Polyphenols increase circulating lipids but improve LDL particle quality and reduce LDL oxidation in postmenopausal women: metabotype- and age-dependent effects in a randomised, placebo-controlled crossover trial

PURPOSE: Menopause increases cardiometabolic risk via dyslipidaemia, oxidative stress, and low-grade inflammation. Polyphenols may modulate these processes, but human evidence is inconsistent. We investigated the effects of polyphenol supplementation on lipid profile, LDL oxidation, and polyphenol-related gut microbiota metabotypes in postmenopausal women. METHODS: In the PolyPAUSE randomised, placebo-controlled, crossover trial, 90 mildly hypercholesterolemic, non-medicated postmenopausal women received a daily polyphenol mixture providing ellagitannins+ellagic acid (312.0 ± 30.9 mg), resveratrol (133.2 ± 10.1 mg), and isoflavones (166.3 ± 27.3 mg) for 8 weeks, followed by a 4-week washout and an 8-week placebo period. Serobiochemical and bone-related markers were analysed at hospital laboratories. Apolipoprotein B (ApoB), oxidised LDL (oxLDL), and lipopolysaccharide-binding protein (LBP) were measured by ELISA, and myeloperoxidase activity by spectrophotometry. Gut microbiota metabotypes were classified as urolithin A/B (UMA/UMB), equol producers/non‑producers (EP/ENP), and lunularin producers/non‑producers (LP/LNP) using UPLC‑ESI‑QTOF‑MS. RESULTS: Polyphenol supplementation did not affect LBP or bone markers. Total cholesterol (Tchol), LDL-cholesterol (LDLc), and triglycerides (TGs) increased by 7%, 9.5%, and 16%, respectively (p < 0.001) in ~ 80% of completers (n = 78), with age‑related increases. ApoB showed a borderline reduction (p = 0.056), and oxLDL decreased (p < 0.001). Ratios indicating LDL particle quality and oxidative burden (LDLc/ApoB, oxLDL/LDLc, oxLDL/ApoB) improved (p < 0.001) despite higher circulating lipid concentrations. Myeloperoxidase activity showed marginal decreases in the full cohort (p = 0.08) and in LNP (p = 0.06). Metabotyping showed that the strongest oxLDL reduction occurred in EP (65%, p < 0.001) and the UMA + EP+LNP cluster (60%, p < 0.001). CONCLUSION: Polyphenol supplementation increased Tchol, LDLc, and TGs age-dependently, yet improved LDL oxidative quality. The extent of oxLDL reduction depended on metabotypes, supporting precision health approaches to better characterise cardiometabolic responses to polyphenol intake in postmenopausal women.