Mucosal diseases such as Inflammatory Bowel Disease (IBD) result from changes in the microbiota (dysbiosis) in the face of ongoing inflammation. Our ongoing studies have identified a significant role for microbial-derived short chain fatty acids (SCFA) in intestinal disease and an important role for the transcriptional regulator hypoxia-inducible factor (HIF) in protection during intestinal inflammation. It remains unclear exactly how the host and the microbiota communicate and whether such communication is relevant to disease progression or inflammatory resolution. This study is designed to test the hypothesis that host-microbial crosstalk via SCFA promotes mucosal integrity, with HIF as the epithelial messenger and the epithelial IL-10R as the target. Three integrated specific aims are proposed to test this hypothesis. First, we will define the SCFA signaling axis for HIF stabilization using an established intestinal epithelial model in vitro and in vivo. Specifically, e will define how the epithelial SCFA signaling receptor GPR109a and impacts HIF stabilization in the mucosa and how such signaling promotes mucosal integrity. Second, we will elucidate the contribution of SCFA-induced HIF on epithelial IL-10R expression and signaling. Third, we will determine the relevance of this SCFA-HIF-IL-10R axis in mucosal inflammatory models. The overall aim of this proposal is to elucidate the host-microbial communication events mediating mucosal epithelial responses to inflammation.
The Inflammatory Bowel Diseases (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD), are diseases of the gastrointestinal tract that result from abnormal immune response to luminal antigens in genetically-susceptible individuals. IBD represents a disease of major interest, with more than 1.5 million American afflicted with this chronic inflammatory disorder. The proposed studies are designed to identify and harness information from novel inflammation-related metabolic pathways that promote tissue healing through interactions with bacteria found in the lumen (i.e. the 'microbiota'). Such studies should provide new avenues into our understanding of why inflammatory diseases develop, and in particular, how innate immune responses contribute to inflammatory resolution.
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