Alterations in gut microbiota composition and functionality are related to obesity-related metabolic diseases. We previously showed that polyphenol supplementation exerts beneficial effects on host metabolism, which may be mediated through changes in the gut microbiota. However, it is not fully clear whether and how polyphenols impact gut microbiota composition, and whether this is sex-specific. Here, we investigated the interactions between combined polyphenol supplementation, fecal microbiota profile, and associations with tissue-specific insulin sensitivity, substrate oxidation and skeletal muscle mitochondrial function in men and women.

Methods:
In a double-blind, randomized, placebo-controlled study, 18 men and 19 women with overweight/obesity received either epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 and 80 mg/day) or placebo for 12 weeks. Before and after the intervention, fecal samples were collected, tissue-specific insulin resistance was determined by a two-step hyperinsulinemic-euglycemic clamp with [6,6-²H₂]-glucose infusion, fasting/postprandial substrate oxidation by indirect calorimetry, and skeletal muscle mitochondrial oxidative capacity by ex vivo respirometry.

Results:
Baseline microbiota composition of specific genera (q < 0.2) and phyla (Verrucomicrobia, q = 0.02) were significantly different between men and women. Overall, 12-week EGCG+RES supplementation did not induce significant changes in fecal microbiota composition (q > 0.05) and α- and β-diversity (p = 0.69 and p = 0.95 respectively). However, baseline abundance of specific microbial genera highly correlated with polyphenol-induced changes in skeletal muscle oxidative capacity in men (p < 0.05), but not in women.

Conclusion:
Our findings suggest that combined polyphenol supplementation has no effect on fecal microbiota composition in individuals with overweight/obesity. However, baseline microbiota composition may be more predictive for changes in metabolic outcomes in men compared to women. Future studies investigating gut microbiome-host metabolism interactions in humans should therefore consider employing a sex-specific approach.