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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月5日

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  • Weijiang Wang,
  • Hongwei Liu,
  • Minheng Zhang,
  • Luodan Wang

摘要

Background

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.

Methods

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.

Results

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.

Conclusions

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.