The gut-muscle-joint axis in osteoarthritis: Mechanistic insights and therapeutic perspectives

Emerging evidence highlights a complex crosstalk between the gut microbiota, musculoskeletal tissues, and the joint microenvironment, revealing osteoarthritis (OA) as a systemic disorder rather than a localized cartilage disease. The gut-muscle-joint interaction integrates microbial dysbiosis, chronic inflammation, and metabolic dysregulation to influence cartilage homeostasis, muscle strength, and neuromuscular stability. Building upon previously described gut-osteoarthritis and gut-muscle interactions, the Gut-Muscle-Joint (GMJ) axis is presented as an integrative framework linking intestinal permeability, microbial metabolites, systemic inflammatory signaling, neuromuscular health, skeletal muscle function, and joint integrity. Perturbations in this axis amplify oxidative stress, mitochondrial dysfunction, and extracellular matrix degradation across musculoskeletal tissues. Understanding GMJ axis-driven mechanisms offers novel preventive and therapeutic strategies that target microbiome restoration, metabolic reprogramming, and neuromuscular health through probiotics, postbiotics, AMPK-SIRT1 activators, and structured exercise. This integrative perspective positions the GMJ axis as a unifying framework for intervention, enabling precision approaches to preserve joint function, reduce sarcopenia, and attenuate OA progression.