Nutrition-Derived Bioactive Polyphenolic Metabolites Produced by Gut Microbiota and Their Potential Role in Bone Health

Bone health is a significant contributor to functional ability and well-being. Bone strength and homeostasis are maintained by a remodeling process involving bone resorption and bone formation. An imbalance in these processes increases bone turnover and triggers loss of bone structures. Excessive loss of bone mineral density and deterioration of bone microarchitecture with an augmented risk of fragility fractures are the hallmarks of osteoporosis. Clinical studies have reported a positive impact of polyphenol-rich nutrition on bone health. Alongside phenolic compounds genuinely present in food sources, additional and potentially bioactive molecules are generated by gut microbiota from polyphenol precursors. These metabolites might contribute significantly to the health effects of dietary polyphenols. Some, such as urolithins or S-(−)-equol, are exclusively produced by gut bacteria and are not present in any food source (obligatory microbial metabolites). Others, such as caffeic or vanillic acid, may either originate from gut microbial biotransformation of precursors or occur naturally in food (facultative microbial metabolites), limiting source-specific interpretation of their reported effects. Evidence for the bioactivity of these metabolites on bone-relevant cellular pathways and metabolic bone markers is summarized, stratified by study type. Most abundant research data are available for S-(−)-equol, and consistent results exist for urolithin A. Notably, structurally unrelated metabolites often target the same signaling pathways. However, most evidence remains mechanistic or preclinical, while clinical confirmation of improved bone mineral density or reduced fracture risk is limited. Nevertheless, the current findings support a potential role of polyphenol-derived microbial metabolites in maintaining bone health.