Diet-induced lipid accumulation contributes significantly to metabolic disorders, highlighting the need for effective nutritional interventions. Resveratrol (RSV), a polyphenol with limited bioavailability, and tomato pectin (TP), a soluble dietary fiber, individually modulates gut microbiota and metabolic health, yet their combined efficacy remains unexplored. This study investigated the combined effects of RSV and TP on hepatic lipid metabolism in mice fed a high-fat diet (HFD). Co-administration of RSV and TP significantly reduced obesity, improved glucose tolerance and insulin sensitivity, and decreased systemic inflammation compared to individual treatments. Histological and biochemical analyses showed alleviated hepatic steatosis, oxidative stress, and liver injury following combination treatment. Mechanistically, RSV and TP together suppressed hepatic lipogenic gene expression and promoted fatty acid β-oxidation. Intestinal barrier function improved via increased tight junction proteins and anti-inflammatory cytokines. Gut microbiota profiling revealed restored diversity and increased beneficial bacteria, such as Akkermansia, alongside reduced pathogenic genera. Fecal short-chain fatty acid levels were elevated, mainly due to TP. Importantly, antibiotic-induced microbiota depletion abolished the metabolic benefits of RSV and TP, indicating a microbiota-dependent mechanism. Targeted bile acids (BA) metabolomics showed that the combined treatment modified BAs composition by increasing primary-to-secondary and conjugated-to-unconjugated BAs ratios, favoring farnesoid X receptor (FXR) activation. Concurrent regulation of hepatic and intestinal FXR signaling components, BAs synthesis enzymes, transporters, and cholesterol metabolism genes were observed. These findings reveal a synergistic effect of RSV and TP that modulates the gut-liver axis via microbiota-mediated BAs-FXR signaling, suggesting a novel dietary intervention approach for the management of metabolic syndrome.
