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Effect of a polyphenol-rich pomegranate extract on plasma trimethylamine N-oxide levels following an oral carnitine challenge: a randomized controlled crossover trial in healthy adults.

  • 2026-05-20
  • Frontiers in nutrition 13
    • Julia E Haarhuis
    • Jennifer Ahn-Jarvis
    • George M Savva
    • Priscilla E Day-Walsh
    • Clare Ferns
    • Sarah Hughes
    • Silas Triller
    • Olla Al-Jaibaji
    • Mark Philo
    • Emrah Acaroz
    • Natalia Perez-Moral
    • Paul A Kroon

Study Design

Type
Clinical Trial
Sample size
n = 34
Population
34 healthy, omnivorous adults
Methods
Two-phase dietary intervention study: Phase I oral carnitine challenge (1.5 g L-carnitine) to identify high TMAO producers; Phase II double-blind, randomized, placebo-controlled, crossover study with two 48-hour pharmacokinetic interventions separated by 10-day washout, consisting of an OCC with concurrent pomegranate extract (1.6 g) or placebo, preceded by a 48-hour low-TMAO precursor run-in diet
Blinding
Double-blind
Duration
18 days
Funding
Unclear

Introduction

Polyphenol-rich pomegranate extract has been shown to inhibit microbial trimethylamine (TMA) production from L-carnitine. Previous clinical studies have examined effects of polyphenol-rich interventions on fasting trimethylamine N-oxide (TMAO) concentrations but have not assessed pharmacokinetic TMAO responses following an oral carnitine challenge (OCC). We investigated whether a single dose of pomegranate extract attenuates the plasma TMAO response to an OCC in healthy adults.

Methods

This two-phase dietary intervention study enrolled 34 healthy, omnivorous adults. In Phase I, participants completed an OCC (1.5 g L-carnitine) to identify high TMAO producers (increase ≥ 5 μmol/L). Twenty high producers entered Phase II; an 18-day double-blind, randomized, placebo-controlled, crossover study with two 48-h pharmacokinetic interventions separated by a 10-day washout. Interventions consisted of an OCC with concurrent pomegranate extract (1.6 g) or placebo. Each OCC was preceded by a 48-h low-TMAO precursor run-in diet. Participants arrived fasted (>8 h), and all meals during the intervention periods were fully standardized to minimize dietary variability. Blood, urine, and stool samples were collected, and TMAO was quantified using LC-MS/MS. Differences in TMAO area under the curve (AUC) were analyzed using linear mixed-effects models.

Results

Ninety one percent of participants meeting the Phase I inclusion criteria produced substantial TMAO quantities from L-carnitine. This proportion exceeds that of earlier reports. Pomegranate extract did not reduce TMAO AUC in the full Phase II cohort (placebo/pomegranate ratio 0.993, 95% CI 0.81-1.22; P = 0.945; n = 16). However, a post hoc subgroup analysis showed that the effect of the pomegranate extract on plasma TMAO differed by age and sex.

Conclusion

Under tightly controlled dietary conditions, a single dose of pomegranate extract did not reduce post-OCC TMAO responses in the overall cohort. Post hoc analyses suggest potential sex- and age-dependent effects, warranting confirmation in larger, adequately powered studies.

Clinical trial registration

https://clinicaltrials.gov/, identifier NCT06518343.

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