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  • Ristocetin A sulfate receptor Here we demonstrate an anti in


    Here we demonstrate an anti-inflammatory and anticancer function for Gpr109a in colon. Gpr109a signaling imposed anti-inflammatory properties in colonic antigen-presenting cells, which in turn induced differentiation of Treg Ristocetin A sulfate receptor and IL-10-producing T cells. Gpr109a was also required for the expression of IL-18. Niacr1 mice showed enhanced susceptibility to colitis and Ristocetin A sulfate receptor colon cancer. Depletion of gut microbiota or dietary fiber increased the risk for colitis and cancer, which is effectively suppressed by niacin in a Gpr109a-dependent manner.
    Discussion The current study defines an essential role of Gpr109a in the suppression of colonic inflammation and carcinogenesis. Commensals induce Treg cells and IL-10-producing T (Tr1) cells in colon (Atarashi et al., 2011, Geuking et al., 2011, Mazmanian et al., 2008, Round and Mazmanian, 2010). They also induce IL-10 expression in colonic DCs and macrophages, which promote differentiation of Tr1 cells (Jeon et al., 2012, Ueda et al., 2010). Our studies provide a molecular mechanism by which the commensals elicit these effects. The bacterial metabolite butyrate functions as a messenger between the commensals and the host. This SCFA induces expression of anti-inflammatory molecules in macrophages and DCs and enables them to support differentiation of Treg and IL-10-producing T cells. The present study also implicates a tumor-suppressive role of Gpr109a-butyrate signaling in colon and suggests that commensals in the gut provide protection to the host not only against colonic inflammation but also against colon cancer. Our conclusion that butyrate is responsible, at least partly, for the actions of gut microbiota on the host colon with regard to suppression of inflammation and carcinogenesis is congruent with previous findings that the frequency of butyrate-producing bacteria and rate of butyrate production are greatly diminished in the colon during ulcerative colitis and colon cancer (Frank et al., 2007, Wang et al., 2012). Butyrate enemas decrease colonic inflammation in ulcerative colitis (Hamer et al., 2008). The present studies also highlight the biological significance of dietary fiber and its relevance to butyrate production. Dietary fiber suppresses colonic inflammation and colorectal cancer (Davis and Milner, 2009, Hamer et al., 2008). The most important aspect of the present studies is the identification of Gpr109a as one of the mediators of the biological effects of butyrate.
    Experimental Procedures
    Niacin (nicotinic acid) is a water-soluble vitamin that at high doses in humans, favourably modulates multiple serum lipid and lipoprotein parameters that are cardiovascular risk factors. Niacin increases high density lipoprotein (HDL) to a greater extent than any other currently used drug and it has been used for many years for the prevention and treatment of cardiovascular disease. Recent mechanistic investigations have shown that niacin interacts with, and may exert its beneficial effects on lipids via, a G-protein coupled receptor (GPCR) expressed on adipocytes. It is postulated that the resultant decrease in intracellular cAMP leads to inhibition of lipolysis via negative modulation of intracellular lipase activity, thereby decreasing plasma free fatty acid (FFA) levels. A further hypothesis suggests that this pathway may ultimately result in elevation of HDL. Two G-coupled orphan GPCRs that share 95% identity and which are both expressed in human adipocytes have been identified as possible molecular targets for niacin. GPR109a (HM74a) is the human orthologue of the previously described rodent receptor (PUMA-G) whereas GPR109b (HM74) differs from GPR109a and PUMA-G mainly in the intracellular C-terminal tail portion and has no rodent equivalent. Niacin has been reported to activate GPR109a with an EC of 250nM in a GTPγS assay and displaces H-niacin from GPR109a expressing CHO cell membranes with an IC of 81nM. It is a much weaker ligand for GPR109b.