Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis

  • Immunity. 2014 Jan 16;40(1):128-39. doi: 10.1016/j.immuni.2013.12.007.
Nagendra Singh  1 ,  Ashish Gurav  2 ,  Sathish Sivaprakasam  2 ,  Evan Brady  2 ,  Ravi Padia  2 ,  Huidong Shi  3 ,  Muthusamy Thangaraju  3 ,  Puttur D Prasad  3 ,  Santhakumar Manicassamy  4 ,  David H Munn  5 ,  Jeffrey R Lee  6 ,  Stefan Offermanns  7 ,  Vadivel Ganapathy  8
Affiliations
  • 1. 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: [email protected].
  • 2. Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
  • 3. 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.
  • 4. Cancer Research Center, Georgia Regents University, Augusta, GA 30912, USA.
  • 5. Cancer Research Center, Georgia Regents University, Augusta, GA 30912, USA; Department of Pediatrics, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
  • 6. Department of Pathology, Charlie Norwood Veterans Administration Medical Center, Augusta, GA 30904, USA.
  • 7. Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany.
  • 8. 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: [email protected].
PMID: 24412617 DOI: 10.1016/j.immuni.2013.12.007
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.