Polymorphisms in susceptibility genes appear to promote development of inflammatory bowel diseases (IBD) by altering the abilities of immune cells to sense protective signals from the microbiome, researchers report. These findings help fill the missing link between genetic risk variants for IBD and dysbiosis of the intestinal microbiome.
More than 200 genes have been implicated as having a role in determining susceptibility to Crohn’s disease. Researchers have believed that these genes regulate detection of pathogenic bacteria and the immune response against them. The model has been that when these genes are defective, the pathogenic bacteria survive, multiply in the gut, and lead to IBD.
“Typically, the signals from these beneficial commensal microbes promote anti-inflammatory responses that dampen inflammation in the gut,” Chu explained to Science Daily. The authors found that mutations in genes that regulate these signals can reduce this anti-inflammatory response.
Chu et al knew that the human commensal Bacteroides fragilis delivers immunomodulatory molecules to immune cells via secretion of outer membrane vesicles. They found that these vesicles require products of the IBD-associated genes, ATG16L1 and NOD2, to activate an autophagy pathway that protects mice from colitis.
The authors found that ATG16L1-deficient dendritic cells did not induce T-regulatory cells (Treg cells) to suppress mucosal inflammation. Immune cells from human subjects with a major IBD risk variant in ATG16L1 had defective Treg-cell responses to the outer membrane vesicles and no anti-inflammatory response to B fragilis.
The authors propose that the faulty versions of these genes contribute to development of Crohn’s disease in 2 different ways: by being unable to assist in destroying pathogenic bacteria and by preventing the beneficial immune signals usually elicited by good bacteria.
These findings improve our understanding of the relationship between the genome and the microbiome, and provide important information for therapeutic strategies. For example, certain populations of patients would not benefit from probiotic treatment with B fragilis because they have genetic variants that block its beneficial, immune-regulatory effects.