Fructooligosaccharides and ellagic acid synergistically enhance muscular endurance via targeting gut microbial urolithin A biosynthesis

INTRODUCTION: Sarcopenia, characterized by the progressive loss of muscle mass and function, may be alleviated by ellagic acid (EA) through its microbial metabolite urolithin A (Uro-A). However, the low in vivo conversion efficiency of EA to Uro-A limits its clinical utility. OBJECTIVES: This study aimed to develop a gut microbiota-targeted dietary strategy to enhance Uro-A biosynthesis and improve muscle performance. METHODS: A combinatorial approach using EA and fructooligosaccharides (FOS) was applied in vivo to modulate microbial metabolism. Gut microbiota composition, urolithin profiles, and muscle performance were assessed. Mechanistic roles of key bacterial species were further explored. RESULTS: EA and FOS synergistically improved muscle endurance and strength by enhancing Uro-A production, compared with either intervention alone. Mechanistically, we identified a previously unrecognized two-step cooperative pathway: Bifidobacterium pseudolongum initiated EA metabolism by converting it to urolithin C (Uro-C), and while Enterococcus faecalis, identified here for the first time, catalyzed the conversion of Uro-C to Uro-A. This newly uncovered cross-feeding partnership between the two species proved essential for maximizing Uro-A biosynthesis and mediating the physiological benefits. CONCLUSION: This study demonstrates a proof-of-concept strategy to boost gut microbial Uro-A biosynthesis through dietary modulation, providing a novel and cost-effective approach for sarcopenia prevention and management.