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

Haarhuis JE, Ahn-Jarvis J, Savva GM, Day-Walsh P, Ferns C, Hughes S, Triller S, Al-Jaibaji O, Philo M, Acaroz E, Perez-Moral N, Kroon P. (2026)

Frontiers in Nutrition

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 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: 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 significant interaction between intervention, age, and sex was observed for TMAO log AUC (P=0.004). In a post hoc subgroup analysis including female participants of premenopausal age (n=3) and all male participants (n=10), pomegranate extract reduced TMAO AUC by 15% compared with placebo (95% CI: 1.01-1.31, P=0.036).

Conclusions: 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 Registry number and website where it was obtained:

NCT06518343 (https://clinicaltrials.gov/).

Frontiers in Nutrition

View Publication