Tier 2 — strong

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

Christen S, Redeuil K, Goulet L, Giner MP, Breton I, Frézal A, Nazari A, Van den Abbeele P, Godin JP, Nutten S, Cuenoud B

Nature Metabolism 2026 Volume 8, issue 1, pages 62–73

Bibliography

DOI: 10.1038/s42255-025-01421-8
PubMed: PMID 41540253
PubMed Central: PMC12855009
Funding: Funded by Nestlé Research (Société des Produits Nestlé SA). The paper does not list an external grant number.
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

Design	Randomised, 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).
Model	Healthy 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.
Sample	67 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.
Intervention	Once-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.
Duration	14 days of daily dosing, with acute 4-hour serial sampling on day 1 and day 14.
Endpoints	Change 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

NAD is a molecule your cells cannot function without. Its concentration falls with age, and several supplement forms — nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and plain nicotinamide (Nam, sometimes called niacinamide) — have been sold and studied as ways to push it back up. Until this trial, no one had put all three head to head in the same people, using the same analytics, over the same timeframe.

Sixty-five healthy adults were randomly assigned to take one of the three precursors or a placebo, once daily for 14 days. NR and NMN were each dosed at 1000 mg per day; nicotinamide at 500 mg. Blood was drawn at baseline and after two weeks, plus intensively over the four hours after the first and last dose. All measurements used a validated mass-spectrometry pipeline.

The result on the primary endpoint was clean. NR and NMN each roughly doubled baseline whole-blood NAD after two weeks, and they did so by similar amounts (about 49 µM and 43 µM above placebo, respectively). Plain nicotinamide did not raise baseline NAD at all over two weeks. What it did do was produce a fast, transient spike over the four hours after each dose — nicotinamide is absorbed and metabolised quickly, and it briefly floods the salvage pathway.

The most interesting part of the paper is the mechanism. The researchers took human gut microbiota out of stool donors and grew them in the lab with NR, NMN or nicotinamide. NR and NMN were rapidly hydrolysed and then deamidated by the microbiota into nicotinic acid (NA) — the acidic sister molecule that classically enters NAD synthesis via the Preiss–Handler pathway. Nicotinamide did not produce this bacterial NA. In parallel, the team exposed fresh human whole blood to each of the six known NAD precursors and confirmed that nicotinic acid is by far the most efficient at raising cellular NAD in blood.

The proposed model: when you take NR or NMN, most of the dose is not absorbed intact — the gut microbiota strips it down to nicotinic acid, and that nicotinic acid is what eventually raises circulatory NAD. It also explains why NR and NMN produced similar effects at similar doses. It shifts the mental model of how these supplements work, and it opens a second potential benefit — NR and NMN also increased bacterial cell counts, short-chain fatty acid production and specific microbes (notably Enterocloster aldensis for NR), suggesting a possible knock-on benefit for gut health.

Key findings

After 14 days, NR (1000 mg/d) raised baseline whole-blood NAD+ by 49.4 µM (95% CI 39.5–59.3, p<0.001 vs placebo). NMN (1000 mg/d) raised it by 43.1 µM (95% CI 32.7–53.4, p<0.001).
Nicotinamide (500 mg/d) did not significantly change baseline whole-blood NAD+ over 14 days (p=0.461 vs placebo).
Nicotinamide did produce a fast, transient rise in the whole-blood NAD+ metabolome over the 4 hours after each dose — a Cmax at ~1 hour and iAUC of 105.2 µM·h — with rapid build-up of its methylated degradation products (MeNam, MeXPY) in blood, plasma and urine, indicating quick absorption and turnover through the salvage pathway.
NR and NMN did not produce an acute 4-hour rise in circulating NR or NMN concentrations (both stayed <2 µM); their effect on NAD+ was chronic rather than acute.
Neither NR, NMN nor nicotinamide caused a detectable rise in circulating nicotinic acid (NA) or nicotinic acid riboside (NAR) in blood or plasma at any measured time point, despite an LLOQ of 0.02 µM — suggesting NA is produced in the gut and immediately consumed.
Ex vivo, human faecal microbiota rapidly cleaved NR to nicotinamide (peak ~2.1 mM at 8 h) and then deamidated it to nicotinic acid (200–400 µM sustained over the final 24 h). NMN followed a similar hydrolysis-then-deamidation route via NAMN. Nicotinamide alone did not yield NA in the microbiome experiments.
NR significantly increased gut bacterial cell counts at 48 h and specifically enriched Enterocloster aldensis across all six healthy donors (p<0.01). NR and NMN both raised short-chain fatty acid production (acetate, propionate) and lowered pH in ex vivo fermentations — consistent effects across healthy adults, healthy older adults and Crohn's-disease donors.
In human whole-blood cell culture at 50 µM equimolar dosing, nicotinic acid (NA) increased NAD+ signal ~170% over 7 hours and was consumed in parallel. NR and NMN did not raise NAD+ in this system — they were rapidly cleaved to nicotinamide and pentose phosphates without net NAD+ gain, indicating that gut conversion is doing the work in vivo.
Nicotinamide dosing produced a large acute rise in plasma homocysteine (>8× median iAUC vs placebo, p<0.005), consistent with methyl-pool depletion during nicotinamide methylation. NR and NMN did not produce this acute homocysteine spike.
All three precursors were well tolerated. Only three probable adverse events across 65 participants (one abdominal pain on placebo, one hypotension on NR, one 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.

Tier 2

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