The Gut-Bone Axis: Molecular Mechanisms and Therapeutic Perspectives in Skeletal Homeostasis

The gut-bone axis represents a paradigm shift in our understanding of skeletal biology, revealing how the gastrointestinal system and its microbial inhabitants profoundly influence bone homeostasis through complex bidirectional communication. This comprehensive review synthesizes recent high-impact research to elucidate the multifaceted mechanisms underlying gut-bone crosstalk, including microbial metabolite signaling, gut barrier integrity, immune modulation, and endocrine regulation. We examine how short-chain fatty acids (SCFAs), tryptophan metabolites, and bile acid derivatives modulate bone remodeling through epigenetic, immunologic, and hormonal pathways. The translational implications of these findings for the management of osteoporosis, osteoarthritis, and inflammatory bone disorders are critically evaluated, with particular emphasis on microbiome-targeted interventions, gut hormone-based therapies, and innovative approaches such as engineered microbial therapeutics. Furthermore, we explore the roles of farnesoid X receptor (FXR) signaling, G protein-coupled receptor activation, and mitochondrial function in bone cells as modulated by gut-derived factors. This review provides a framework for developing novel diagnostic and therapeutic strategies that target the gut-bone axis, highlighting the transition from traditional calcium-centric bone health paradigms toward integrated microbiome-targeted approaches that address the systemic nature of bone metabolism regulation.