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

Abstract

Abstract 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.