Gut Eggerthella lenta promotes the efficacy of resveratrol through reductive metabolism

Resveratrol (RSV) is a plant-derived natural product with diverse biological activities. It has attracted considerable attention for its notable efficacy in nutritional health and disease treatment. The physiological impact of RSV in the human body is closely connected to the gut microbiota; however, the primary gut microorganisms responsible for RSV metabolism and the underlying mechanisms remain unclear. Here, based on the ex vivo culturing of the gut microbiota from human feces, we isolated a bacterium capable of efficiently metabolizing RSV, namely Eggerthella lenta J01. Through the induced enrichment transcriptomics and bioinformatic analyses, we further identified a resveratrol reductase (RER) from E. lenta J01, which specifically catalyzes the hydrogenation of the C9-C10 double bond of RSV and initiates RSVs in vivo metabolism. RER and its homologs represent a novel class of ene-reductases. The abundance of RER in the gut microbiota of healthy individuals was significantly higher than that in patients with inflammatory bowel disease, suggesting its crucial physiological function. Cell culture experiments and animal studies showed that dihydroresveratrol (DHR), a metabolite of RSV catalyzed by RER, exhibited stronger biological activity in inhibiting the growth of colon cancer cells and alleviating symptoms of enteritis in mouse models. Our results expand the understanding of gut microbial metabolism of RSV and its medicinal functions, providing possible guidance for optimizing RSV bioavailability in the human body.