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Nicotinamide mononucleotide (NMN) deamidation by the gut microbiome and evidence for indirect upregulation of the NAD+ metabolome

By Lynn-Jee Kim, Timothy J. Chalmers, Greg C. Smith, Abhirup Das, Eric Wing Keung Poon, Jun Wang, Simon P. Tucker, David A. Sinclair, Lake-Ee Quek, Lindsay Wu

Posted 11 Sep 2020
bioRxiv DOI: 10.1101/2020.09.10.289561

Treatment with nicotinamide mononucleotide (NMN) is a prominent strategy to address the age-related decline in nicotinamide adenine dinucleotide (NAD+) levels for maintaining aspects of late-life health. It is assumed that exogenous NMN is directly incorporated into NAD+ in mammals by the canonical recycling pathway, however the need for NAD+ is conserved across evolution, including bacteria in the gut microbiome, which can deamidate NMN to nicotinic acid mononucleotide (NaMN). Here, we use strategic isotope labelling studies to demonstrate a role for the gut microbiome in deamidating orally delivered NMN into NaMN prior to its uptake and incorporation in mammals. Microbiome depletion increased the overall abundance of NAD metabolites, suggesting a competition relationship. Strikingly, treatment with labelled NMN increased the production of unlabelled NAD precursors, with a greater than 3-fold increase in endogenous NR levels in the gut of antibiotics treated animals upon labelled NMN treatment. These data suggest that exogenous NMN impacts the NAD metabolome through indirect means, rather than through its direct incorporation, including through the production of endogenous NR via an as-yet unidentified pathway, and demonstrate an important role for the gut microbiome in the assimilation of orally delivered NMN. ### 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.

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