The Crohns disease polymorphism ATG16L1T300A alters the gut microbiota and enhances the local Th1 and Th17 response

The relationship between the gut microbiota, host genetics and the immune system in inflammatory bowel disease (IBD) pathogenesis is complex. Variation in patient genotype, disease natural history, and gut microbial composition make determining disease causality difficult. Significant knowledge gaps remain regarding whether there are specific changes in the gut microbiota linked to individual genetic risk loci for IBD. Herein, we employ a model of intestinal injury and inflammation and gnotobiotics involving IBD patient fecal microbiota transfers in mice bearing the Crohns disease risk allele ATG16L1T300A to determine the effects of this allele on the gut microbiota and the gut immune system. We observed an increase in Bacteroides ovatus as well as an increase in Th1 and Th17 cells within the gut lamina propria of T300A knock-in mice. These changes appear to occur before the onset of disease, suggesting that risk alleles may contribute initially to dysbiosis and immune infiltration prior to manifestation of symptoms and overt signs of intestinal inflammation. Understanding how IBD risk alleles can shape the gut microbiota may provide insight into disease subtypes, aid in targeted therapeutic treatments for IBD patients and inform earlier diagnostics.