Examination of sex-specific interactions between gut microbiota and host metabolism after 12-week combined polyphenol supplementation in individuals with overweight or obesity

Polyphenols exert beneficial effects on host metabolism, which may be mediated by the gut microbiota. We investigated sex-specific differences in microbiota composition and interactions with cardiometabolic parameters after polyphenol supplementation in individuals with overweight/obesity. In a double-blind, randomized, placebo-controlled trial, 19 women and 18 men with normal glucose tolerance and body mass index >25 kg/m² received epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 + 80 mg/d) or placebo supplements for 12 weeks. Fecal microbiota composition (16S rRNA gene amplicon sequencing, V3-V4 region), <i>in vivo</i> whole-body fat oxidation (indirect calorimetry), and mitochondrial respiration in permeabilized skeletal muscle fibers (SkM-Ox; <i>ex vivo</i> respirometry) were determined pre- and post-intervention. Overall, EGCG+RES supplementation did not affect gut microbiota composition. <i>Akkermansia, Ruminococcaceae UCG-002, Subdoligranulum</i>, and <i>Lachnospiraceae UCG-004</i> were more abundant, while <i>Veillonella, Tyzzerella 4, Clostridium innocuum group, Ruminococcus gnavus group, Escherichia-Shigella</i>, and an uncultured Ruminococcaceae family genus were less abundant in women compared to men. In women, only baseline <i>Eubacterium ventriosum group</i> abundance correlated with EGCG+RES-induced changes in SkM-Ox. In men, low <i>Dorea</i>, <i>Barnsiella</i>, <i>Anaerotruncus</i>, <i>Ruminococcus</i>, <i>Subdoligranulum</i>, <i>Coprococcus</i>, <i>Eubacterium ventriosum group, Ruminococcaceae UCG-003</i>, and a <i>Ruminococcaceae</i> family genus abundance, and high <i>Blautia</i> abundance at baseline were associated with improvements in SkM-Ox. Changes in whole-body fat oxidation were not associated with gut microbiota features. We conclude that baseline microbiota composition predicts changes in SkM-Ox as a result of EGCG+RES supplementation in men but not in women. Men may be more prone to diet-induced, gut microbiota-related improvements in cardiometabolic health. These sex-differences should be further investigated in future precision-based intervention studies.