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Gut microbiome competes with host for orally administered NMN by reducing its availability and altering uptake pathways

Lynn-Jee Kim

University of New South Wales, Sydney, New South Wales, Australia

Nicotinamide mononucleotide (NMN) supplementation is a promising strategy to treat age-related diseases by reversing age-related decline in nicotinamide adenine dinucleotide (NAD+). A better understanding of how NMN is metabolised can help improve the efficacy of this strategy, in particular the first-pass survival of these precursors through the gastrointestinal environment during oral administration. As both the host and the microbiome have not evolved to deal with large bolus amount of NMN, we sought to determine whether the gut microbiome metabolise these precursors, and thus altering their delivery and availability to host tissues. Using isotopically labelled forms of NMN, we quantified whether NMN is directly transported intact into tissues, through the recently characterised NMN transporter, or is dephosphorylated into nicotinamide riboside (NR) prior to tissue uptake via nicotinamide riboside kinases (NRK1/2). We found the latter the main route for NMN assimilation in mice, with NR abundantly detected in tissues. On the other hand, NMN is being taken up intact only after ablating the microbiome with ampicillin. Interestingly, NMN administration following ampicillin treatment significantly increased levels of NAD+ and precursors in the intestinal epithelium, indicating that orally administered NAD+ precursors are readily sequestered by the gut microbiome. Together the results suggest the gut microbiome can alter both quantity and quality of administered NMN, potentially negatively impacting how NMN and its products are made available to host tissues. Importantly, this work has provided a better understanding of the complex competition between the host and microbiome for NAD+ precursors. This can be leveraged to enhance the use of NMN supplementation to treat age-related diseases.