Gene-environment interactions in inflammatory bowel disease: microbiota and genes.
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ABSTRACT:
SUBMITTER: Aldhous MC
PROVIDER: S-EPMC5517276 | biostudies-other | 2012 Jul
REPOSITORIES: biostudies-other
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Project description:Inflammatory bowel disease (IBD) is associated with risk variants in the human genome and dysbiosis of the gut microbiome, though unifying principles for these findings remain largely undescribed. The human commensal Bacteroides fragilis delivers immunomodulatory molecules to immune cells via secretion of outer membrane vesicles (OMVs). We reveal that OMVs require IBD-associated genes, ATG16L1 and NOD2, to activate a noncanonical autophagy pathway during protection from colitis. ATG16L1-deficient dendritic cells do not induce regulatory T cells (T(regs)) to suppress mucosal inflammation. Immune cells from human subjects with a major risk variant in ATG16L1 are defective in T(reg) responses to OMVs. We propose that polymorphisms in susceptibility genes promote disease through defects in "sensing" protective signals from the microbiome, defining a potentially critical gene-environment etiology for IBD.
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Project description:BackgroundInflammatory bowel disease (IBD) is a chronic relapsing-remitting disease. An adverse immune reaction toward the intestinal microbiota is involved in the pathophysiology and microbial perturbations are associated with IBD in general and with flares specifically. Although medical drugs are the cornerstone of current treatment, responses vary widely between patients and drugs. The intestinal microbiota can metabolize medical drugs, which may influence IBD drug (non-)response and side effects. Conversely, several drugs can impact the intestinal microbiota and thereby host effects. This review provides a comprehensive overview of current evidence on bidirectional interactions between the microbiota and relevant IBD drugs (pharmacomicrobiomics).MethodsElectronic literature searches were conducted in PubMed, Web of Science and Cochrane databases to identify relevant publications. Studies reporting on microbiota composition and/or drug metabolism were included.ResultsThe intestinal microbiota can both enzymatically activate IBD pro-drugs (e.g., in case of thiopurines), but also inactivate certain drugs (e.g., mesalazine by acetylation via N-acetyltransferase 1 and infliximab via IgG-degrading enzymes). Aminosalicylates, corticosteroids, thiopurines, calcineurin inhibitors, anti-tumor necrosis factor biologicals and tofacitinib were all reported to alter the intestinal microbiota composition, including changes in microbial diversity and/or relative abundances of various microbial taxa.ConclusionVarious lines of evidence have shown the ability of the intestinal microbiota to interfere with IBD drugs and vice versa. These interactions can influence treatment response, but well-designed clinical studies and combined in vivo and ex vivo models are needed to achieve consistent findings and evaluate clinical relevance.
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Project description:Inflammatory bowel disease (IBD) is a complex set of diseases that lead to chronic inflammation in the gastrointestinal tract. Although the etiology of IBD is not fully understood, it is well-known that the intestinal microbiota is associated with the development and maintenance of IBD. Manipulation of the gut microbiota, therefore, may represent a target for IBD therapy. Fecal microbiota transplantation (FMT), where fecal microbiota from a healthy donor is transplanted into a patient's GI tract, is already a successful therapy for Clostridium difficile infection. FMT is currently being explored as a potential therapy for IBD as well. In this review, the associations between the gut microbiota and IBD and the emerging data on FMT for IBD will be discussed.
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Project description:Interactions among the gut microbiome, dysregulated immune responses, and genetic factors contribute to the pathogenesis of inflammatory bowel disease (IBD). Nlrx1-/- mice have exacerbated disease severity, colonic lesions, and increased inflammatory markers. Global transcriptomic analyses demonstrate enhanced mucosal antimicrobial defense response, chemokine and cytokine expression, and epithelial cell metabolism in colitic Nlrx1-/- mice compared to wild-type (WT) mice. Cell-specificity studies using cre-lox mice demonstrate that the loss of NLRX1 in intestinal epithelial cells (IEC) recapitulate the increased sensitivity to DSS colitis observed in whole body Nlrx1-/- mice. Further, organoid cultures of Nlrx1-/- and WT epithelial cells confirm the altered patterns of proliferation, amino acid metabolism, and tight junction expression. These differences in IEC behavior can impact the composition of the microbiome. Microbiome analyses demonstrate that colitogenic bacterial taxa such as Veillonella and Clostridiales are increased in abundance in Nlrx1-/- mice and in WT mice co-housed with Nlrx1-/- mice. The transfer of an Nlrx1-/--associated gut microbiome through co-housing worsens disease in WT mice confirming the contributions of the microbiome to the Nlrx1-/- phenotype. To validate NLRX1 effects on IEC metabolism mediate gut-microbiome interactions, restoration of WT glutamine metabolic profiles through either exogenous glutamine supplementation or administration of 6-diazo-5-oxo-l-norleucine abrogates differences in inflammation, microbiome, and overall disease severity in Nlrx1-/- mice. The influence NLRX1 deficiency on SIRT1-mediated effects is identified to be an upstream controller of the Nlrx1-/- phenotype in intestinal epithelial cell function and metabolism. The altered IEC function and metabolisms leads to changes in barrier permeability and microbiome interactions, in turn, promoting greater translocation and inflammation and resulting in an increased disease severity. In conclusion, NLRX1 is an immunoregulatory molecule and a candidate modulator of the interplay between mucosal inflammation, metabolism, and the gut microbiome during IBD.
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Project description:Inflammatory bowel disease (IBD) is a family of conditions characterized by chronic, relapsing inflammation of the gastrointestinal tract. IBD afflicts over 3 million adults in the United States and shows increasing prevalence in the Westernized world. Current IBD treatments center on modulation of the damaging inflammatory response and carry risks such as immunosuppression, while the development of more effective treatments is hampered by our poor understanding of the molecular mechanisms of IBD pathogenesis. Previous genome-wide association studies (GWAS) have demonstrated that gene variants linked to the cellular response to microorganisms are most strongly associated with an increased risk of IBD. These studies are supported by mechanistic work demonstrating that IBD-associated polymorphisms compromise the intestine's anti-microbial defense. In this review, we summarize the current knowledge regarding IBD as a disease of defects in host-microbe interactions and discuss potential avenues for targeting this mechanism for future therapeutic development.
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Project description:BackgroundInflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), affect millions of people worldwide with increasing incidence.ObjectivesSeveral studies have shown a link between gut microbiota composition and IBD, but results are often limited by small sample sizes. We aimed to re-analyze publicly available fecal microbiota data from IBD patients.MethodsWe extracted original fecal 16S rRNA amplicon sequencing data from 45 cohorts of IBD patients and healthy individuals using the BioProject database at the National Center for Biotechnology Information. Unlike previous meta-analyses, we merged all study cohorts into a single dataset, including sex, age, geography, and disease information, based on which microbiota signatures were analyzed, while accounting for varying technical platforms.ResultsAmong 2518 individuals in the combined dataset, we discovered a hitherto unseen number of genera associated with IBD. A total of 77 genera associated with CD, of which 38 were novel associations, and a total of 64 genera associated with UC, of which 28 represented novel associations. Signatures were robust across different technical platforms and geographic locations. Reduced alpha diversity in IBD compared to healthy individuals, in CD compared to UC, and altered microbiota composition (beta diversity) in UC and especially in CD as compared to healthy individuals were found.ConclusionsCombining original microbiota data from 45 cohorts, we identified a hitherto unseen large number of genera associated with IBD. Identification of microbiota features robustly associated with CD and UC may pave the way for the identification of new treatment targets.
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Project description:Strong evidence suggests that the gut microbiota is altered in inflammatory bowel disease (IBD), indicating its potential role in noninvasive diagnostics. However, no clinical applications are currently used for routine patient care. The main obstacle to implementing a gut microbiota test for IBD is the lack of standardization, which leads to high interlaboratory variation. We studied the between-hospital and between-platform batch effects and their effects on predictive accuracy for IBD. Fecal samples from 91 pediatric IBD patients and 58 healthy children were collected. IS-pro, a standardized technique designed for routine microbiota profiling in clinical settings, was used for microbiota composition characterization. Additionally, a large synthetic data set was used to simulate various perturbations and study their effects on the accuracy of different classifiers. Perturbations were validated in two replicate data sets, one processed in another laboratory and the other with a different analysis platform. The type of perturbation determined its effect on predictive accuracy. Real-life perturbations induced by between-platform variation were significantly greater than those caused by between-laboratory variation. Random forest was found to be robust to both simulated and observed perturbations, even when these perturbations had a dramatic effect on other classifiers. It achieved high accuracy both when cross-validated within the same data set and when using data sets analyzed in different laboratories. Robust clinical predictions based on the gut microbiota can be performed even when samples are processed in different hospitals. This study contributes to the effort to develop a universal IBD test that would enable simple diagnostics and disease activity monitoring.
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