NAD metabolism fuels human and mouse intestinal inflammation

Gut. 2018 Oct;67(10):1813-1823. doi: 10.1136/gutjnl-2017-314241. Epub 2017 Sep 6.


Objective: Nicotinamide phosphoribosyltransferase (NAMPT, also referred to as pre-B cell colony-enhancing factor or visfatin) is critically required for the maintenance of cellular nicotinamide adenine dinucleotide (NAD) supply catalysing the rate-limiting step of the NAD salvage pathway. NAMPT is strongly upregulated in inflammation including IBD and counteracts an increased cellular NAD turnover mediated by NAD-depleting enzymes. These constitute an important mechanistic link between inflammatory, metabolic and transcriptional pathways and NAD metabolism.

Design: We investigated the impact of NAMPT inhibition by the small-molecule inhibitor FK866 in the dextran sulfate sodium (DSS) model of colitis and the azoxymethane/DSS model of colitis-associated cancer. The impact of NAD depletion on differentiation of mouse and human primary monocytes/macrophages was studied in vitro. Finally, we tested the efficacy of FK866 compared with dexamethasone and infliximab in lamina propria mononuclear cells (LPMNC) isolated from patients with IBD.

Results: FK866 ameliorated DSS-induced colitis and suppressed inflammation-associated tumorigenesis in mice. FK866 potently inhibited NAMPT activity as demonstrated by reduced mucosal NAD, resulting in reduced abundances and activities of NAD-dependent enzymes including PARP1, Sirt6 and CD38, reduced nuclear factor kappa B activation, and decreased cellular infiltration by inflammatory monocytes, macrophages and activated T cells. Remarkably, FK866 effectively supressed cytokine release from LPMNCs of patients with IBD. As FK866 was also effective in Rag1-⁄- mice, we mechanistically linked FK866 treatment with altered monocyte/macrophage biology and skewed macrophage polarisation by reducing CD86, CD38, MHC-II and interleukin (IL)-6 and promoting CD206, Egr2 and IL-10.

Conclusion: Our data emphasise the importance of NAD immunometabolism for mucosal immunity and highlight FK866-mediated NAMPT blockade as a promising therapeutic approach in acute intestinal inflammation.

Keywords: Colonic Mucosal Metabolism; Energy Metabolism; Gut Inflammation; IBD Basic Research; Inflammatory Bowel Disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrylamides / pharmacology*
  • Animals
  • Cell Differentiation / drug effects*
  • Colitis, Ulcerative* / immunology
  • Colitis, Ulcerative* / metabolism
  • Colonic Neoplasms* / immunology
  • Colonic Neoplasms* / metabolism
  • Dexamethasone / pharmacology*
  • Energy Metabolism
  • Gastrointestinal Agents / pharmacology
  • Humans
  • Infliximab / pharmacology*
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / metabolism
  • Macrophages / metabolism
  • Macrophages / pathology
  • Mice
  • Monocytes / metabolism
  • Monocytes / pathology
  • NAD / metabolism*
  • Nicotinamide Phosphoribosyltransferase / metabolism*
  • Piperidines / pharmacology*


  • Acrylamides
  • Gastrointestinal Agents
  • N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide
  • Piperidines
  • NAD
  • Dexamethasone
  • Infliximab
  • Nicotinamide Phosphoribosyltransferase