The Gut Microbiome in Health and Disease

Abstract

Gary D. WuView Large Image Figure ViewerDownload Hi-res image Download (PPT)Every May, Gastroenterology publishes a supplemental thirteenth issue devoted to a topic of particular interest and importance to both the practice and science of gastroenterology. The editorial board selected a series of reviews on the intestinal microbiome for this issue.Increasing evidence suggests that environmental factors play a role in the dramatic rise in the incidence of many human diseases specifically associated with residence in industrialized nations.1Kelsen J.R. Wu G.D. The gut microbiota, environment and diseases of modern society.Gut Microbes. 2012; 3: 374-382Crossref PubMed Scopus (38) Google Scholar, 2Virgin H.W. Todd J.A. Metagenomics and personalized medicine.Cell. 2011; 147: 44-56Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 3Blumberg R. Powrie F. Microbiota, disease, and back to health: a metastable journey.Sci Transl Med. 2012; 4: 137rv7Crossref PubMed Scopus (214) Google Scholar However, the characterization and quantification of environmental factors that influence health is challenging because humans are free-living organisms. Advances in DNA sequencing technology combined with new biocomputational tools enable scientists to describe our microbial environment with unprecedented precision.4Caporaso J.G. Kuczynski J. Stombaugh J. et al.QIIME allows analysis of high-throughput community sequencing data.Nat Methods. 2010; 7: 335-336Crossref PubMed Scopus (23769) Google Scholar Together with functional studies in animal models, the characterization of the human microbiome in various disease states suggests that our microbial environment plays a critical role in both the maintenance of health and the pathogenesis of disease.3Blumberg R. Powrie F. Microbiota, disease, and back to health: a metastable journey.Sci Transl Med. 2012; 4: 137rv7Crossref PubMed Scopus (214) Google Scholar, 5Backhed F. Fraser C.M. Ringel Y. et al.Defining a healthy human gut microbiome: Current concepts, future directions, and clinical applications.Cell Host Microbe. 2012; 12: 611-622Abstract Full Text Full Text PDF PubMed Scopus (458) Google Scholar As the most densely populated and diverse of the microbial communities, the intestinal microbiome may be particularly important. The effectiveness of fecal microbiota transplantation in the treatment of refractory Clostridium difficile infection is proof of principle that modification of the intestinal microbiome can be a therapeutic strategy for the treatment of human disease.6van Nood E. Vrieze A. Nieuwdorp M. et al.Duodenal infusion of donor feces for recurrent Clostridium difficile.N Engl J Med. 2013; 368: 407-415Crossref PubMed Scopus (2460) Google Scholar, 7Lemon K.P. Armitage G.C. Relman D.A. et al.Microbiota-targeted therapies: an ecological perspective.Sci Transl Med. 2012; 4: 137rv5Crossref PubMed Scopus (176) Google ScholarReflecting the evolution of intestinal microbiome research, the reviews address three themes: (1) basic concepts in the mammalian gut microbiome; (2) gut microbiome and disease, and (3) modification of the gut microbiome to maintain health or treat disease.Drs Xochitl C. Morgan and Curtis Huttenhower (pages 1437–1448) begin the issue with a review of the technologies and techniques used to characterize the composition of and the small-molecule production of the intestinal microbiome (Figure 1).8Morgan X.C. Huttenhower C. Meta'omic analytic techniques for studying the intestinal microbiome.Gastroenterology. 2014; 146: 1437-1448Scopus (116) Google Scholar From genomics to transcriptomics, metabolomics, and proteomics, the authors provide a primer by which these “omic” technologies are used to reveal the basic biology of the complex microbial communities in the intestine. The use of these tools has significantly advanced the understanding of the intestinal microbiome in health, and led to explorations of associations with disease. Drs Emily B. Hollister, Chunxu Gao, and James Versalovic (pages 1449–1458) describe how these tools have allowed scientists to characterize the composition of the intestinal microbiome, as well as associated functional features, such as gene representation throughout the longitudinal axis of the intestine.9Hollister E.B. Gao C. Versalovic J. Compositional and functional features of the gastrointestinal microbiome and their effects on human health.Gastroenterology. 2014; 146: 1449-1458Scopus (275) Google Scholar Alterations of the intestinal microbiome during development and in response to aging are considered, as well as core functions, such as carbohydrate and protein/amino acid metabolism. In addition to bacteria, other microbes inhabit the environment of the intestinal niche. To expand on the description of the intestinal microbiome, Drs Jason M. Norman, Scott A. Handley, and Herbert W. Virgin (pages 1459–1469) describe how nonbacterial organisms, primarily in the virome and the mycobiome, influence both health and disease.10Norman J.M. Handley S.A. Virgin H.W. Kingdom-agnostic metagenomics and the importance of complete characterization of enteric microbial communities.Gastroenterology. 2014; 146: 1459-1469Scopus (123) Google Scholar The virome is composed of prokaryotic (the bacteriophage) and eukaryotic viruses, which play critical roles in gut microecology and its impact on the host. Emerging evidence suggests that the mycobiome (fungi) may also play a role in disease pathogenesis.Figure 1Technical approach to characterizing both the composition and function of the gut microbiome. High throughput “omic” technologies can be used to characterize DNA (genomics), RNA (transcriptomics), and small molecules (metabolomics) to determine the proportional abundance of various microbes in a biospecimen, as well as infer their possible functions.View Large Image Figure ViewerDownload Hi-res image Download (PPT)The gut microbiome can significantly affect the metabolism of the host. In fact, gut microbes represent an extended reservoir of metabolic capabilities providing the host with a wide range of otherwise inaccessible metabolic capabilities.11Qin J. Li R. Raes J. et al.A human gut microbial gene catalogue established by metagneomic sequencing.Nature. 2010; 464: 59-65Crossref PubMed Scopus (7030) Google Scholar Drs Luke K. Ursell, Henry J. Haiser, Will Van Treuren, Neha Garg, Lavanya Reddivari, Jairam Vanamala, Pieter C. Dorrestein, Peter J. Turnbaugh, and Rob Knight (pages 1470–1476) discuss how recent advances in metabolomics, coupled with metagenomics, help us to understand how microbes influence metabolite production from dietary and xenobiotic sources and ultimately affect human health.12Ursell L.K. Haiser H.J. Van Treuren W. et al.The intestinal metabolome: an intersection between microbiota and host.Gastroenterology. 2014; 146: 1470-1476Scopus (168) Google Scholar Advances in this field will provide valuable information for clinical application leading to personalized medicine.Germ-free animals show abnormal gut epithelial and immune function, indicating a critical role for the gut microbiota in the maturation of the host immune system. Conversely, the gut immune system regulates the composition and function of the microbiota. This bidirectional interaction between the gut microbiota and the immune system is well balanced in health and its breakdown may lead to disorders such as the inflammatory bowel diseases (IBD) or metabolic diseases.13Kamada N. Seo S.U. Chen G.Y. et al.Role of the gut microbiota in immunity and inflammatory bowel disease.Nat Rev Immunol. 2013; 13: 321-335Crossref PubMed Scopus (1322) Google Scholar Drs Nobuhiko Kamada and Gabriel Núñez (pages 1477–1488) review the mechanisms known to regulate the interaction between resident intestinal bacteria and the surrounding environment.14Kamada N. Núñez G. Regulation of the immune system by the resident intestinal bacteria.Gastroenterology. 2014; 146: 1477-1488Scopus (175) Google Scholar Complex interaction between the resident bacteria and the immune system leads to the development of immune tolerance. The indigenous bacteria may also stimulate the immune system to protect against proinflammatory commensal bacteria and exogenous pathogens.15Kamada N. Kim Y.G. Sham H.P. et al.Regulated virulence controls the ability of a pathogen to compete with the gut microbiota.Science. 2012; 336: 1325-1329Crossref PubMed Scopus (406) Google Scholar Understanding these complex interactions may unravel the pathogenesis of intestinal inflammation and lead to novel therapeutics.The second section of this issue is dedicated to the relationship between the gut microbiome and disease. Phylogenetic profiling of the gut microbiome in IBD demonstrates a characteristic shift in the composition of the intestinal microbiota, which results in an enrichment of potentially deleterious bacteria taxa belonging to the Proteobacteria and Actinobacteria phyla, and a reduction of protective Firmicutes species. However, our understanding of the functional role of the human microbiome in IBD remains incomplete. Drs Aleksandar D. Kostic, Ramnik J. Xavier, and Dirk Gevers (pages 1489–1499) review IBD genetic studies that suggest interplay between the host immune system and gut microbiota.16Kostic A.D. Xavier R.J. Gevers D. The microbiome in inflammatory bowel disease: current status and the future ahead.Gastroenterology. 2014; 146: 1489-1499Scopus (1070) Google Scholar Host genetics appear to play a prominent role in shaping the composition and structure of the gut microbiota. Metagenomic and metabolomic studies elucidate the function and pathways that lead to intestinal inflammation. The authors propose future directions for research that may clarify the role of microbiome in IBD.Preclinical studies suggest that the ability of the gut microbiota to modulate the bidirectional interactions of the gut–brain axis may influence the pathogenesis of irritable bowel syndrome (IBS). Studies indicate that gut dysbiosis occurs in subpopulations of IBS patients17Jeffery I.B. O’Toole P.W. Ohman L. et al.An irritable bowel syndrome subtype defined by species-specific alterations in faecal microbiota.Gut. 2012; 61: 997-1006Crossref PubMed Scopus (582) Google Scholar and improvement of symptoms following manipulation of gut microbiota with antibiotics or probiotics. The causal association between the dysbiotic IBS-associated microbiota and pathogenesis of IBS symptoms, however, remains incompletely defined. Drs. Emeran A. Mayer, Tor Savidge and Robert J. Shulman (pages 1500–1512) provide a critical review of the studies linking gut dysbiosis to abnormal brain-gut interaction, and discuss potential mediators generated by the bacteria and/or the host.18Mayer E.A. Savidge T. Shulman R.J. Brain–gut microbiome interactions and functional bowel disorders.Gastroenterology. 2014; 146: 1500-1512Scopus (286) Google Scholar It is interesting to note that germ-free animals show abnormal development of CNS mechanisms related to the functioning of the HPA axis19Ghazarian L. Diana J. Simoni Y. et al.Prevention or acceleration of type 1 diabetes by viruses.Cell Mol Life Sci. 2013; 70: 239-255Crossref PubMed Scopus (27) Google Scholar and the affective behavior. This suggests that mediators resulting from the interaction between microbes and the gut epithelium/immune system may shape the post-partum brain. However, it is unclear if these findings apply to humans. The authors propose new studies to gain further insight into the interaction between the gut microbes and the gut–brain axis.Drs Bernd Schnabl and David A. Brenner (pages 1513–1524) describe the role that the intestinal microbiome may play in the pathogenesis of liver disease; specifically, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, alcoholic liver disease, and cirrhosis.20Schnabl B. Brenner D.A. Interactions between the intestinal microbiome and liver diseases.Gastroenterology. 2014; 146: 1513-1524Scopus (599) Google Scholar Although these are a diverse set of diseases, there are common themes related to the role of the intestinal microbiome, such as the development of dysbiosis, translocation of bacteria and their products due to disruption in barrier function, and immune activation. It appears that these microbiome-associated alterations may work in concert with other extrinsic factors, such as a Western diet and alcohol consumption, to influence the development of liver disease.An exciting new finding in microbiome research is that intestinal microbes regulate the host’s metabolic function and energy balance. Mounting evidence suggests an altered microbial ecology may contribute to the development of obesity and other metabolic disorders. Drs Max Nieuwdorp, Pim W. Gilijamse, Nikhil Pai, and Lee M. Kaplan (pages 1525–1533) review the relationships between the gut microbiota and host metabolism and discuss potential mechanism of interaction, including the participation of mucus layer, bile acids, and immune responses.21Nieuwdorp M. Gilijamse P.W. Pai N. et al.Role of the microbiome in energy regulation and metabolism.Gastroenterology. 2014; 146: 1525-1533Scopus (237) Google Scholar The ability of the microbiota to transfer metabolic phenotypes among mice raises the exciting prospect of using fecal microbial transplantation to treat metabolic diseases.Drs Maria T. Abreu and Richard M. Peek Jr (pages 1534–1546) consider the role the intestinal microbiome may play in the pathogenesis of both upper and lower gastrointestinal malignancies, mainly gastric and esophageal malignancies, as well as colon cancer.22Abreu M.T. Peek Jr., R.M. Gastrointestinal malignancy and the microbiome.Gastroenterology. 2014; 146: 1534-1546Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar Although the principal microbe responsible for the development of gastric cancer, Helicobacter pylori, has been identified and some of the effector pathways have been characterized, this is not the case for the other 2 neoplastic diseases, although there is compelling functional data in rodent models. Nevertheless, the development of microbe-induced chronic inflammation is a common finding for all 3 diseases.The great success of fecal microbiota transplantation in treating recurrent C difficile infection with donor stools suggests that restoration of a diverse intestinal microbial community can interrupt the disease cycle. Drs Robert A. Britton and Vincent B. Young (pages 1547–1553) discuss specific mechanisms by which the microbiota can inhibit growth and persistence of C difficile.23Britton R.A. Young V.B. Role of the intestinal microbiota in resistance to colonization by Clostridium difficile.Gastroenterology. 2014; 146: 1547-1553Scopus (266) Google Scholar Competition for nutritional resources may contribute to the suppression of C difficile invasion by the intestinal microbiota. The role of bile salts (whose composition can be significantly altered by intestinal microbes) in C difficile spore germination and vegetative growth are reviewed.The third section focuses on the translation of the knowledge gained from the previous 2 sections, specifically addressing the notion that the intestinal microbiome is a modifiable environmental factor that can be a target for both the maintenance of health and the treatment of disease. Drs Fergus Shanahan and Eamonn M.M. Quigley (pages 1554–1563) highlight the challenges and controversies regarding therapeutic manipulation of the microbiota of patients with IBD or IBS.24Shanahan F. Quigley E.M.M. Manipulation of the microbiota for treatment of IBS and IBD––challenges and controversies.Gastroenterology. 2014; 146: 1554-1563Scopus (126) Google Scholar They examine the rationale for microbial strategies in these groups of disorders, comment on the disparities between findings from animal models and human studies, and conclude with a thoughtful prospective outlining the priorities for the next generation of microbial-based therapies.Diet is a major factor in the modulation of the composition and metabolic functions of microorganisms in the gut.25Wu G.D. Chen J. Hoffmann C. et al.Linking long-term dietary patterns with gut microbial enterotypes.Science. 2011; 334: 105-108Crossref PubMed Scopus (3940) Google Scholar Drs Lindsey G. Albenberg and Gary D. Wu (pages 1564–1572) review how diet specifically helps to shape the composition of the intestinal microbiota as well as influences the microbial metabolome, which may, in turn, affect host physiology and immune function.26Albenberg L.G. Wu G.D. Diet and the intestinal microbiome: associations, functions, and implications for health and disease.Gastroenterology. 2014; 146: 1564-1572Scopus (378) Google Scholar Recent research provides some understanding of how diet contributes to the pathogenesis of disorders, such as coronary vascular disease and IBD, through its impact on the gut microbiota and its metabolome. This knowledge may be used to develop therapeutic strategies for prevention or treatment of these and other disorders.We conclude the issue with a review by Drs Elaine O. Petrof and Alexander Khoruts (pages 1573–1582) on fecal microbiota transplantation (FMT) and the next generation of microbiota therapeutics.27Petrof E.O. Khoruts A. From stool transplants to next-generation microbiota therapeutics.Gastroenterology. 2014; 146: 1573-1582Scopus (132) Google Scholar The high level of efficacy of FMT for treatment refractory C difficile infection not only supports the notion of the intestinal microbiota as a therapeutic target in humans, but it also highlights the complex ethical, regulatory, and safety issues associated with procedures designed to modify the intestinal microbiota.28Hecht G.A. Blaser M.J. Gordon J. et al.What is the value of a Food and Drug Administration investigational new drug for fecal microbiota transplantation in Clostridium difficile infection?.Clin Gastroenterol Hepatol. 2014; 12: 289-291Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar Alternative strategies to FMT, such as standardized full-spectrum microbiota therapies and defined microbiota ecosystems are discussed as emerging therapeutic modalities.29Smits L.P. Bouter K.E. de Vos W.M. et al.Therapeutic potential of fecal microbiota transplantation.Gastroenterology. 2013; 145: 946-953Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar, 30Kassam Z. Lee C.H. Yuan Y. et al.Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis.Am J Gastroenterol. 2013; 108: 500-508Crossref PubMed Scopus (655) Google ScholarIn summary, advances in DNA sequencing and bioinformatics have revolutionized our understanding of the microorganisms that inhabit the gut. This genomic revolution offers an exceptional opportunity to identify the molecular mechanisms governing commensal host–bacterial relationships. This new knowledge helps us understand how these interactions contribute to normal physiology and provides the foundation to formulate novel therapeutic strategies. This issue covers the spectrum of intestinal microbiome research, from basic concepts in mammalian gut microbiome to disease associations and therapeutic implications. Our intent was to provide comprehensive and up-to-date information on the human gut microbiome and its association with disease, but also, to stimulate research that will lead to further discoveries and novel therapeutics. We thank our authors for their tremendous contributions and our reviewers for their insightful appraisals of the submitted manuscripts. Finally, we are grateful to the editorial staff for preparing this issue for publication. Every May, Gastroenterology publishes a supplemental thirteenth issue devoted to a topic of particular interest and importance to both the practice and science of gastroenterology. The editorial board selected a series of reviews on the intestinal microbiome for this issue. Increasing evidence suggests that environmental factors play a role in the dramatic rise in the incidence of many human diseases specifically associated with residence in industrialized nations.1Kelsen J.R. Wu G.D. The gut microbiota, environment and diseases of modern society.Gut Microbes. 2012; 3: 374-382Crossref PubMed Scopus (38) Google Scholar, 2Virgin H.W. Todd J.A. Metagenomics and personalized medicine.Cell. 2011; 147: 44-56Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 3Blumberg R. Powrie F. Microbiota, disease, and back to health: a metastable journey.Sci Transl Med. 2012; 4: 137rv7Crossref PubMed Scopus (214) Google Scholar However, the characterization and quantification of environmental factors that influence health is challenging because humans are free-living organisms. Advances in DNA sequencing technology combined with new biocomputational tools enable scientists to describe our microbial environment with unprecedented precision.4Caporaso J.G. Kuczynski J. Stombaugh J. et al.QIIME allows analysis of high-throughput community sequencing data.Nat Methods. 2010; 7: 335-336Crossref PubMed Scopus (23769) Google Scholar Together with functional studies in animal models, the characterization of the human microbiome in various disease states suggests that our microbial environment plays a critical role in both the maintenance of health and the pathogenesis of disease.3Blumberg R. Powrie F. Microbiota, disease, and back to health: a metastable journey.Sci Transl Med. 2012; 4: 137rv7Crossref PubMed Scopus (214) Google Scholar, 5Backhed F. Fraser C.M. Ringel Y. et al.Defining a healthy human gut microbiome: Current concepts, future directions, and clinical applications.Cell Host Microbe. 2012; 12: 611-622Abstract Full Text Full Text PDF PubMed Scopus (458) Google Scholar As the most densely populated and diverse of the microbial communities, the intestinal microbiome may be particularly important. The effectiveness of fecal microbiota transplantation in the treatment of refractory Clostridium difficile infection is proof of principle that modification of the intestinal microbiome can be a therapeutic strategy for the treatment of human disease.6van Nood E. Vrieze A. Nieuwdorp M. et al.Duodenal infusion of donor feces for recurrent Clostridium difficile.N Engl J Med. 2013; 368: 407-415Crossref PubMed Scopus (2460) Google Scholar, 7Lemon K.P. Armitage G.C. Relman D.A. et al.Microbiota-targeted therapies: an ecological perspective.Sci Transl Med. 2012; 4: 137rv5Crossref PubMed Scopus (176) Google Scholar Reflecting the evolution of intestinal microbiome research, the reviews address three themes: (1) basic concepts in the mammalian gut microbiome; (2) gut microbiome and disease, and (3) modification of the gut microbiome to maintain health or treat disease. Drs Xochitl C. Morgan and Curtis Huttenhower (pages 1437–1448) begin the issue with a review of the technologies and techniques used to characterize the composition of and the small-molecule production of the intestinal microbiome (Figure 1).8Morgan X.C. Huttenhower C. Meta'omic analytic techniques for studying the intestinal microbiome.Gastroenterology. 2014; 146: 1437-1448Scopus (116) Google Scholar From genomics to transcriptomics, metabolomics, and proteomics, the authors provide a primer by which these “omic” technologies are used to reveal the basic biology of the complex microbial communities in the intestine. The use of these tools has significantly advanced the understanding of the intestinal microbiome in health, and led to explorations of associations with disease. Drs Emily B. Hollister, Chunxu Gao, and James Versalovic (pages 1449–1458) describe how these tools have allowed scientists to characterize the composition of the intestinal microbiome, as well as associated functional features, such as gene representation throughout the longitudinal axis of the intestine.9Hollister E.B. Gao C. Versalovic J. Compositional and functional features of the gastrointestinal microbiome and their effects on human health.Gastroenterology. 2014; 146: 1449-1458Scopus (275) Google Scholar Alterations of the intestinal microbiome during development and in response to aging are considered, as well as core functions, such as carbohydrate and protein/amino acid metabolism. In addition to bacteria, other microbes inhabit the environment of the intestinal niche. To expand on the description of the intestinal microbiome, Drs Jason M. Norman, Scott A. Handley, and Herbert W. Virgin (pages 1459–1469) describe how nonbacterial organisms, primarily in the virome and the mycobiome, influence both health and disease.10Norman J.M. Handley S.A. Virgin H.W. Kingdom-agnostic metagenomics and the importance of complete characterization of enteric microbial communities.Gastroenterology. 2014; 146: 1459-1469Scopus (123) Google Scholar The virome is composed of prokaryotic (the bacteriophage) and eukaryotic viruses, which play critical roles in gut microecology and its impact on the host. Emerging evidence suggests that the mycobiome (fungi) may also play a role in disease pathogenesis. The gut microbiome can significantly affect the metabolism of the host. In fact, gut microbes represent an extended reservoir of metabolic capabilities providing the host with a wide range of otherwise inaccessible metabolic capabilities.11Qin J. Li R. Raes J. et al.A human gut microbial gene catalogue established by metagneomic sequencing.Nature. 2010; 464: 59-65Crossref PubMed Scopus (7030) Google Scholar Drs Luke K. Ursell, Henry J. Haiser, Will Van Treuren, Neha Garg, Lavanya Reddivari, Jairam Vanamala, Pieter C. Dorrestein, Peter J. Turnbaugh, and Rob Knight (pages 1470–1476) discuss how recent advances in metabolomics, coupled with metagenomics, help us to understand how microbes influence metabolite production from dietary and xenobiotic sources and ultimately affect human health.12Ursell L.K. Haiser H.J. Van Treuren W. et al.The intestinal metabolome: an intersection between microbiota and host.Gastroenterology. 2014; 146: 1470-1476Scopus (168) Google Scholar Advances in this field will provide valuable information for clinical application leading to personalized medicine. Germ-free animals show abnormal gut epithelial and immune function, indicating a critical role for the gut microbiota in the maturation of the host immune system. Conversely, the gut immune system regulates the composition and function of the microbiota. This bidirectional interaction between the gut microbiota and the immune system is well balanced in health and its breakdown may lead to disorders such as the inflammatory bowel diseases (IBD) or metabolic diseases.13Kamada N. Seo S.U. Chen G.Y. et al.Role of the gut microbiota in immunity and inflammatory bowel disease.Nat Rev Immunol. 2013; 13: 321-335Crossref PubMed Scopus (1322) Google Scholar Drs Nobuhiko Kamada and Gabriel Núñez (pages 1477–1488) review the mechanisms known to regulate the interaction between resident intestinal bacteria and the surrounding environment.14Kamada N. Núñez G. Regulation of the immune system by the resident intestinal bacteria.Gastroenterology. 2014; 146: 1477-1488Scopus (175) Google Scholar Complex interaction between the resident bacteria and the immune system leads to the development of immune tolerance. The indigenous bacteria may also stimulate the immune system to protect against proinflammatory commensal bacteria and exogenous pathogens.15Kamada N. Kim Y.G. Sham H.P. et al.Regulated virulence controls the ability of a pathogen to compete with the gut microbiota.Science. 2012; 336: 1325-1329Crossref PubMed Scopus (406) Google Scholar Understanding these complex interactions may unravel the pathogenesis of intestinal inflammation and lead to novel therapeutics. The second section of this issue is dedicated to the relationship between the gut microbiome and disease. Phylogenetic profiling of the gut microbiome in IBD demonstrates a characteristic shift in the composition of the intestinal microbiota, which results in an enrichment of potentially deleterious bacteria taxa belonging to the Proteobacteria and Actinobacteria phyla, and a reduction of protective Firmicutes species. However, our understanding of the functional role of the human microbiome in IBD remains incomplete. Drs Aleksandar D. Kostic, Ramnik J. Xavier, and Dirk Gevers (pages 1489–1499) review IBD genetic studies that suggest interplay between the host immune system and gut microbiota.16Kostic A.D. Xavier R.J. Gevers D. The microbiome in inflammatory bowel disease: current status and the future ahead.Gastroenterology. 2014; 146: 1489-1499Scopus (1070) Google Scholar Host genetics appear to play a prominent role in shaping the composition and structure of the gut microbiota. Metagenomic and metabolomic studies elucidate the function and pathways that lead to intestinal inflammation. The authors propose future directions for research that may clarify the role of microbiome in IBD. Preclinical studies suggest that the ability of the gut microbiota to modulate the bidirectional interactions of the gut–brain axis may influence the pathogenesis of irritable bowel syndrome (IBS). Studies indicate that gut dysbiosis occurs in subpopulations of IBS patients17Jeffery I.B. O’Toole P.W. Ohman L. et al.An irritable bowel syndrome subtype defined by species-specific alterations in faecal microbiota.Gut. 2012; 61: 997-1006Crossref PubMed Scopus (582) Google Scholar and improvement of symptoms following manipulation of gut microbiota with antibiotics or probiotics. The causal association between the dysbiotic IBS-associated microbiota and pathogenesis of IBS symptoms, however, remains incompletely defined. Drs. Emeran A. Mayer, Tor Savidge and Robert J. Shulman (pages 1500–1512) provide a critical review of the studies linking gut dysbiosis to abnormal brain-gut interaction, and discuss potential mediators generated by the bacteria and/or the host.18Mayer E.A. Savidge T. Shulman R.J. Brain–gut microbiome interactions and functional bowel disorders.Gastroenterology. 2014; 146: 1500-1512Scopus (286) Google Scholar It is interesting to note that germ-free animals show abnormal development of CNS mechanisms related to the functioning of the HPA axis19Ghazarian L. Diana J. Simoni Y. et al.Prevention or acceleration of type 1 diabetes by viruses.Cell Mol Life Sci. 2013; 70: 239-255Crossref PubMed Scopus (27) Google Scholar and the affective behavior. This suggests that mediators resulting from the interaction between microbes and the gut epithelium/immune system may shape the post-partum brain. However, it is unclear if these findings apply to humans. The authors propose new studies to gain further insight into the interaction between the gut microbes and the gut–brain axis. Drs Bernd Schnabl and David A. Brenner (pages 1513–1524) describe the role that the intestinal microbiome may play in the pathogenesis of liver disease; specifically, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, alcoholic liver disease, and cirrhosis.20Schnabl B. Brenner D.A. Interactions between the intestinal microbiome and liver diseases.Gastroenterology. 2014; 146: 1513-1524Scopus (599) Google Scholar Although these are a diverse set of diseases, there are common themes related to the role of the intestinal microbiome, such as the development of dysbiosis, translocation of bacteria and their products due to disruption in barrier function, and immune activation. It appears that these microbiome-associated alterations may work in concert with other extrinsic factors, such as a Western diet and alcohol consumption, to influence the development of liver disease. An exciting new finding in microbiome research is that intestinal microbes regulate the host’s metabolic function and energy balance. Mounting evidence suggests an altered microbial ecology may contribute to the development of obesity and other metabolic disorders. Drs Max Nieuwdorp, Pim W. Gilijamse, Nikhil Pai, and Lee M. Kaplan (pages 1525–1533) review the relationships between the gut microbiota and host metabolism and discuss potential mechanism of interaction, including the participation of mucus layer, bile acids, and immune responses.21Nieuwdorp M. Gilijamse P.W. Pai N. et al.Role of the microbiome in energy regulation and metabolism.Gastroenterology. 2014; 146: 1525-1533Scopus (237) Google Scholar The ability of the microbiota to transfer metabolic phenotypes among mice raises the exciting prospect of using fecal microbial transplantation to treat metabolic diseases. Drs Maria T. Abreu and Richard M. Peek Jr (pages 1534–1546) consider the role the intestinal microbiome may play in the pathogenesis of both upper and lower gastrointestinal malignancies, mainly gastric and esophageal malignancies, as well as colon cancer.22Abreu M.T. Peek Jr., R.M. Gastrointestinal malignancy and the microbiome.Gastroenterology. 2014; 146: 1534-1546Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar Although the principal microbe responsible for the development of gastric cancer, Helicobacter pylori, has been identified and some of the effector pathways have been characterized, this is not the case for the other 2 neoplastic diseases, although there is compelling functional data in rodent models. Nevertheless, the development of microbe-induced chronic inflammation is a common finding for all 3 diseases. The great success of fecal microbiota transplantation in treating recurrent C difficile infection with donor stools suggests that restoration of a diverse intestinal microbial community can interrupt the disease cycle. Drs Robert A. Britton and Vincent B. Young (pages 1547–1553) discuss specific mechanisms by which the microbiota can inhibit growth and persistence of C difficile.23Britton R.A. Young V.B. Role of the intestinal microbiota in resistance to colonization by Clostridium difficile.Gastroenterology. 2014; 146: 1547-1553Scopus (266) Google Scholar Competition for nutritional resources may contribute to the suppression of C difficile invasion by the intestinal microbiota. The role of bile salts (whose composition can be significantly altered by intestinal microbes) in C difficile spore germination and vegetative growth are reviewed. The third section focuses on the translation of the knowledge gained from the previous 2 sections, specifically addressing the notion that the intestinal microbiome is a modifiable environmental factor that can be a target for both the maintenance of health and the treatment of disease. Drs Fergus Shanahan and Eamonn M.M. Quigley (pages 1554–1563) highlight the challenges and controversies regarding therapeutic manipulation of the microbiota of patients with IBD or IBS.24Shanahan F. Quigley E.M.M. Manipulation of the microbiota for treatment of IBS and IBD––challenges and controversies.Gastroenterology. 2014; 146: 1554-1563Scopus (126) Google Scholar They examine the rationale for microbial strategies in these groups of disorders, comment on the disparities between findings from animal models and human studies, and conclude with a thoughtful prospective outlining the priorities for the next generation of microbial-based therapies. Diet is a major factor in the modulation of the composition and metabolic functions of microorganisms in the gut.25Wu G.D. Chen J. Hoffmann C. et al.Linking long-term dietary patterns with gut microbial enterotypes.Science. 2011; 334: 105-108Crossref PubMed Scopus (3940) Google Scholar Drs Lindsey G. Albenberg and Gary D. Wu (pages 1564–1572) review how diet specifically helps to shape the composition of the intestinal microbiota as well as influences the microbial metabolome, which may, in turn, affect host physiology and immune function.26Albenberg L.G. Wu G.D. Diet and the intestinal microbiome: associations, functions, and implications for health and disease.Gastroenterology. 2014; 146: 1564-1572Scopus (378) Google Scholar Recent research provides some understanding of how diet contributes to the pathogenesis of disorders, such as coronary vascular disease and IBD, through its impact on the gut microbiota and its metabolome. This knowledge may be used to develop therapeutic strategies for prevention or treatment of these and other disorders. We conclude the issue with a review by Drs Elaine O. Petrof and Alexander Khoruts (pages 1573–1582) on fecal microbiota transplantation (FMT) and the next generation of microbiota therapeutics.27Petrof E.O. Khoruts A. From stool transplants to next-generation microbiota therapeutics.Gastroenterology. 2014; 146: 1573-1582Scopus (132) Google Scholar The high level of efficacy of FMT for treatment refractory C difficile infection not only supports the notion of the intestinal microbiota as a therapeutic target in humans, but it also highlights the complex ethical, regulatory, and safety issues associated with procedures designed to modify the intestinal microbiota.28Hecht G.A. Blaser M.J. Gordon J. et al.What is the value of a Food and Drug Administration investigational new drug for fecal microbiota transplantation in Clostridium difficile infection?.Clin Gastroenterol Hepatol. 2014; 12: 289-291Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar Alternative strategies to FMT, such as standardized full-spectrum microbiota therapies and defined microbiota ecosystems are discussed as emerging therapeutic modalities.29Smits L.P. Bouter K.E. de Vos W.M. et al.Therapeutic potential of fecal microbiota transplantation.Gastroenterology. 2013; 145: 946-953Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar, 30Kassam Z. Lee C.H. Yuan Y. et al.Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis.Am J Gastroenterol. 2013; 108: 500-508Crossref PubMed Scopus (655) Google Scholar In summary, advances in DNA sequencing and bioinformatics have revolutionized our understanding of the microorganisms that inhabit the gut. This genomic revolution offers an exceptional opportunity to identify the molecular mechanisms governing commensal host–bacterial relationships. This new knowledge helps us understand how these interactions contribute to normal physiology and provides the foundation to formulate novel therapeutic strategies. This issue covers the spectrum of intestinal microbiome research, from basic concepts in mammalian gut microbiome to disease associations and therapeutic implications. Our intent was to provide comprehensive and up-to-date information on the human gut microbiome and its association with disease, but also, to stimulate research that will lead to further discoveries and novel therapeutics. We thank our authors for their tremendous contributions and our reviewers for their insightful appraisals of the submitted manuscripts. Finally, we are grateful to the editorial staff for preparing this issue for publication.