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Inflammatory bowel disease (IBD) - comprised of Crohn's disease (CD) and ulcerative colitis (UC) - is believed to arise from a combination of genetic susceptibility and environmental factors that trigger an inappropriate mucosal immune response to constituents of the intestinal microbiome. There is now an extensive literature demonstrating that the microbiome has profound effects on immune function and, conversely, that the immune system can shape the microbiome. I hypothesized that genetic variation in mucosal immune gardening of the intestinal microbiome can result in pro-inflammatory dysbiosis, which acts as a risk factor for overt IBD. To evaluate whether individuals at risk for IBD develop dysbiosis prior to the onset of disease, a family based study was performed to characterize the microbiome and metabolome of pediatric IBD patients and their first degree relatives. These relatives are at higher risk for dysbiosis than the general population due to shared genetic and environmental factors with the IBD proband. A subset of healthy relatives in this cohort had dysbiosis with fecal metabolomic profiles (metabotypes) shared with IBD patients. The effect of the transcription factor RORgt on the intestinal microbiome was then investigated as a model of how perturbation of immune gardening could result in dysbiosis. Mice deficient in RORgt had an altered small intestinal and colonic mucosa-associated microbiome characterized by overgrowth of segmented filamentous bacteria (SFB), a microbe previously shown to promote colitis. Further knockout and cell engraftment experiments demonstrated that small intestinal gardening of SFB was mediated by RORgt-dependent T cells in a manner independent of IL-17A. The protective rs4845604 polymorphism in the RORC gene encoding RORgt was associated with altered microbial composition in mucosal wash samples from IBD patients and healthy individuals. These findings demonstrated that RORgt-dependent T cells garden the intestinal microbiome and suggest that genetic variation in this process could influence susceptibility to IBD.
Dr. Fasano holds stocks in Alba Therapeutics and receives financial support from Takeda Pharmaceuticals. Dr. Taneja receives financial support from Elysium Health and Evelo Biosciences. The other Topic Editors declare no competing interests with regards to the Research Topic subject.
Inflammatory bowel disease (IBD) is a set of chronic, relapsing inflammatory diseases of the intestine. The two major subtypes of IBD are Crohn's disease (CD) and ulcerative colitis (UC). Although the pathogenesis of IBD remains largely unknown, Crohn's disease is considered to result from the interaction of environmental factors, including intestinal microbiota, with host immune mechanisms in genetically susceptible individuals. Recent advances in sequencing technologies have allowed us to characterize the IBD associated dysbiosis in unprecedented depth. However, phylogenetic profiling can only provide limited information on the functional implication of these alterations. To address this analytical challenge, we developed the novel mucosal lavage sampling approach, which enabled the profiling of multi'omic molecular features including microbiome, metaproteome and metabolome. Combined with host genomic information, these tools can provide us with unprecedented understanding of the dynamics of host-microbial interaction, and help us to investigate the pathogenesis of inflammatory bowel diseases. Another analytical challenge to identify microbial taxa consistently representing IBD associated dysbiosis is the high complexity and low inter-individual overlap of intestinal microbial composition. This difficulty can be overcome by an ecologic analytic strategy to identify modules of interacting bacteria (rather than individual bacteria) as quantitative reproducible features of microbial composition in normal and IBD mucosa. We developed the strategy to analyze microbial composition using microbial co-occurrence network approach. This strategy uncovered 5 reproducible functional microbial communities (FMCs) detectable in the mucosa of all individuals. The quantitative levels of two FMCs were significantly associated with IBD states. Imputed metagenome analysis indicated the functional importance of the disease associated modules reflected by the enrichment of virulent and pathogenic pathways. Thus, these modules appear to define novel microbial communities within the intestinal microbial ecology, some of which are commonly and stably modified by the IBD disease state, and may be of particular relevance for microbial pathogenesis and intervention. Using this experimental and bioinformatic framework, we investigated the microbial gardening effect of FUT2 gene and its link to Crohn's disease. Fucosyltransferase 2 (FUT2) is an enzyme that is responsible for the synthesis of the H antigen in body fluids and on the intestinal mucosa. Non-secretors, who are homozygous for the loss-of-function alleles of FUT2 gene (sese), have increased susceptibility to Crohn's disease. In healthy individuals, imputed metagenomic analysis revealed perturbations of energy metabolism in the microbiome of non-secretor and heterozygote individuals, notably the enrichment of carbohydrate and lipid metabolism, cofactor and vitamin metabolism, and glycan biosynthesis and metabolism related pathways; and, the depletion of amino acid biosynthesis and metabolism. Similar changes were observed in mice bearing the FUT2−1− genotype. Metabolomic analysis of human specimens revealed concordant as well as novel changes in the levels of several metabolites. Human metaproteomic analysis indicated that these functional changes were accompanied by sub-clinical levels of inflammation in the local intestinal mucosa. In an extended cohort containing both healthy and CD individuals, the phylogenetic composition of intestinal mucosal microbiota was affected by an interaction of Crohn's disease status and FUT2 genotype. Decreased abundances of Firmicutes were associated with both CD and FUT2 risk allele. At metagenomic level, a distinct signature of amino acid metabolism deficiency was identified in CD and non-secretor microbiome. Such changes were also reflected at metabolomic level in the proximal gut region. Taken together, FUT2 gene increased the risk of Crohn's disease by changing the microbial composition and function to a disease-like state. The CD associated perturbations of metagenome and metabolome were driven by the FUT2 risk allele. The same experimental and bioinformatic approach can also be applied to study the composition and functional changes of mucosal associated microbiota in other chronic inflammatory disease, namely HIV-1 infection. In the rectal mucosa, microbial composition and imputed function in HIV-positive individuals not receiving cART was significantly different from HIV-negative individuals. Genera including Roseburia, Coprococcus, Ruminococcus, Eubacterium, Alistipes and Lachnospira were depleted in HIV-infected subjects not receiving cART, while Fusobacteria, Anaerococcus, Peptostreptococcus and Porphyromonas were significantly enriched. HIV-positive subjects receiving cART exhibited similar depletion and enrichment for these genera, but were of intermediate magnitude and did not achieve statistical significance. Imputed metagenomic functions, including amino acid metabolism, vitamin biosynthesis, and siderophore biosynthesis differed significantly between healthy controls and HIV-infected subjects not receiving cART. In the cervicovaginal mucosa, significant differences in alpha and beta diversity were observed between HIV-negative and HIV-positive women, with the latter enriched of organisms associated with bacterial vaginosis and depleted of Lactobacilli. These ecologic changes occurred concomitantly with significant metagenomic and immunologic differences. Such functional pathways may represent novel interventional targets for HIV therapy if normalizing the microbial composition or functional activity of the microbiota proves therapeutically useful.
The Gut Microbiota in Health and Disease An accessible overview of the varied microorganisms of the gut The human gut contains an extraordinary array of microorganisms existing in intricate symbiosis with the body. The gut microbiota plays a crucial role in maintaining overall gut health and warding off disease. With up to 15% of the global population suffering from Irritable Bowel Syndrome (IBS) caused by improper composition of gut microbiota, understanding these organisms and their vital contribution to human health has never been more important. The Gut Microbiota in Health and Disease provides a concise, accessible introduction to gut microbiota and their contribution to human health. It offers not only an overview of the relevant microorganisms and their roles in the body, but also extended discussion of diseases caused by gut dysbiosis. It presents a crucial window into this growing body of research into a critical area of overall human health. The Gut Microbiota in Health and Disease, readers will also find: Detailed analysis of dysbiotic health conditions including obesity, diabetes, and more Thorough treatment of molecular techniques for the analysis gut microbial composition Discussion of the lowering diversity of bacteria in the gut and the corresponding impact on global health The Gut Microbiota in Health and Disease is essential for researchers and clinicians working in immunology, gastroenterology, clinical microbiology, and related fields, as well as for clinical dieticians and postgraduate or medical students studying in these areas.
Inflammatory bowel disease (IBD) comprises a group of idiopathic diseases of the intestine characterized by chronic inflammation of the bowel with periods of exacerbation and remission. Although the exact cause of IBD remains undetermined, the condition appears to be related to a combination of genetic and environmental factors resulting in an aberrant activation of the mucosal immune system. This book contains a series of interdisciplinary discussions between clinical and basic scientists focusing on key issues such as: Epithelial cell and molecular biology, including apoptosis, necrosis and cell survival The role of bacterial milieu and mucosal bacteria in the IBD and of prebiotic and probiotic therapy The progress towards the identification of susceptibility genes and phenotype-determining genes The pharmacogenetics of IBD Mucosal immunology and therapeutic strategies stemming therefrom
Probiotics, Prebiotics, and Synbiotics: Bioactive Foods in Health Promotion reviews and presents new hypotheses and conclusions on the effects of different bioactive components of probiotics, prebiotics, and synbiotics to prevent disease and improve the health of various populations. Experts define and support the actions of bacteria; bacteria modified bioflavonoids and prebiotic fibrous materials and vegetable compounds. A major emphasis is placed on the health-promoting activities and bioactive components of probiotic bacteria. - Offers a novel focus on synbiotics, carefully designed prebiotics probiotics combinations to help design functional food and nutraceutical products - Discusses how prebiotics and probiotics are complementary and can be incorporated into food products and used as alternative medicines - Defines the variety of applications of probiotics in health and disease resistance and provides key insights into how gut flora are modified by specific food materials - Includes valuable information on how prebiotics are important sources of micro-and macronutrients that modify body functions
The amount of information on the pathogenesis of inflammatory bowel disease is growing rapidly. This is reflected by a continuous increase in the number of papers presented at international GI meetings. To make things more difficult for practicing physicians, there is also a large number of new clinical trials being published which require periodical critical reviews and recommendations. Faced with these issues, the scientific commitee of the Falk Symposium No. 140 decided to take a different approach and to apply a novel format that is reflected in the title of the Symposium: "Translation from basic research to clinical practice". This book contains the proceedings of that Symposium, held in Dubrovnik, Croatia, on May 7–8, 2004. The sections are designed so that they start with the information from basic sciences on different aspects of these complex diseases and further lead to their clinical implications. Special attention is paid to the mechanisms of actions of established drugs. The last two sections are clinically oriented and focus on the most difficult aspects of both Crohn's disease and ulcerative colitis. This format provides state-of-the-art chapters by leading experts in the field and at the same time up-to-date information on the clinical application of the new knowledge.
The inflammatory bowel diseases, of unknown etiology and for which there are no cures, continue to attract the attention and interest of gastroenterologists, internists and surgeons. International symposia are common and it is safe to say that there is at least one major symposium held somewhere in the world each year. This book encompasses the proceedings of two recent symposia held in Victoria, British Columbia, Canada. The symposia were the fifth and sixth international meetings focused on inflammatory bowel disease in Canada in the last eight years. Once again they were sponsored by Axcan Pharma, Inc. (formerly Interfalk Canada, Inc.) and endorsed by the Canadian Association of Gastroenterology. As has become traditional at such meetings the faculty was drawn from an international roster ofleaders in the field of inflammatory bowel disease and gastroenterology. The chapters of the proceedings provide a timely, up-to-date review of the major issues, including those within the realm of basic science and others dealing with clinical problems. The first symposium, 'Basic Research and Clinical Implications', was co-ordinated by John Wallace in association with Stephen Collins and Stephan Targan. The themes of this section were organized under the general topics of predisposing factors (genetics, animal models, infection, permeability, and immune deficits) and the pathophysiology of intestinal inflammation. The second symposium, Trends in Therapy' was organized by Lloyd Sutherland along with Franc;:ois Martin, Robin McLeod and Noel Williams.
This is the first comprehensive volume to look at the importance of short-chain fatty acids in digestion, the function of the large intestine and their role in human health. Short-chain fatty acids are the major product of bacterial fermentation of dietary carbohydrates in the human and animal large intestine. They represent the major end products of digestive processes occurring in the caecum and large intestine. As such, they form an important dietary component and it is increasingly recognised that they may have a significant role in protecting against large bowel cancer and in metabolism. Prepared by an international team of contributors who are at the forefront of this area of research, this volume will be an essential source of reference for gastroenterologists, nutritionists and others active in this area.