Precision health targeting TMAO in postmenopausal women: polyphenol effects modulated by urolithin A and equol metabotypes in a randomised, placebo-controlled crossover trial

Abstract

Menopause increases cardiometabolic risk, partly by reducing the protective effects of estrogens and inducing gut microbiota dysbiosis, which can promote the production of atherogenic metabolites such as trimethylamine N-oxide (TMAO). Polyphenols may reduce TMAO levels, though interindividual variability limits reproducibility. We compared urinary and serum TMAO levels, and urinary trimethylamine (TMA) and dimethylamine (DMA) levels between healthy women of reproductive age (Pre-M, n = 120) and non-medicated postmenopausal women (Post-M, n = 90) using UPLC-QqQ-MS/MS. In Post-M women, we conducted a randomised, placebo-controlled crossover study to evaluate the effects of a polyphenol-rich extract mixture containing pomegranate, Polygonum cuspidatum, and red clover (sources of ellagitannins, resveratrol, and isoflavones) on TMAO, TMA, and DMA in the whole group and after metabotyping. Because medication is common in Post-M women due to age and cardiometabolic risk, trials in non-medicated participants are challenging, yet avoiding drug-diet interactions allows clearer attribution of dietary effects. Urinary TMAO and DMA levels were higher in Post-M than in Pre-M. No changes were observed in serum TMAO. However, the intervention reduced urinary TMAO and DMA versus baseline and placebo. The effects varied by metabotype. TMAO reduction was significant in urolithin A metabotype (UMA), equol producers (EP), and lunularin non-producers (LNP). Reductions and effect sizes were most pronounced in the metabotype clusters MC3 (UMA + EP + LP) and MC7 (UMA + EP + LNP), which represented 39% of participants. DMA decreased selectively in UMA. No correlations were found between TMAO or DMA changes and BMI, age at menopause onset, or years since menopause. These findings show that polyphenol supplementation reduces urinary TMAO in a metabotype-dependent manner and support metabotyping as a precision-health strategy to mitigate cardiometabolic risk after menopause.