A major type of inflammatory bowel disease (IBD) may be caused in part by genetic variants that prevent beneficial bacteria in the gut from doing their job, according to a new study published today in the journal Science.
Investigators found that the beneficial effects of Bacteroides fragilis bacterium, one of billions of microscopic organisms that normally inhabit the human gastrointestinal system, were negatively impacted by variations in the ATG16L1 gene.
These genetic variations increase the risk of developing Crohn's disease, one of the two common forms of IBD. As a result, the bacteria were prevented from carrying out one of their critical functions: suppressing inflammation of the intestinal lining.
The human commensal Bacteroides fragilis delivers immunomodulatory molecules to immune cells via secretion of outer membrane vesicles (OMVs). Authors reveal that OMVs require IBD-associated genes, ATG16L1 and NOD2, to activate a non-canonical autophagy pathway during protection from colitis.
ATG16L1-deficient dendritic cells do not induce regulatory T cells (Treg) to suppress mucosal inflammation. Immune cells from human subjects with a major risk variant in ATG16L1 are defective in Treg responses to OMVs.
Researchers 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.