br Author contributions br Acknowledgements The work was

Author contributions
Acknowledgements The work was financially supported by a grant from the Investigator-Initiated Studies Program (Ref. #38124) from Merck Sharp & Dohme, and, in part, from Research Grants Council of the Hong Kong Special Administrative Region, China (Ref. No.: 14110314), awarded to PS Leung.
Introduction Commensal microbiota in the gut have profound effects on human health (Bäckhed et al., 2005, Honda and Littman, 2012). Germ-free and antibiotic-treated mice are more susceptible to dextran sulfate sodium (DSS)-induced colonic inflammation (Maslowski et al., 2009, Rakoff-Nahoum et al., 2004). Bacteroides fragilis and Clostridium clusters IV and XIVa protect against trinitrobenzenesulfonic acid- or DSS-induced colitis (Atarashi et al., 2011, Mazmanian et al., 2008). Multiple intestinal neoplasia (Min, ApcMin/+) mice carry a germline-truncating mutation in one copy of Apc and spontaneoulsy develop adenomas throughout the intestinal tract. Lactobacillus acidophilus and certain gut microbial metabolites such as conjugated linoleic acids decrease intestinal tumorigenesis in ApcMin/+ mice (Davis and Milner, 2009, Urbanska et al., 2009). In contrast, depletion of microbiota ameliorates intestinal inflammation and cancer in mouse models of spontaneous colitis (Il10, Tbx21Rag2, or ApcMin/+) (Garrett et al., 2009, Grivennikov et al., 2012, Li et al., 2012, Uronis et al., 2009). Bacteroides fragilis toxin (BFT) and Bacteroides vulgatus increases inflammation and colon cancer in ApcMin/+ and Il10 mice, respectively (Uronis et al., 2009, Wu et al., 2009). Thus, commensal bacteria promote as well as suppress colonic inflammation and colon cancer in a context-dependent manner. One of the mechanisms by which gut microbiota promote colonic health is through production of the short-chain fatty acids (SCFAs) acetate, propionate, and butyrate by fermentation of dietary fiber. Among SCFAs, butyrate has received most attention for its effects on colonic health (Hamer et al., 2008). The functions of butyrate in promoting colonic health range from being LY 255283 source for colonocytes to being a key mediator of anti-inflammatory and antitumorigenic effects. Gut microbiome analysis has revealed a significant decrease in the number of butyrate-producing bacteria in colon of patients with ulcerative colitis and colon cancer (Frank et al., 2007, Wang et al., 2012). Colonic irrigation with butyrate suppresses inflammation during ulcerative colitis (Hamer et al., 2008). IL-10 deficiency leads to spontaneous colitis (Huber et al., 2011, Izcue et al., 2009, Rubtsov et al., 2008). Polymorphisms in the genes that encode IL-10 or IL-10 receptor are linked to increased incidence of ulcerative colitis and inflammatory bowel disease (Franke et al., 2008, Glocker et al., 2009). Human monocyte-derived dendritic cells (DCs), when matured in the presence of butyrate, have increased expression of IL-10 and decreased production of IL-6 (Millard et al., 2002, Wang et al., 2008). IL-18 plays an essential role in suppression of colonic inflammation and inflammation-associated cancers (Chen et al., 2011, Dupaul-Chicoine et al., 2010, Elinav et al., 2011, Salcedo et al., 2010, Zaki et al., 2010). Moreover, an IL-18 gene promoter polymorphism leading to decreased expression is found at higher frequency in patients with ulcerative colitis (Takagawa et al., 2005). Butyrate induces expression of IL-18 in colonic epithelium (Kalina et al., 2002). In addition, the G protein-coupled receptor 43 (Gpr43) mediates proliferation of colonic regulatory T (Treg) cells in response to exogenously administered SCFAs but not under steady-state conditions (Smith et al., 2013). Although these studies demonstrate that SCFAs serve as anti-inflammatory agents in the colon, the underlying molecular mechanisms remain poorly understood. The most widely studied function of butyrate is its ability to inhibit histone deacetylases. However, cell surface receptors have been identified for butyrate; these receptors, GPR43 and GPR109A (also known as hydroxycarboxylic acid receptor 2 or HCA2), are G protein coupled and are expressed in colonic epithelium, adipose tissue, and immune cells (Blad et al., 2012, Ganapathy et al., 2013). GPR43-deficient mice undergo severe colonic inflammation and colitis in DSS-induced colitis model and the GPR43 agonist acetate protects germ-free mice from DSS-induced colitis (Maslowski et al., 2009). Although GPR43 is activated by all three SCFAs, GPR109A (encoded by Niacr1) is activated only by butyrate (Blad et al., 2012, Taggart et al., 2005). GPR109A is also activated by niacin (vitamin B3) (Blad et al., 2012, Ganapathy et al., 2013). In colonic lumen, butyrate is generated at high concentrations (10–20 mM) by gut microbiota and serves as an endogenous agonist for GPR109A (Thangaraju et al., 2009). We have shown that Gpr109a expression in colon is induced by gut microbiota and is downregulated in colon cancer (Cresci et al., 2010, Thangaraju et al., 2009). Gpr109a in immune cells plays a nonredundant function in niacin-mediated suppression of inflammation and atherosclerosis (Lukasova et al., 2011). Gut microbiota also produce niacin. Niacin deficiency in humans results in pellagra, characterized by intestinal inflammation, diarrhea, dermatitis, and dementia (Hegyi et al., 2004). It is of great clinical relevance that lower abundance of GPR109A ligands niacin and butyrate in gut is associated with colonic inflammation.