Project Summary/Abstract Inflammatory bowel diseases are frequently complicated by diseases of the skin. It is not understood why disease of the surface epithelial tissues of the skin influences the severity of disease of the very different barrier epithelia in the gut. This proposal will test the central hypothesis that the “inflammatory cross” talk between skin and the intestine is a consequence of release of hyaluronic acid (HA) from the extracellular matrix of the skin that then promotes reactive adipogenesis of the intestinal submucosa. Reactive adipogenesis is a newly recognized innate immune response in both skin and intestine, and important for antimicrobial defense. Our preliminary data will show that skin injury, or targeted expression of hyaluronidase in the skin, has a major affect on the intestinal stroma, resulting in alterations in gut inflammation and the fecal microbiome. The mechanism we propose to explain how this occurs centers around our discovery that HA is key for the capacity of submucosal intestinal fibroblasts to differentiate into adipocytes. Fragments of HA generated in the skin circulate to the gut to stimulate adipogenesis and induce transcriptional changes in preadipocytes. The stromal cells undergoing differentiation into adipocytes and then release antimicrobial peptides and adipokines that alter the immune status of the intestine. Thus, our central hypothesis is that injury to the skin modulates host defense in the intestine by the capacity of HA fragments to stimulate adipocyte differentiation. This proposal will test this hypothesis, carefully define the influence of adipogenesis on local host defense and define the mechanisms responsible for these observations. This data can be critical toward developing new and innovative treatments for intestinal inflammation.