It is well recognized that innate and adaptive immunity are inappropriately activated in inflammatory bowel diseases (IBD) and promote tissue destruction. Innate mechanisms protecting intestinal epithelial cells have been recently identified but are less well understood. We will dissect the mechanisms leading to IL-22-mediated epithelial protection, granuloma formation and granuloma-mediated epithelial barrier repair program in the context of IBD. These studies may lead us to identify innate immune targets for the treatment of IBD.