NAD+ DEPLETION IN THE INTESTINAL EPITHELIUM RESULTS IN MITOCHONDRIAL DYSFUNCTION AND INFLUENCES THE PATHOGENESIS OF EXPERIMENTAL COLITIS

Abstract We have previously shown that mitochondrial dysfunction and disruption of biogenesis contribute to the pathogenesis IBD. Peroxisome Proliferator-activated Receptor–gamma Coactivator 1-alpha (PGC1α) is primary regulator biogenesis. In patients with ulcerative colitis (UC) mice undergoing experimental colitis, transcript protein levels PGC1α are reduced, which concomitant a decrease in function, derangement structure, an increase oxidative stress. Further, lacking intestinal epithelium develop severe disease during acute chronic models. primarily activated via deacetylation by nicotinamide adenine dinucleotide (NAD+)-dependent Sirtuin 1 (SIRT1). Thus, we hypothesized decreased NAD+ inflammation renders SIRT1 unable activate PGC1α, resulting subsequent dysfunction. Here, show deacetylated (active) within UC (n=4), implying Sirt1 may be inactivated diseased tissue. also found intestional (n=10; p<0.001)). Similar findings humans, not only murine models DSS p<0.001) infectious (Citrobacter rodentium-induced) p<0.001), but both (n=10 per group model). further colitic (n=8; p<0.0001). Although no significant mRNA NAD+-synthesizing enzymes tissue (p>0.05), there was 1.5-fold NAD+-consuming DNA-repair enzyme Poly(ADP-ribose) polymerase-1 (PARP1) as well dramatic enzymatic activity PARP1 DSS-subjected relative controls. Treatment NAD+precursor [nicotinamide riboside (NR), 500 mg/kg/day] severity restored function (p<0.001), increased active (p<0.05). NR treatment did benefit villincre;PGCfl/flmice (mice lack specifically epithelium; n=10; p>0.05) suggesting therapeutic effects require PGC1α. future approaches targeting turn health, complement for IBD improve outcomes patients.