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Main Text From birth to adulthood, humans progressively acquire and maintain a complex microbial ecosystem at various body sites and cavities. Early on, these microorganisms establish a complex relationship with the host, resulting in the modulation of several biological functions. A prime example of such a relationship is the intestine, where trillions of microorganisms influence nutritional and immunological functions. Understanding and deciphering the dialog occurring between the microbiota and the intestine at homeostasis as well as during disease states has been the subject of intense investigation. From a metabolic standpoint, the microbiome operates at an organ level, extracting energy and nutrients and generating numerous and important by-products from the diet, all of which benefit bacterial communities (adaptation, growth, maintenance), but most importantly assure essential host homeostatic function (Nicholson et al., 2012). For example, dietary fibers and nondigestible nae inhibitor (starch, cellulose, fructans, xylans, inulin) are processed by various microbial enzymatic systems to produce diverse beneficial compounds such as essential vitamins (vitamin K, biotin, cobalamin, riboflavin, and niacin) and short chain fatty acids (SCFA) such as propionate, acetate, and butyrate (Nicholson et al., 2012). However, microbial disturbances as identified in patients with inflammatory bowel diseases (IBD) and colorectal cancer (CRC) bring changes to the “functional” aspect of the microbiome, among them the depletion of butyrate-producing bacteria (Guzman et al., 2013). Butyrate not only represents a primary source of energy for intestinal epithelial cells (IECs) but also modulates host immune response, thereby acting as a key microbial metabolite for intestinal homeostasis. Various G protein-coupled receptors (Gpr) such as Gpr41, Gpr43, and Grp109a mediate SCFA activities, but the molecular and cellular events responsible for butyrate-mediated beneficial effects in the intestine are still unclear. In this issue, Singh et al. (2014) provide key evidence that bacterial-derived butyrate and dietary fibers attenuate intestinal inflammation and CRC development through Gpr109a-mediated T regulatory (Treg) cell differentiation (Figure 1). The study shows how diet, microbiota, and immune cells form an intricate communication network essential for the maintenance of intestinal homeostasis. How could the microbiota and associated metabolites exert a protective role in the intestine? Singh et al. (2014) first observed that Foxp3+ (Treg) cell number and frequency in the lamina propria of Grp109a mice were significantly lower than in WT mice, a profile matching impaired immunosuppressive IL-10 secretion and enhanced production of proinflammatory IL-17. This inflammatory intestinal phenotype may be the consequence of defective tolerogenic instruction provided by mononuclear cells. Indeed, when Singh et al. (2014) coincubated colonic macrophages and DCs from Grp109a mice with naive CD4+ T cells obtained from OT-II TCR transgenic mice, they noticed that these mononuclear cells were unable to induce Treg cell differentiation compared to their WT counterpart. The fact that butyrate-treated splenic DCs and macrophages from Grp109a mice failed to release both IL-10 and class 1A aldehyde dehydrogenase (Aldh1a) and to promote a Treg cell phenotype (high IL-10, low IL-17) in a coculture assay clearly shows the key role of the receptor in mediating butyrate immune response. Moreover, niacin, which is also a Gpr109a ligand and bacterial-derived product, reproduces butyrate effect on DC, macrophage, and Treg cell activities. This highlights the central role of Gpr109a in capturing and processing signaling generated by microbial-derived metabolites. Antibiotic treatment causes massive perturbation in microbial ecosystems, and loss of microbial entities with concurrent decreased biochemical activities (metabolites) are bound to influence intestinal immune regulation. Singh et al. (2014) observed that niacin supplementation restores the number of Treg cells depleted by antibiotic treatment of WT mice, an effect nullified in Gpr109a mice. These findings demonstrate that Gpr109a is essential for mucosal immunoregulatory functions afforded by the microbial metabolite butyrate.