The Polyphenol–Microbiota Axis: Molecular Mechanisms, Metabolic Pathways, and Therapeutic Perspectives in Human Health

Polyphenols are a diverse class of bioactive phytochemicals increasingly recognized for their ability to modulate human physiology through extensive interactions with the gut microbiota. This review provides a comprehensive and updated synthesis of the bidirectional polyphenol-microbiota relationship, emphasizing how dietary polyphenols reshape microbial community structure while intestinal microorganisms metabolize polyphenols into smaller, more bioavailable derivatives. These microbial metabolites-such as urolithins, phenolic acids, and dihydroresveratrol-exert amplified biological activities compared to their parent molecules, acting on key molecular pathways linked to oxidative stress, inflammation, energy homeostasis, and metabolic regulation. Through integration of mechanistic studies, multi-omics analyses, and emerging clinical evidence, this review outlines the potential of the polyphenol-microbiota-metabolite axis as a target for precision nutrition and microbiota-informed therapeutic interventions. The manuscript highlights ongoing challenges, including inter-individual variability in polyphenol metabolism, and proposes future research directions to advance the field of personalized nutrition.