The Gut-Bone Axis: A Systematic Review on the Potential Intervention Pathways for Bone Health.

Osteoporosis arises from disrupted bone remodeling, and growing evidence shows that gut microbiota and their metabolites have a major influence on skeletal health through the gut-bone and gut-brain-bone axes. In this systematic review, we synthesize findings from 932 studies to identify key microbial taxa, metabolites, and signaling pathways that modulate osteoblast and osteoclast activities. Short-chain fatty acids (SCFA), tryptophan-derived metabolites, and β-D-glucuronidase-related estrogen regulation emerge as central microbial mechanisms affecting bone formation and resorption. By integrating these data with the Phylobone extracellular matrix proteins database, we highlight Osteopontin and Cathepsin K as important downstream mediators linking microbial signals to bone matrix turnover. Probiotic strains (particularly Lactobacillus rhamnosus GG and L. reuteri) show potential to improve bone health through metabolic, immune, and endocrine pathways. Together, these findings outline a mechanistic framework connecting gut function to skeletal biology and identify promising microbiome-based targets for osteoporosis interventions.