The Crohn's disease polymorphism, T300A, alters the gut microbiota and enhances the local Th1/Th17 response.

Inflammatory bowel disease (IBD) is driven by dysfunction between host genetics, the microbiota, and immune system. Knowledge gaps remain regarding how IBD genetic risk loci drive gut microbiota changes. The Crohn's disease risk allele T300A results in abnormal Paneth cells due to decreased selective autophagy, increased cytokine release, and decreased intracellular bacterial clearance. To unravel the effects of T300A on the microbiota and immune system, we employed a gnotobiotic model using human fecal transfers into T300A knock-in mice. We observed increases in and Th1 and Th17 cells in T300A mice. Association of altered Schaedler flora mice with specifically increased Th17 cells selectively in T300A knock-in mice. Changes occur before disease onset, suggesting that T300A contributes to dysbiosis and immune infiltration prior to disease symptoms. Our work provides insight for future studies on IBD subtypes, IBD patient treatment and diagnostics.