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 commensalBacteroides fragilisdelivers immunomodulatory molecules to immune cells via secretion of outer membrane vesicles (OMVs). We reveal that OMVs require IBD-associated genes,ATG16L1andNOD2, to activate a noncanonical autophagy pathway during protection from colitis. ATG16L1-deficient dendritic cells do not induce regulatory T cells (Tregs) to suppress mucosal inflammation. Immune cells from human subjects with a major risk variant inATG16L1are defective in Treg 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.