Project Summary/Abstract This project is directed at understanding the pathogenesis of inflammatory bowel diseases, which include ulcerative colitis and Crohn's disease. These chronic debilitating diseases affect between 1 and 2 million US citizens and have significant health, social and economic impact on patients. The causes of IBD are not known but likely involve the reaction of the intestinal immune system to an undefined environmental trigger. The overall objective of this proposal is to understand the role of innate immune cells in the pathology of inflammatory bowel disease. The approach is based on a new model of spontaneous innate immune-mediated colitis that we have recently developed. Colitis occurring spontaneously in the absence of adaptive (T or B cells) immune cells will allow us to interrogate the specific contributions of innate immunity to the pathology of inflammatory bowel disease. Studying this model will allow us to interrogate innate immune cellular, cytokine and signaling mechanisms that contribute to intestinal inflammation and to investigate how microbes contribute to innate immune inflammation in the gut. The aims of the work are to (1) Identify the cell and molecular mechanisms of inflammation in TRAG colitis; (2) Test the efficacy of JAK inhibitors in TRAG colitis; and (3) Identify microbes exhibiting altered biogeography in the intestine of TRAG mice that induce asialo Gm1+ cells and are colitogenic. Together these studies have the potential to advance our understanding of pathological innate immune mechanisms that can cause intestinal inflammation, to identify new targets for treatments for inflammatory bowel disease, and to understand the mechanism of action of therapies currently under development as inflammatory bowel disease treatments.