Multidimensional regulatory mechanisms and targeted intervention strategies of the gut-joint axis in metabolic...

Osteoarthritis (OA) is increasingly recognized as a heterogeneous disease driven not only by mechanical overload but also by systemic metabolic and inflammatory disturbances, among which metabolic osteoarthritis (Met OA) represents a distinct and highly prevalent subtype. Met OA is closely associated with obesity, insulin resistance, and metabolic syndrome, yet the underlying molecular and immunometabolic mechanisms remain incompletely defined. Emerging evidence supports a pivotal role of the gut-joint axis, whereby gut microbiota (GM) dysbiosis and its metabolites reshape intestinal barrier integrity, systemic immune-inflammatory status, and joint microenvironment homeostasis. In this review, we focus specifically on Met OA as a unique OA subtype and systematically dissect how the gut-joint axis orchestrates disease onset and progression through four interrelated dimensions: metabolic stress, inflammatory stress, immune stress, and oxidative stress. We highlight key GM-derived metabolic pathways-including short-chain fatty acids, tryptophan metabolites, and bile acids/FXR-TGR5-GLP‑1 signaling-as central hubs linking metabolic imbalance to cartilage degeneration and subchondral bone remodeling. On this mechanistic basis, we further summarize current and emerging gut-targeted and immunometabolic interventions, such as dietary modulation, probiotics and prebiotics, fecal microbiota transplantation, and repurposed metabolic drugs. By integrating Met OA subtype concept with a four‑axis stress framework and gut‑directed therapeutic strategies, this review proposes a multidimensional model of the gut-joint axis in Met OA. This model provides a rationale for refined phenotypic classification, biomarker discovery, and the development of precision, gut‑centered interventions for patients with metabolic osteoarthritis.