The Mediating Role of Bioactive Molecules in Gut Microbiota–Bone Metabolism Crosstalk

The interaction between the gut microbiota and the skeletal system has evolved into a new research focus. Studies underscore the role of bioactive metabolites in sustaining systemic balance via the “gut microbiota–endocrine–skeleton” axis, where they modulate metabolic processes and organ morphology through intracellular signaling. A key bidirectional relationship exists with the gut: shifts in gut microbiota affect host metabolism and subsequent metabolite profiles, while these metabolites can, in turn, reshape the intestinal microenvironment. This review explores how short-chain fatty acids (SCFAs), estrogen, and vitamin D modulate osteoporosis via the gut–bone axis. It synthesizes evidence of their signaling pathways and metabolic roles, identifies research gaps from recent clinical studies, and evaluates gut microbiota-targeted therapeutic strategies for potential clinical translation.