It is now well recognized that IBD develops as a result of complex gene-environment interactions. Since there is no cure for IBD, treatment has focused on alleviating the symptoms. A better understanding of the fundamental mechanisms that drive the development and progression of IBD would allow for the design of more specific and effective treatments. Bacteria that naturally live in our intestine (called the microbiota) have been definitively linked to intestinal inflammation, but how this relationship is regulated is not well understood. Epigenetics refers to modifications that allow genes to be turned on or off and we have found unique epigenetic changes that occur in the intestine in response to signals from the microbiota. Further, we have identified similar epigenetic differences in intestinal cells of pediatric IBD patients. Based on these findings, studies in this proposal will use samples from pediatric IBD patients and mouse models to define how these newly-identified epigenetic changes are regulated by intestinal bacteria. We will also determine whether these targets enable us to predict patient prognosis and employ animal models and human intestine grown in culture to decipher their function. We anticipate that these studies will direct new approaches for preventing and treating IBD.