Pulling the plug- NAD energy depletion as a novel treatment strategy in IBD

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Background: Crohn's disease (CD) and ulcerative Colitis (UC) constitute the two major entities of human inflammatory bowel disease (IBD). Despite notable advances, IBD treatment remains challenging in some patients. We have demonstrated high PBEF/NAMPT/Visfatin serum levels and colonic mRNA expression in IBD patients before. Inflammation requires high amounts of energy usually provided by energy-rich substrates and enzymatic co-factors. PBEF/NAMPT/Visfatin exerts an important role in maintaining the cellular energy supply during chronic inflammation by catalyzing the rate-limiting step of NAD from the NAD salvage pathway. Thus, we assessed the activation state of PBEF/NAMPT/Visfatin pathway in animal models and human IBD and tested the anti-inflammatory and therapeutic potential of its blockage. Methods: We investigated the efficacy of FK866, a small molecule inhibitor of PBEF/Nampt/Visfatin, in animal models for IBD. Colitis was induced by 3.5% DSS in C57/BL6 mice. The treatment group received 20 mg/kg/d FK866, the control group vehicle only. Clinical and histological features as well as pro-inflammatory cytokines were determined. NAD + and its metabolite levels in epithelium were measured by HPLC/mass-spectrometry. In additional experiments, lamina propria cells were isolated from IBD patient's biopsies and treated with dexamethasone, infliximab, FK866 or vehicle control. Supernatants were assayed for pro-inflammatory mediators to compare therapeutic efficacy. Results: FK866 treated animals showed an improved clinical activity index, reduced histological inflammation and pro-inflammatory cytokines in the colon. In vitro, FK866 was as effective as dexamethasone and superior to infliximab in LPMNCs isolated from human IBD biopsies. Conclusion: Taken together, administration of FK866 resulted in energy shortage, as reflected by NAD-depletion, and was associated with reduced inflammation and improved histological and biochemical outcomes in IBD models. Furthermore, FK866 was effective in human LPMNCs. Our data highlight the NAD salvage pathway as a potential novel therapeutic target in IBD.

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