1–6); (2) the molecular mechanism of action of gut microbiota via microbial metabolites and direct interaction with host cancer or immune cells (Chaps. 7–11); (3) key methodologies for studying the role of gut microbiota in cancers (Chaps. 12 and 13); and (4) the potential application of gut microbes for the prevention and treatment of gastrointestinal cancers (Chaps. 14–17). To open our discussion on the gut microbiome, Lau et al. provide an overview of the role of gut microbiome in health and disease (Chap. 2). This is followed by detailed review and discussion on the phenomenon of microbial dysbiosis in specific gastrointestinal cancers, such as colorectal cancer (Chap. 3), gastric cancer (Chap. 4), and liver cancer (Chap. 5), major GI cancers worldwide. These chapters provide succinct description of the changing gut microbiome landscape in tumorigenesis, highlight their potential molecular mechanisms, and briefly discuss potential clinical implications. In earlier studies, our evaluation of the gut microbiome is largely restricted to bacteria. Nevertheless, accumulating data have shown that microbial dysregulation in cancer also extends to the gut viruses, fungi, and even archaea, the latter of which are thought to exist only in extreme environments. In this regard, Chap. 6 is devoted to these emerging microbes, their dysregulation and potential contributions to tumorigenesis of GI cancers. Collectively, these chapters consolidate the view that gut microbiome is dysregulated in GI cancers, and is criti- cally involved in disease initiation and progression. Studying the underlying molecular mechanisms of gut microbiome is essential to establishing the causality of dysregulated gut microbiome in GI cancers. To this end, Chaps. 7–11 mainly dealt with the molecular mechanisms by which gut microbiota could interact with the host and alter host physiology. In Chap. 7, Lee provides a detailed discussion of the role of microbial metabolome as the link between a dysregulated microbiome and host disease. Particular focus is placed on the gut– liver axis as an important mediator of fatty liver disease. This followed by Chap. 8 describing how gut microbiome–liver axis and metabolite transfer contribute to the pathogenesis of NAFLD and its associated liver cancer. Diet has a significant influence on the gut microbiota. Chapter 9 attempts to extend the notion of “you are what you eat” to the gut microbiome by exploring studies highlighting 3-way crosstalk between diet, gut microbiome, and GI tumorigenesis. Chapters 10 and 11 then provide in-depth review of the mechanisms of host–microbiome interactions in GI cancers, with a focus on signaling pathways modulated by gut microbiome (Chap. 10) and influence of the gut microbiome on antitumor immune response (Chap. 11). Complementing these reviews, Chaps. 12 and 13 are dedicated summaries to state- of-the-art tools in studying the gut microbiome in GI cancers. Animal models, espe- cially germ-free mice, are vital tools to studying gut microbiome and they summarized in Chap. 12. Chapter 13 describes the bioinformatic tools that are fun- damental to metagenome analysis, and potential applications of artificial intelli- gence in microbiome analysis. 1 Introduction 3 Given the close association between gut microbiome and GI cancers, how we can harness the power of microbes in clinical translation has become a subject of intensive investigations. Accumulating evidence has indicated that beneficial com- mensals are depleted in tumorigenesis, thus providing the biological basis of restor- ing a health microbiome for disease prevention or treatment. Au-Doung et al. review the evidence in support of application of probiotics and prebiotics in GI cancer management in Chap. 14. Chapters 15 and 16 cover the impact of gut microbiome in affecting treatment efficacy in GI cancers, including chemotherapy and immune checkpoint blockade (ICB) therapy. Chapter 17 outlines the strategies that could be used for targeting the gut microbiome in GI cancers, including probiotics, prebiotics, diet, and fecal microbial transplantation (FMT). These chapters collectively demonstrate the tremendous potential in the clinical translation of gut microbiome in GI cancers. Last but not least, Lau et al. provide an interesting and timely review on COVID-19 and gut microbiota, their potential interaction and biological significance. This series is unique in that we will bring together a group of experts to provide their perspectives on the subject from the viewpoint of basic, translational, and clinical research. We are grateful to all our contributors, including international experts in molecular biology, microbiology, metabolomics, bioinformatics, and physician scientists to provide in-depth review of this subject. We hope that this book will offer a rich resource of information on this important topic for graduate students, basic researchers as well as physicians. Conflict of Interest All authors declare no conflict of interest. Chapter 2 Gut Microbiome in Health and Gastrointestinal Cancer Harry Cheuk-Hay Lau Abstract Human gastrointestinal tract harbours trillions of microbes including bacteria, fungi, and viruses to form the gut microbiome. The recent advance in both bioinformatic analyses and functional investigations has greatly improved under- standings of the complex host–microbe interactions. The gut microbiome has shown their impacts across a variety of physiological functions. Whereas dysbiosis or alter- ations in the gut microbiome is correlated with pathogenesis and progression of numerous diseases including cancer. In this chapter, the contribution of a healthy gut microbiome to digestion and immunity of the host is discussed. The association of a dysbiotic microbiome with the development of common gastrointestinal cancers (colorectal cancer, gastric cancer, and hepatopancreatic cancer) is also explored. The article is summarised with highlight of the current limitations and opportunities to advance this line of research. Keywords Gut microbiome · Healthy microbiome · Digestion · Immunity · Dysbiosis · Gastrointestinal cancer 2.1 Introduction The surface barriers of the human body are inhabited by trillions of microbes including bacteria, fungi, viruses, archaea, and protozoa (Lloyd-Price et al. 2016). Together, these microbes form complex microbial communities to make up the human microbiota, whilst the genomes of these microbes collectively form the H. C.-H. Lau (*) Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 5 J. Yu (ed.), Microbiome in Gastrointestinal Cancer, https://doi.org/10.1007/978-981-19-4492-5_2