title: Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis.
abstract: Commensal gut microflora and dietary fiber protect against colonic inflammation and colon cancer through unknown targets. Butyrate, a bacterial product from fermentation of dietary fiber in the colon, has been implicated in this process. GPR109A (encoded by Niacr1) is a receptor for butyrate in the colon. GPR109A is also a receptor for niacin, which is also produced by gut microbiota and suppresses intestinal inflammation. Here we showed that Gpr109a signaling promoted anti-inflammatory properties in colonic macrophages and dendritic cells and enabled them to induce differentiation of Treg cells and IL-10-producing T cells. Moreover, Gpr109a was essential for butyrate-mediated induction of IL-18 in colonic epithelium. Consequently, Niacr1(-/-) mice were susceptible to development of colonic inflammation and colon cancer. Niacin, a pharmacological Gpr109a agonist, suppressed colitis and colon cancer in a Gpr109a-dependent manner. Thus, Gpr10a has an essential role in mediating the beneficial effects of gut microbiota and dietary fiber in colon.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA; Cancer Research Center, Georgia Regents University, Augusta, GA 30912, USA. Electronic address: nasingh@gru.edu.
authors.forename: Nagendra
authors.initials: N
authors.lastname: Singh
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Ashish
authors.initials: A
authors.lastname: Gurav
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Sathish
authors.initials: S
authors.lastname: Sivaprakasam
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Evan
authors.initials: E
authors.lastname: Brady
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Padia
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA; Cancer Research Center, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Huidong
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA; Cancer Research Center, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Thangaraju
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA; Cancer Research Center, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Puttur D
authors.initials: PD
authors.lastname: Prasad
authors.affiliation: Cancer Research Center, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Santhakumar
authors.initials: S
authors.lastname: Manicassamy
authors.affiliation: Cancer Research Center, Georgia Regents University, Augusta, GA 30912, USA; Department of Pediatrics, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Munn
authors.affiliation: Department of Pathology, Charlie Norwood Veterans Administration Medical Center, Augusta, GA 30904, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA; Cancer Research Center, Georgia Regents University, Augusta, GA 30912, USA. Electronic address: vganapat@gru.edu.
authors.forename: Vadivel
authors.initials: V
authors.lastname: Ganapathy
mesh_terms: D000818:Animals; D002087:Butyrates / Q000276:immunology; D063646:Carcinogenesis / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003092:Colitis / Q000150:complications / Q000188:drug therapy / Q000276:immunology*; D003106:Colon / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D003110:Colonic Neoplasms / Q000209:etiology / Q000517:prevention & control*; D003713:Dendritic Cells / Q000276:immunology; D004198:Disease Susceptibility; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology*; D016753:Interleukin-10 / Q000378:metabolism; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064307:Microbiota; D009525:Niacin / Q000008:administration & dosage; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D002087:Butyrates; C473652:Hcar2 protein, mouse; D020382:Interleukin-18; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D016753:Interleukin-10; D009525:Niacin