The three-layer defense system of gut microbiota in regulating bone development and homeostasis: homeostatic maintenance, stress sensing, and programmed repair

The gut microbiota functions as a critical regulator of bone development and homeostasis through a proposed 'three-layer defense system': basal homeostatic maintenance, danger sensing, and active repair. Microbial metabolites such as short-chain fatty acids, tryptophan derivatives, and vitamin K modulate bone metabolism via GPCR signaling, epigenetic regulation, and immune modulation, establishing a foundation for skeletal health. Endocrine axes - including estrogen, GH/IGF-1, and PTH - interact with the gut microbiota to influence bone remodeling, with dysbiosis contributing to inflammatory amplification and osteoclast activation via RANKL/NF-κB pathways. The third-layer defense involves targeted repair through probiotics and bacterial extracellular vesicles, which restore immune homeostasis, enhance osteogenesis, and suppress bone resorption. Therapeutic strategies targeting this multi-layer system - including probiotic interventions, fecal microbiota transplantation, and bioactive compound supplementation - offer promising avenues for personalized prevention and treatment of metabolic bone diseases.