"Gut-Joint Axis" Perspective on Immunometabolic Crosstalk in Osteoarthritis: A Narrative Review of Mechanistic Insights and Targeted Strategies.

Osteoarthritis (OA) is a heterogeneous whole-joint disease in which local mechanical injury interacts with systemic metabolic dysfunction and chronic low-grade inflammation. Increasing evidence links gut microbiota dysbiosis to OA, but the mechanisms through which gut-derived perturbations contribute to joint structural damage remain incompletely integrated. This narrative review synthesizes clinical and experimental evidence on the gut-joint axis, focusing on a mechanistic sequence in which dysbiosis impairs intestinal barrier integrity, increases systemic exposure to gut-derived inflammatory signals, activates pattern-recognition receptor (PRR) signaling, and induces immunometabolic reprogramming in joint-resident cells. This process may amplify synovial inflammation, cartilage catabolism, and subchondral bone remodeling, thereby contributing to structural degeneration. Unlike previous reviews that primarily summarize microbiota-associated alterations or individual interventions, this review positions immunometabolic reprogramming as the mechanistic bridge between gut-derived inflammatory inputs and local joint degeneration. We further discuss therapeutic opportunities targeting microbiota homeostasis, intestinal barrier repair, inflammatory amplification, immunometabolic pathways, and natural products and phytochemicals. Overall, the gut-joint axis is best viewed as an amplifier of inflammatory and metabolic susceptibility rather than an independent initiator of OA. This framework may support biomarker-guided stratification and targeted interventions for metabolically driven OA.