Metabolic Disease, NAD Metabolism, Nicotinamide Riboside, and the Gut Microbiome: Connecting the Dots from the Gut to Physiology

The effort to use nutrients as interventions to treat human disease has been important to medicine. A current example in this vein pertains to NAD(+) boosters, such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), which are in many clinical trials in a variety of disease conditions. Independent laboratories have shown that ingested NR (or NMN) has mitigating effects on metabolic syndrome in mice. V. V. Lozada-Fernández, O. deLeon, S. L. Kellogg, F. L. Saravia, et al. (mSystems 7:e00230-21, 2022, https://doi.org/10.1128/mSystems.00230-21) show that NR shifts gut microbiome contents and that the transplantation of an NR-conditioned microbiome by fecal transfer reproduces some effects of NR in mice on a high-fat diet. The involvement of the gut microbiome as a factor in NR effects is linked to changes to the gut microbiome and its activity to transform NR and downstream catabolites. This commentary draws attention to these findings and focuses on some puzzling aspects of NAD(+) boosters, exploring the still murky interactions between NAD(+) metabolism, energy homeostasis, and the gut microbiome.