Nicotinamide Riboside-Conditioned Microbiota Deflects High-Fat Diet-Induced Weight Gain in Mice

The gut microbiome plays an essential role in host energy homeostasis and influences the development of obesity and related conditions. Studies demonstrate that nicotinamide riboside (NR) supplementation for diet-induced obesity (DIO) reduces weight gain and increases energy expenditure in mice. NR is a vitamin B₃ derivative and an NAD⁺ precursor with potential for treating human diseases arising from mitochondrial degeneration, including obesity and type 2 diabetes. Gut bacteria produce vitamin B₃ in the colon and are capable of salvaging and metabolizing vitamin B₃ and its derivatives. However, it is unknown how dietary supplementation of NR alters the microbiome and if those alterations contribute to deflection of weight gain. In this study, we fed C57BL/6J male mice a high-fat diet (HFD) supplemented with or without NR and performed a fecal material transfer (FMT) to establish a link between NR-conditioned microbiota and NR-induced deflection of weight gain. FMT from NR-treated donors to naive mice fed a HFD was sufficient to deflect weight gain by increasing energy expenditure. We also investigated the effects of NR on the microbiome by using metagenomics sequencing. We found that NR-treated mice displayed an altered gut microbial composition relative to controls and that fecal transplant resulted in a distinct functional metabolic profile characterized by enrichment of butyrate-producing Firmicutes. NR-treated donors and subsequent FMT recipients share a similar enrichment of metagenomic biomarkers relative to controls. These findings suggest that microbial factors contribute to the beneficial effects of dietary NR supplementation, which may be useful to enhance the therapeutic effects of NR. IMPORTANCE With obesity and type 2 diabetes (T2D) at epidemic levels, we need to understand the complex nature of these diseases to design better therapeutics. The underlying causes of both obesity and T2D are complex, but both are thought to develop, in part, based on contributions from the gut microbiota. Nicotinamide riboside is a gut-derived vitamin B₃ derivative and NAD⁺ precursor which has the potential to treat and prevent metabolic disorders by ameliorating mitochondrial dysfunction. Understanding how NR affects the gut microbiome and whether NR-conditioned microbiota contributes to weight loss in the host would (i) improve diagnosis and treatments for obesity and other metabolic pathologies, (ii) tailor treatments to satisfy the needs of each individual moving toward the future of precision medicine, and (iii) benefit other scientific fields that currently investigate the effects of NR in other disease pathologies.