Dietary (poly)phenols, the gut-brain axis, and menopause: a perspective on an overlooked biological crossroad

Abstract

Hormonal decline, chronic low-grade inflammation, metabolic alterations and polypharmacy shape the postmenopausal period. These factors remodel the gut microbiota and influence the production of microbial metabolites that modulate immune, endocrine, and neural communication. The gut-brain axis provides a framework for understanding how microbial activity affects cognition, mood, stress responses, neuroinflammation, and gastrointestinal function. Dietary (poly)phenols depend on gut microbial transformation to generate metabolites with distinct biological activity targeting mechanisms, such as intestinal and blood-brain barrier integrity, inflammatory signalling, redox balance, neurotransmitter synthesis, tryptophan metabolism, short-chain fatty acid production, and bile acid remodelling. These pathways are sensitive to hormonal decline, inflammaging, and polypharmacy, which modify microbial metabolism, host conjugation processes, enterohepatic cycling, and physiological response to dietary compounds. Despite this mechanistic basis, no human intervention study has examined these interactions in postmenopausal women. This perspective integrates three dimensions that are usually addressed separately: the physiological and pharmacological characteristics of postmenopause, the communication pathways of the gut-brain axis, and the gut microbial transformation of dietary (poly)phenols. We review human trials assessing (poly)phenols and gut-brain outcomes and highlight the scarcity of mechanistic endpoints, including microbial metabolites, barrier markers, neuroimmune mediators, and bile acid profiles. We also highlight how chronic medications reshape microbial composition and functionality, and how host targets of (poly)phenols, together with interindividual variability in polyphenol-related microbiota metabotypes, such as equol- and urolithin-producing metabotypes, influence biological responses and support personalised strategies. By identifying gaps and research priorities, this perspective provides a conceptual basis for developing precision health for postmenopausal women.