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

NAD metabolism fuels human and mouse intestinal inflammation.

Author information

1
Division of Internal Medicine I, Department of Medicine, Medical University Innsbruck, Innsbruck, Austria.
2
Christian Doppler Laboratory for Mucosal Immunology, Medical University Innsbruck, Innsbruck, Austria.
3
Division of Translational Cell Genetics, Department for Pharmacology and Genetics, Medical University Innsbruck, Innsbruck, Austria.
4
Institute of Legal Medicine and Core Facility Metabolomics, Medical University Innsbruck, Innsbruck, Austria.
5
Department of Pathology, Medical University Innsbruck, Innsbruck, Austria.

Abstract

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

PMID:
28877980
PMCID:
PMC6145287
DOI:
10.1136/gutjnl-2017-314241
[Indexed for MEDLINE]
Free PMC Article

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