The differential impact of three different NAD+ boosters on circulatory NAD and microbial metabolism in humans.

Fourteen days of supplementation with NR and NMN, but not Nam, comparably increased circulatory NAD+ concentrations in healthy adults.

• Randomized, open-label, placebo-controlled study in 65 healthy participants
• Supplementation duration was 14 days
• NR and NMN produced comparable increases in circulatory NAD+ concentrations
• Nam did not produce a significant chronic increase in circulatory NAD+ concentrations
• ClinicalTrials.gov identifier: NCT05517122

Only Nam acutely and transiently affects the whole-blood NAD+ metabolome, unlike the chronic effects observed with NR and NMN.

• The acute effect of Nam on the whole-blood NAD+ metabolome was transient
• This acute effect was distinct from the chronic 14-day supplementation effects
• NR and NMN did not produce the same acute whole-blood NAD+ metabolome changes as Nam
• The differential acute versus chronic effects highlight mechanistic differences between the three precursors

Ex vivo fermentation with human microbiota demonstrated that NR and NMN give rise to nicotinic acid (NA) and specifically enhance microbial growth and metabolism.

• Ex vivo fermentation experiments were conducted using human microbiota
• NR and NMN were converted to nicotinic acid (NA) by the gut microbiota
• This microbial conversion specifically enhanced microbial growth and metabolism
• Nam did not show the same pattern of microbial conversion to NA
• These findings confirm in a human microbiota model the mechanism previously suggested in rodent studies

Ex vivo whole blood experiments demonstrated that NA is a potent NAD+ booster, while NMN, NR, and Nam are not.

• Experiments were conducted ex vivo in whole blood
• NA showed potent NAD+-boosting activity in whole blood
• NMN, NR, and Nam did not boost NAD+ levels in whole blood ex vivo
• This finding supports the hypothesis that NR and NMN require conversion to NA by gut microbiota to exert their systemic NAD+-boosting effects

A gut-dependent model is proposed in which NR and NMN elevate circulatory NAD+ via the Preiss-Handler pathway following microbial conversion to NA, while rapidly absorbed Nam acutely affects NAD+ levels via the salvage pathway.

• NR and NMN are proposed to be converted by gut microbiota to nicotinic acid (NA)
• NA then enters the Preiss-Handler pathway to elevate circulatory NAD+
• Nam is rapidly absorbed and acts acutely through the salvage pathway
• The model distinguishes gut-dependent (NR, NMN) from gut-independent (Nam) mechanisms of NAD+ precursor action
• This model is consistent with prior rodent research suggesting NAD+-boosting effects of NR and NMN depend on microbial conversion to NA

NR and NMN and their microbially produced metabolite NA are proposed to have a dual effect: a sustained increase in systemic NAD+ levels and a potent modulator of gut health.

• The dual effect encompasses both systemic NAD+ elevation and gut microbiota modulation
• Microbially produced NA is implicated in both systemic and gut effects
• NR and NMN specifically enhanced microbial growth and metabolism in ex vivo fermentation
• Nam did not share this dual effect profile

Recent rodent research suggesting that NAD+-boosting effects of NR and NMN depend on their microbial conversion to nicotinic acid had not previously been confirmed in humans prior to this study.

• Prior preclinical studies had examined effects of NAD+ precursors but lacked direct human comparisons
• Rodent studies previously suggested gut microbiota-dependent conversion of NR and NMN to NA
• This study represents the first confirmation of the microbial conversion mechanism in humans using human microbiota ex vivo fermentation
• The human clinical trial component further supports the translational relevance of the rodent findings