Inflammatory Bowel Disease-associated Dysbiosis and Immune Gardening of the Intestinal Microbiome
Inflammatory bowel disease (IBD) – comprised of Crohn’s disease (CD) and ulcerative colitis (UC) – is believed to arise from a combination of genetic susceptibility and environmental factors that trigger an inappropriate mucosal immune response to constituents of the intestinal microbiome. There is now an extensive literature demonstrating that the microbiome has profound effects on immune function and, conversely, that the immune system can shape the microbiome. I hypothesized that genetic variation in mucosal immune gardening of the intestinal microbiome can result in pro-inflammatory dysbiosis, which acts as a risk factor for overt IBD. To evaluate whether individuals at risk for IBD develop dysbiosis prior to the onset of disease, a family based study was performed to characterize the microbiome and metabolome of pediatric IBD patients and their first degree relatives. These relatives are at higher risk for dysbiosis than the general population due to shared genetic and environmental factors with the IBD proband. A subset of healthy relatives in this cohort had dysbiosis with fecal metabolomic profiles (metabotypes) shared with IBD patients. The effect of the transcription factor RORgt on the intestinal microbiome was then investigated as a model of how perturbation of immune gardening could result in dysbiosis. Mice deficient in RORgt had an altered small intestinal and colonic mucosa-associated microbiome characterized by overgrowth of segmented filamentous bacteria (SFB), a microbe previously shown to promote colitis. Further knockout and cell engraftment experiments demonstrated that small intestinal gardening of SFB was mediated by RORgt-dependent T cells in a manner independent of IL-17A. The protective rs4845604 polymorphism in the RORC gene encoding RORgt was associated with altered microbial composition in mucosal wash samples from IBD patients and healthy individuals. These findings demonstrated that RORgt-dependent T cells garden the intestinal microbiome and suggest that genetic variation in this process could influence susceptibility to IBD.