Integrative multi-omics analysis reveals gut microbiota-derived metabolites and immune regulatory pathways in osteoarthritis pathogenesis.

Abstract

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by cartilage degradation, synovial inflammation, and progressive joint dysfunction. Emerging evidence suggests that gut microbiota dysbiosis contributes to OA development through immune modulation and metabolite-mediated pathways. We applied a comprehensive multi-omics strategy that integrated differential gene expression analysis, functional enrichment, machine learning (ML), SHapley Additive exPlanations (SHAP), Mendelian randomization (MR), and single-cell transcriptomics to identify key microbial metabolites and molecular targets involved in OA pathogenesis. We constructed a Microbiota-Metabolite-Target (M-M-T) network linking 34 gut microbial species, 19 metabolites, and the hub gene Arginase 1 (ARG1), thereby revealing potential regulatory mechanisms involved in immune cell communication. Functional enrichment analyses and cell-cell interaction profiling identified key roles for the Macrophage Migration Inhibitory Factor (MIF) and visfatin signaling pathways in modulating inflammatory responses and tissue metabolic processes. Seven gut microbiota-derived metabolites with favorable drug-like properties and minimal predicted toxicity were further identified, and molecular docking indicated that these metabolites form stable interactions with ARG1. These findings provide new insights into the gut-joint axis, suggesting that targeting microbial metabolites and immune regulatory pathways may offer potential therapeutic strategies for OA and pave the way for future in vitro and in vivo investigations.