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Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease.

ABSTRACT: 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.

SUBMITTER: Chu H

PROVIDER: S-EPMC4996125 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease.

Chu Hiutung H Khosravi Arya A Kusumawardhani Indah P IP Kwon Alice H K AH Vasconcelos Anilton C AC Cunha Larissa D LD Mayer Anne E AE Shen Yue Y Wu Wei-Li WL Kambal Amal A Targan Stephan R SR Xavier Ramnik J RJ Ernst Peter B PB Green Douglas R DR McGovern Dermot P B DP Virgin Herbert W HW Mazmanian Sarkis K SK

Science (New York, N.Y.) 20160505 6289

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-deficien ...[more]

PMID: 27230380

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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.

Dataset Information

Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease.

Publications

Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease.

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