Background/Objectives: Interindividual variability in polyphenol metabolism may help explain the inconsistent effects of polyphenol intake on health outcomes. This study compared, for the first time, (i) polyphenol-related gut microbiota metabotypes (urolithins: UM0, UMA, UMB; equol: EP, ENP; lunularin: LP, LNP) and their clusters (MCs) in non-medicated premenopausal (Pre-M) and postmenopausal (Post-M) women and (ii) the impact of an 8-week intake of a polyphenol-rich plant extract mixture (PPs) on the quality of life (QoL) of Post-M. Methods: Polyphenol metabotypes were determined in urine via UPLC-QTOF-MS after a 3-day intake of PPs containing resveratrol, pomegranate (ellagitannins and ellagic acid), and red clover (isoflavones) in Pre-M (n = 120) and Post-M (n = 90) women. QoL was assessed with the short-form Cervantes Scale in a randomized, placebo-controlled crossover trial (8-week PPs vs. placebo), completed by 78 Post-M participants. Results: At baseline, Pre-M and Post-M women showed only minor differences in metabotype and MC distributions linked to menopausal status. MC3 (UMA+EP+LP) predominated in Pre-M, while MC7 (UMA+EP+LNP) was most frequent in Post-M. PPs intake in Post-M women led to modest shifts in metabotype and MC distributions toward Pre-M patterns. Quantitative metabolite production was comparable between groups, except for equol, which showed a median 2.8-fold increase after PPs intake in EP Post-M women. Clinically meaningful improvements (score reduction ≥ 6.7 points) in QoL were observed in the Psychic domain in EP women (28%, p = 0.039) and in the Menopause and Health domain, specifically in EP (24.1%, p = 0.004), MC3 (22.5%, p = 0.043), and MC4 (UMB+EP+LP; 41.3%, p = 0.022), were mainly driven by a reduction in hot flashes (p = 0.001). Conclusions: These findings support metabotyping as a tool to guide targeted dietary strategies and enhance QoL through precision health in Post-M women.

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.