The gut-joint axis in osteoarthritis: integrating microbiota-driven metaflammation and immunosenescence

Osteoarthritis (OA) has traditionally been viewed as a mechanical degenerative disease, but in recent years, the paradigm has gradually shifted from "mechanical wear and tear degenerative disease" to a complex condition driven by systemic low-grade inflammation and Immunosenescence. As a key linking pathway between gut microbiota, metaflammation, and Immunosenescence, the gut-joint axis has attracted widespread attention. The composition of gut microbiota and its metabolites influences the occurrence and development of OA by regulating gut barrier function and systemic inflammation levels. Numerous animal models and clinical studies have confirmed that gut microbiota imbalance is closely related to the clinical manifestations of OA. The mechanisms of microbiota-driven metaflammation and Immunosenescence jointly promote the pathological process of OA, revealing its heterogeneity and complexity. This article proposes a core hypothesis: the gut-joint axis acts as a key upstream pathway in which gut microbiota imbalance weakens gut barrier integrity and triggers microbiota-driven metaflammation. This process further accelerates inflammaging, thereby amplifying the inflammatory response and structural degeneration of the cartilage-synovium-subchondral-bone unit. To integrate dispersed evidence and better explain the clinical heterogeneity of OA, we construct a unified framework of "microbiota, barrier, inflammation, aging, and phenotype," correlating microbial functional outputs with key phenotypes such as inflammation dominance, metaflammation, aging-driven changes, and pain hypersensitivity. This framework provides a theoretical basis for biomarker-based patient stratification and combination strategies targeting both microbiota and anti-aging interventions. It also offers a roadmap for advancing OA precision management and the development of disease-modifying treatments.