The Microbiota Metabolite-Joint Axis: Mechanistic Insights and Therapeutic Targets for Osteoarthritis

Background: Osteoarthritis (OA) is the most common degenerative joint disease globally, with its pathogenesis yet to be fully elucidated. Accumulating evidence has redefined OA as a systemic low-grade inflammatory disorder. While the gut microbiota-joint axis is widely recognized as a key regulatory pathway in OA progression, a definitive causal and mechanistic framework linking microbiota-derived metabolites to OA pathology has not yet been established. Aim of Review: This review aims to comprehensively evaluate the roles of microbiota-derived metabolites in OA pathogenesis by integrating cutting-edge multi-omics data, causal evidence from Mendelian randomization studies, and advanced translational strategies. We propose a conceptual framework linking microbial dysbiosis to joint degeneration and discuss potential therapeutic targets for OA. Key Scientific Concepts of Review: Microbiota-derived signals, including lipopolysaccharides, peptidoglycans, short-chain fatty acids, bile acids, tryptophan metabolites, and hydrogen sulfide, are associated with mucosal barrier impairment, aberrant immune activation, and metabolic-endocrine dysfunction. These systemic host responses, in turn, may collectively contribute to the three core pathological hallmarks of OA: cartilage degeneration, synovial inflammation, and subchondral bone remodeling. We highlight novel regulatory pathways, including bile acid-glucagon-like peptide-1(GLP-1) signaling, aryl hydrocarbon receptor (AhR) modulation, and ferroptosis regulation, as potential critical mediators of OA. Causal evidence from multi-omics and Mendelian randomization analyses is synthesized to move beyond simple descriptive associations. Furthermore, we discuss translational strategies, such as metabolite-targeted interventions (GUDCA, IPA, HDCA) and engineered bacterial extracellular vesicle delivery systems, providing a potential framework for the precision theranostics of OA.