Nicotinamide riboside and nicotinamide mononucleotide facilitate NAD+ synthesis via enterohepatic circulation

This preclinical study traced how NMN and nicotinamide riboside (NR) are processed after oral and intravenous administration in mice. The investigators combined NAD+ metabolomics, stable-isotope tracing, germ-free mice, Naprt-knockout mice, antibiotic treatment, bile-duct ligation, and cell experiments to distinguish direct precursor uptake from indirect metabolic routes.

The paper reported that only a small fraction of orally administered NMN or NR was directly absorbed from the small intestine. Much of the administered precursor was converted to nicotinamide and then deamidated by gut microbiota to nicotinic acid, which was preferentially used for hepatic NAD+ synthesis through the Preiss-Handler pathway.

After intravenous administration, NMN and NR were also rapidly converted to nicotinamide; biliary secretion, gut-microbial deamidation, reabsorption, and enterohepatic circulation contributed to liver NAD+ synthesis. These experiments clarify precursor metabolism in mice, but they do not establish the same quantitative routes or proportions in humans.

• Oral NMN produced a rapid rise in intestinal NMN, showing that some direct uptake occurs, but the study concluded that direct absorption represents only a small part of the overall metabolic fate.
• Gut microbiota were required for the later rise in deamidated metabolites after oral NMN or NR; germ-free experiments strongly suppressed this pathway.
• Nicotinic-acid-derived metabolites and the Preiss-Handler pathway made a major contribution to liver NAD+ synthesis after oral NMN and NR.
• Intravenous NMN and NR were rapidly degraded to nicotinamide, and bile carried NAD+ precursors back to the gut, supporting an enterohepatic recycling route.
• Bile-duct ligation reduced deamidated-metabolite accumulation and attenuated the liver NAD+ response to NMN, supporting a functional role for enterohepatic circulation.
• The relative precursor fate differed between liver and skeletal muscle, so findings about one tissue cannot be assumed to apply uniformly across organs.

• The in-vivo experiments were performed in mice, not humans; the quantitative contribution of direct absorption, microbial deamidation, and enterohepatic recycling may differ in people.
• Much of the mechanistic mapping used single high-dose oral gavage or intravenous dosing, which does not reproduce routine long-term human supplementation.
• Repeated oral NMN was also tested for two weeks, but the study was not designed to establish long-term safety, efficacy, or clinical outcomes.
• Gut-microbiome composition can materially affect deamidation pathways, limiting direct transfer of the observed mouse metabolic proportions to different human populations.
• The study compared metabolic fate and NAD+ synthesis pathways rather than consumer outcomes, disease treatment, or equivalence among commercial NMN formulations.