Gut dysbiosis and vitamin-dependent immune regulation in degenerative musculoskeletal and bone diseases.

Degenerative musculoskeletal and metabolic bone diseases are increasingly recognized as conditions sustained not only by endocrine and mechanical factors, but also by chronic low-grade immune activation and osteo-immune imbalance. This Perspective proposes a mechanistic framework in which gut dysbiosis may contribute to skeletal degeneration through alterations in vitamin-dependent immune regulation, with particular attention to the interaction between vitamin D signaling and microbiota-derived menaquinones. Dysbiosis may impair intestinal barrier integrity and increase exposure to microbial-associated molecular patterns, thereby sustaining innate and adaptive immune activation and promoting a pro-inflammatory cytokine milieu involving IL-6, TNF-α, IL-17, and IL-1β. These pathways may promote osteoclastogenesis and disrupt bone remodeling through the RANKL/RANK/OPG axis. While the immunomodulatory role of vitamin D is well established, microbiota-derived menaquinones may represent a less explored but biologically plausible interface between microbial metabolism, inflammatory signaling, and skeletal homeostasis . However, the extent to which microbiota-derived menaquinones significantly contribute to systemic vitamin K status in humans remains controversial and incompletely characterized. Within this framework, dietary patterns are conceptualized as modulators of microbial ecology and immune activation, while microbiota-modulating strategies may indirectly influence osteo-immune balance through immune-mediated mechanisms. This Perspective integrates microbial, immunological, and vitamin-dependent pathways into an immunology-centered model of skeletal degeneration and highlights the need for studies combining microbiome profiling, immune phenotyping, vitamin-dependent signaling, and bone remodeling outcomes.