Metabolic messengers from the gut to the joint: Toward precision management of osteoarthritis (Review)

Osteoarthritis has evolved from a mechanical concept to a metabolic whole‑organ disease driven by systemic inflammation. The ‘gut‑joint axis’ represents a ‘biological highway’ where intestinal dysbiosis permits the translocation of microbial metabolites into synovial joints. This review focuses on three pivotal metabolite classes with opposing roles: Short‑chain fatty acids (SCFAs), which function as anti‑inflammatory guardians; trimethylamine N‑oxide (TMAO), which acts as a pro‑inflammatory aggressor; and bile acids (BAs), which serve as complex regulators that balance homeostasis and catabolism. This review further proposes a novel ‘metabolite homeostasis imbalance’ theoretical framework, which posits that osteoarthritis pathogenesis is driven by the disruption of the dynamic equilibrium between protective (SCFAs), destructive (TMAO) and context‑dependent regulatory (BAs) microbial metabolites. This integrative ‘metabolite homeostasis imbalance’ model deconstructs the ‘biological highway’ metaphor into a three‑tier mechanistic schema encompassing intestinal barrier integrity, systemic metabolite trafficking and tissue‑specific effector functions in the joint microenvironment, thereby providing a unifying conceptual foundation bridging scattered single‑metabolite research and mechanism‑targeted precision OA management. Additionally, the potential of sports medicine interventions, including exercise and probiotics, to modulate this axis is evaluated. This synthesis provides a comprehensive theoretical basis for novel clinical strategies targeting gut‑derived metabolic networks to preserve joint health and mitigate disease progression.