| First Author | Novak EA | Year | 2023 |
| Journal | Front Immunol | Volume | 14 |
| Pages | 1231700 | PubMed ID | 37744380 |
| Mgi Jnum | J:341216 | Mgi Id | MGI:7532074 |
| Doi | 10.3389/fimmu.2023.1231700 | Citation | Novak EA, et al. (2023) Epithelial NAD(+) depletion drives mitochondrial dysfunction and contributes to intestinal inflammation. Front Immunol 14:1231700 |
| abstractText | INTRODUCTION: We have previously demonstrated that a pathologic downregulation of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC1alpha) within the intestinal epithelium contributes to the pathogenesis of inflammatory bowel disease (IBD). However, the mechanism underlying downregulation of PGC1alpha expression and activity during IBD is not yet clear. METHODS: Mice (male; C57Bl/6, Villincre/+;Pgc1afl/fl mice, and Pgc1afl/fl) were subjected to experimental colitis and treated with nicotinamide riboside. Western blot, high-resolution respirometry, nicotinamide adenine dinucleotide (NAD+) quantification, and immunoprecipitation were used to in this study. RESULTS: We demonstrate a significant depletion in the NAD+ levels within the intestinal epithelium of mice undergoing experimental colitis, as well as humans with ulcerative colitis. While we found no decrease in the levels of NAD+-synthesizing enzymes within the intestinal epithelium of mice undergoing experimental colitis, we did find an increase in the mRNA level, as well as the enzymatic activity, of the NAD+-consuming enzyme poly(ADP-ribose) polymerase-1 (PARP1). Treatment of mice undergoing experimental colitis with an NAD+ precursor reduced the severity of colitis, restored mitochondrial function, and increased active PGC1alpha levels; however, NAD+ repletion did not benefit transgenic mice that lack PGC1alpha within the intestinal epithelium, suggesting that the therapeutic effects require an intact PGC1alpha axis. DISCUSSION: Our results emphasize the importance of PGC1alpha expression to both mitochondrial health and homeostasis within the intestinal epithelium and suggest a novel therapeutic approach for disease management. These findings also provide a mechanistic basis for clinical trials of nicotinamide riboside in IBD patients. |
