Journal
SCIENCE
Volume 352, Issue 6289, Pages 1116-1120Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aad9948
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Funding
- National Institutes of Health (NIH) under a Ruth L. Kirschtein National Research Service Award [DK100109]
- NIH [DK097485, PO1DK046763, AI079145, AI40646, U19 AI109725, DK062413, DE023789-01, AI109725, DK078938, GM099535]
- Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute Research Funds
- Feintech Family Chair in IBD
- Wayne and Gladys Valley Foundation
- Lupus Research Institute
- Lisa Z. Greer Endowed Chair in IBD Genetics
- European Union [305479]
- Crohn's and Colitis Foundation of America
- Leona M. and Harry B. Helmsley Charitable Trust
- Heritage Medical Research Institute
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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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