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

Stefan Christen, Karine Redeuil, Laurence Goulet, Maria-Pilar Giner, Isabelle Breton, Riccardo Rota, Adrien Frézal, Atiye Nazari, Pieter Van den Abbeele, Jean-Philippe Godin, Sophie Nutten, Bernard Cuenoud
Nature Metabolism 2026 Volume 8, issue 1, pages 62–73

Bibliography

PubMed
PMID 41540253
PubMed Central
PMC12855009
DOI
10.1038/s42255-025-01421-8
Funding
No separate external funding statement is displayed in the article. The clinical study was conducted at the Clinical Innovation Lab, Nestlé Research; the acknowledgements credit Nestlé Research staff and its Clinical Research Unit for operational, analytical, supply, project-management and medical support.
Competing interests
S.C., S.N., K.R., L.G., M.-P.G., I.B., R.R., A.F., A.N. and J.-P.G. are employees of Nestlé Research, which is part of Société des Produits Nestlé SA. B.C. is an employee of Nestlé Health Science. P.V.d.A. is an employee of Cryptobiotix SA.

Study snapshot

DesignRandomised, open-label, placebo-controlled, four-arm parallel-group trial with paired ex vivo faecal-fermentation experiments (SIFR platform) and human whole-blood culture experiments to interrogate mechanism. Pre-registered at ClinicalTrials.gov (NCT05517122).
ModelHealthy adults aged 18–50 y with BMI 18.5–27 kg/m², free of significant medical history, no NAD+ precursor supplements, no interacting medications. Complementary ex vivo work used faecal microbiota from healthy adults, healthy older adults and Crohn's-disease patients, and fresh whole blood from healthy adult donors.
Sample67 randomised, 65 in the modified intention-to-treat analysis (2 received the wrong product): placebo n=17, NR n=16, NMN n=15, nicotinamide n=17.
InterventionOnce-daily oral dosing for 14 consecutive days: placebo (500 mg microcrystalline cellulose), NR (1000 mg / 3.4 mmol, TRU NIAGEN Pro), NMN (1000 mg / 3 mmol, UltraHealth) or nicotinamide (500 mg / 4.1 mmol, Pure Encapsulations). On day 1 and day 14, product was taken with 200 ml water after a standardised BOOST Plus Calories liquid breakfast; on all other days it was taken at or within 30 min of the participant's usual breakfast.
Duration14 days of daily dosing, with acute 4-hour serial sampling on day 1 and day 14.
EndpointsChange in baseline whole-blood NAD+ concentration from day 1 to day 14 (primary); Acute 4-hour NAD+ metabolome response in whole blood on day 1 and day 14 (secondary); NAD+ metabolome in plasma and urine (exploratory); Targeted and untargeted plasma and urine metabolomics (exploratory); Ex vivo faecal fermentation parameters (pH, gas, SCFAs, bacterial cell counts, taxonomic composition) after NR, NMN or nicotinamide exposure; Ex vivo whole-blood metabolism of NR, NMN, nicotinamide, nicotinic acid, NAR and NAMN

What the study showed, in plain terms

This randomized, open-label, placebo-controlled trial compared three NAD+ precursors head to head in healthy adults: nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and nicotinamide. Sixty-seven participants were randomized and 65 were included in the modified intention-to-treat analysis after two participants received the wrong product.

After 14 days, 1,000 mg/day NR and 1,000 mg/day NMN each approximately doubled baseline whole-blood NAD+, with similar increases versus placebo. Nicotinamide at 500 mg/day did not significantly raise the baseline NAD+ concentration over two weeks, although it caused a rapid transient post-dose NAD-metabolome response and a marked acute homocysteine rise.

The mechanistic work is especially interesting but needs careful framing. In ex vivo human fecal-microbiome experiments, NR and NMN were converted through pathways that generated nicotinic acid, while complementary whole-blood experiments showed nicotinic acid was highly effective at raising cellular NAD+. On that basis, the authors propose a gut-microbiome-dependent model in which conversion to nicotinic acid contributes importantly to the sustained circulatory NAD+ rise after NR or NMN.

That mechanism was not directly traced in vivo from swallowed NR or NMN through gut-derived nicotinic acid into systemic NAD+. The human trial did not detect a measurable rise in circulating nicotinic acid, and the proposed pathway therefore remains a strongly supported mechanistic model rather than a directly proven human tracer pathway.

Key findings

  • After 14 days, NR (1,000 mg/day) raised baseline whole-blood NAD+ by 49.4 µM versus placebo (95% CI 39.5–59.3; p<0.001), while NMN (1,000 mg/day) raised it by 43.1 µM (95% CI 32.7–53.4; p<0.001).
  • Nicotinamide (500 mg/day) did not significantly change the 14-day baseline whole-blood NAD+ concentration versus placebo (p=0.461).
  • Nicotinamide produced a rapid transient acute effect on the NAD+ metabolome, with whole-blood Nam peaking at about 1 hour and an iAUC of 105.2 µM·h; methylated degradation products also increased.
  • NR and NMN concentrations in whole blood remained below 2 µM and did not show an acute 4-hour rise after their respective doses.
  • Ex vivo human faecal microbiota converted NR through Nam toward nicotinic acid; separate experiments with microbiota from older donors showed NMN produced a comparable build-up of Nam and nicotinic acid.
  • In ex vivo human whole blood at 50 µM, nicotinic acid increased the NAD+ signal by about 170%, whereas NR and NMN were rapidly degraded without increasing NAD+ under those culture conditions. Together with the clinical metabolomic footprint, these experiments support the authors' proposed gut-dependent mechanism but do not directly demonstrate microbial conversion in vivo in the trial participants.
  • NR increased bacterial cell density, acetate and propionate in ex vivo fermentations and selectively increased Enterocloster aldensis in the six healthy-adult donors; NR and NMN produced broadly similar metabolic adaptations in the separate older-donor experiment.
  • A strong acute homocysteine increase occurred after nicotinamide but was not detected after NR or NMN.
  • The three precursors were generally well tolerated in the 65-person modified intention-to-treat population; three adverse events were judged probably related to product (abdominal pain on placebo, hypotension on NR, headache on NMN).

What this study can and cannot tell us

The trial was open-label rather than double-blind. The primary endpoint was a laboratory measure (whole-blood NAD+) analysed by a validated LC–MS/MS assay, which limits expectancy bias on the outcome itself, but readers should note the design.

The population was healthy adults aged 18–50 with a narrow BMI range. The trial does not tell us how NR, NMN or nicotinamide behave in older adults, in people with metabolic disease, or in the disease populations where NAD-boosting is proposed to matter clinically. The authors call this out and describe the study as a healthy-population baseline for future disease-population trials.

The proposed gut-microbiome mechanism is well supported by the ex vivo fermentation and whole-blood work but is inferential rather than directly demonstrated in vivo. The team did not detect a rise in circulating nicotinic acid in venous blood after NR or NMN dosing — they attribute this to fast production, uptake and metabolism in the splanchnic circulation, but a stool-sampling or portal-vein tracer arm would be needed to close the loop. Enterohepatic recirculation is not ruled out.

The ex vivo microbiome experiments used shallow shotgun sequencing, which gives reliable taxonomic profiling but limited detection of low-abundance taxa and no functional gene-level analysis. They also cannot capture host–microbiome interactions or bile-mediated effects.

The whole-blood culture experiment could not reproduce the mild acute NAD+ rise seen after oral nicotinamide in vivo, which the authors attribute to the missing organ compartments and possibly to short-term deamidation activity via CD38 or BST1 in tissues other than blood.

Conflict-of-interest exposure is substantial and disclosed clearly. All but one of the human authors are employees of Nestlé Research or Nestlé Health Science; one author is an employee of the microbiome-analytics company Cryptobiotix. Nestlé Health Science sells NAD-precursor products commercially. The trial was pre-registered (NCT05517122) and used a validated in-house analytical pipeline, which mitigates but does not eliminate the interpretation risk.

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