Gut microbiota–immune crosstalk in osteoarthritis: pathogenic mechanisms and emerging therapeutic opportunities

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Osteoarthritis (OA) has traditionally been viewed as a degenerative joint disorder primarily associated with mechanical stress and progressive structural damage. Increasing evidence, however, indicates that immune imbalance and persistent low-grade inflammation are critically involved in disease initiation and progression. In this context, alterations in the gut microbiota have attracted growing attention due to their capacity to influence systemic immune responses. Here, we provide an integrated overview of the interactions between the gut microbiota and the immune system in OA and introduce the concept of a "gut microbiota-immune-joint axis" to describe this interconnected regulatory network. Disruption of the gut microbial ecosystem may impair intestinal barrier function and facilitate the entry of microbe-derived signals into the circulation. These signals subsequently activate inflammatory pathways, including TLR4/NF-κB and JAK/STAT cascades, leading to immune cell reprogramming, altered macrophage polarization, and imbalanced T-cell responses. The resulting chronic inflammatory state can extend beyond the intestine and contribute to pathological changes in synovial tissue, cartilage, and subchondral bone. In addition, we summarize current progress in microbiota-oriented therapeutic strategies, particularly the use of probiotics and prebiotics, and discuss their potential roles in modulating immune responses and restoring systemic homeostasis. Finally, we highlight existing challenges and propose future directions, emphasizing the importance of multi-omics integration and longitudinal clinical studies to better understand the dynamic nature of microbiota-immune interactions and to support the development of targeted interventions in OA.