The oral–gut microbiome axis in systemic bone-related diseases

The oral microbiome is increasingly recognized as an upstream ecological interface with systemic relevance beyond oral disease. Emerging evidence links oral dysbiosis to skeletal pathology through an oral–gut axis involving salivary microbial transfer, gut remodeling, barrier dysfunction, and microbiota-derived metabolites. In this review, we summarize current evidence supporting the oral–gut–bone axis in systemic bone-related diseases and propose an integrated framework in which oral ecological disturbance may contribute to skeletal vulnerability through gut-dependent metabolic and inflammatory relay mechanisms. We highlight three major mechanistic architectures: metabolite-centered osteoimmune regulation, barrier dysfunction with inflammatory amplification, and oral-derived microbial signaling. Across rheumatoid arthritis, osteoarthritis, and osteoporosis, these pathways are associated with distinct downstream phenotypes, including inflammatory bone erosion, degenerative joint remodeling, and systemic bone loss. Short-chain fatty acids, valeric acid, bile acid derivatives, and tryptophan-derived indoles emerge as key intermediates linking microbial ecology to osteoclastogenesis, osteoblast activity, immune polarization, and joint homeostasis. We also discuss translational opportunities involving metabolite restoration, microbiota-targeted intervention, host-pathway modulation, and mechanism-guided biomarker development. Despite recent progress, most current evidence remains associative, and major gaps persist in causal inference and functional validation.