GPR120 regulation of intestinal IgA responses and gut IgA-coated bacteria

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Abstract Increasing evidence suggests that the interactions between diet and the gut microbiota may play a critical role in promoting or alleviating intestinal inflammation. However, little is known about the mechanisms involved. Free fatty acids provide important energy sources as dietary nutrients, and act as signaling molecules in various cellular processes. Most notable among the free fatty acids targets are mammalian G protein-coupled receptors (GPR). GPR120 (also known as free fatty acid receptor 4, FFAR4) has been identified as a bona fide receptor for long-chain fatty acids (LCFA) from dietary products and has a critical role in various physiological homeostasis mechanisms such as adipogenesis. Its agonists are suggested as therapeutic targets for diabetes, metabolic disorders, and inflammatory diseases. However, the mechanisms involved are still largely unknown. Intestinal mucosal surfaces are protected by a first-line defense mediated by secretory Immunoglobulin A (SIgA), which has been shown to be critical in mucosal immune defense. Intestinal IgA can be produced by both T cell- dependent and T cell-independent pathways, however, the relative importance of each and how they are regulated are still largely unclear. Although both are enriched in the intestines, there is a significant knowledge gap regarding how LCFA regulate intestinal IgA responses as well as the role of the LCFA-IgA axis in the regulation of host responses to microbiota and intestinal homeostasis. In this application, we will test the hypothesis that GPR120 promotes intestinal IgA responses to microbiota through either substituting for TGFβ, which is a critical cytokine in induction of B cell production of IgA, or through promoting TGFβ production by B cells to enhance IgA production, leading to the preservation of intestinal immune homeostasis by regulating the function and composition of gut microbiota. Aim 1 will define the molecular mechanisms by which GPR120 promotes intestinal IgA responses, and Aim 2 will determine whether GPR120-mediated intestinal production of IgA alters gut microbiota to contribute to intestinal homeostasis. If successful, this project will potentially provide a novel therapeutic target for treatment of patients with inflammatory bowel disease.