Potential link between Gordonibacter pamelaeae and phospholipase C gamma 1 in osteoarthritis.

The gut-joint axis has been increasingly implicated in osteoarthritis (OA), yet the causal contribution of specific gut microbes and their downstream molecular mechanisms remain unclear. We employed a multi-stage, two-sample Mendelian randomization (MR) framework. This approach utilized summary-level data from large-scale genome-wide association studies (GWAS) for gut microbiota, plasma proteins, and OA. The analysis involved three steps: (1) identifying gut microbial taxa with potential causal associations with OA risk; (2) screening of pyroptosis-related proteins using pQTL data; and (3) performing mediation analysis to evaluate potential intermediate mechanisms. We also performed transcriptomic analysis of human cartilage and in vitro experiments in chondrocytes to support the biological relevance of our findings. Our MR analysis identified Gordonibacter pamelaeae as a suggestive microbial taxon inversely associated with OA risk. Among 11 candidate pyroptosis-related proteins, only Phospholipase C Gamma 1 (PLCG1) showed a significant inverse association with OA. MR analysis further suggested that G. pamelaeae was positively associated with genetically predicted PLCG1 levels. Mediation analysis indicated that PLCG1 partially mediated the association between G. pamelaeae and OA. Consistent with these findings, PLCG1 mRNA levels were reduced in human OA cartilage. Furthermore, our in vitro experiments demonstrated that PLCG1 knockdown enhanced IL-1β-induced inflammatory and pyroptotic responses in chondrocytes. This study suggests a potential link involving gut microbiota and OA through PLCG1-related signaling. PLCG1 may act as a context-dependent regulator that limits excessive inflammatory responses under stress conditions. These findings refine the current understanding of the gut-joint axis and may help identify potential targets for OA intervention.