Nicotinamide mononucleotide (NMN) deamidation by host-microbiome interactions

Oral administration of nicotinamide mononucleotide (NMN) is a prominent strategy to elevate nicotinamide adenine dinucleotide (NAD+) levels to treat age-related pathologies, where it is assumed to be directly incorporated into the NAD+ metabolome through the canonical recycling pathway. During oral delivery, NMN is exposed to the gut microbiome, which can modify the NAD+ metabolome through enzyme activities that are not present in mammals. Here, we show that orally delivered NMN can undergo direct deamidation and incorporation in mammalian tissue via the de novo pathway, and that this deamidation is reduced in animals treated with antibiotics to ablate the gut microbiome. Further, we show that antibiotics treatment increases the overall availability of NAD+ metabolites in the gut epithelium, with one possibility that the gut microbiome could be in competition with the host for dietary NAD+ precursors. Together, these data highlight previously undescribed interactions between orally delivered NMN and the gut microbiome. ### Competing Interest Statement Acknowledgements Funding was from the National Health and Medical Research (NHMRC) of Australia as a Career Development Fellowship APP1122484 to LEW, and sponsored research from Jumpstart Fertility. We wish to thank anonymous donors for philanthropic support. EWKP and JW are employees and shareholders of GeneHarbor Biotechnologies. SPT is the CEO of Jumpstart Fertility, which is developing NAD+ raising compounds for therapeutic use. LEW and DAS are co-founders, shareholders, directors and advisors of Jumpstart Fertility and the Life Biosciences group which includes Jumpstart Fertility, Continuum Biosciences, Senolytic Therapeutics, Selphagy, and Animal Biosciences. LEW and DAS are also advisors to and shareholders in the EdenRoc group of companies, which includes Metro Biotech NSW and Metro International Biotech, Arc-Bio, Dovetail Genomics, Claret, Revere Biosciences, and Liberty Biosecurity. LEW is an advisor and shareholder in Intravital Pty Ltd. DAS is an inventor on a patent application that has been licensed to Elysium Health. Updated affiliation are at https://genetics.med.harvard.edu/sinclair-test/people/sinclair-other.php.