Gene-Microbiota Interactions Contribute to the Pathogenesis of Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is associated with risk variants in the human genome, and dysbiosis of the gut microbiome. However, molecular mechanisms unifying beneficial gene-microbiota interactions remain largely undescribed. The human commensal Bacteroides fragilis produces immunomodulatory molecules that are delivered to the mucosal immune system via secretion of outer membrane vesicles (OMVs). We reveal that OMVs require IBD-associated genes, ATG16L1 and NOD2, to activate a non-canonical autophagy pathway during protection from experimental colitis. ATG16L1-deficient dendritic cells do not support induction of regulatory T cells (Treg) that suppress intestinal inflammation. Immune cells from human subjects with a major risk variant in ATG16L1 are defective in Treg responses to OMVs. Thus, polymorphisms in susceptibility genes may contribute to disease through defects in 'sensing' protective signals from the gut microbiome, defining a novel gene-environment etiology for IBD.