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Multidimensional regulatory mechanisms and targeted intervention strategies of the gut-joint axis in metabolic osteoarthritis
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DOI：10.1016/j.trsl.2026.07.003.png)
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Abstract
En 中文
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.
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