Immune cells mediated the causal relationship between gut microbiota and carpal tunnel syndrome: A Mendelian...

Studies have shown that carpal tunnel syndrome (CTS) is associated with inflammation and immunity. Additionally, recent research indicates that the gut microbiota can influence the development and progression of immune and inflammatory responses. We aim to investigate the causal impact of gut microbiota on CTS and identify potential immune cell mediators. We made use of the summary statistics of 412 gut microbiota (from 7738 individuals), 731 immune cells (from 3757 individuals), and CTS (FinnGen consortium), from the extensive genome-wide association studies to date. To determine the causal links between gut microbiota and CTS, we employed bidirectional Mendelian randomization (MR) analyses, Bayesian-weighted Mendelian randomization (BWMR) and further employed 2-step MR to confirm potential mediating roles of immune cells. Moreover, we conducted rigorous sensitivity analyses to assess the heterogeneity, robustness, and horizontal pleiotropy of our findings. Bidirectional MR analysis and BWMR revealed that 15 bacterial traits were significantly associated with CTS, while the reversed causal relationship was not existed. Moreover, the mediation analysis demonstrated that 4 immune cells mediated the causal relationships of 3 gut microbiota species on CTS: CD14 on CD33dim HLA-DR+ CD11b+ cells and CD39 on CD39+ secreting CD4 regulatory T cells mediated the effects of s_Bacteroides_salyersiae on CTS, with indirect effect sizes of -0.0035 and -0.0015, accounting for 10.44% and 4.41% of the total effect, respectively. CD25 on IgD+ CD24+ B cells mediated the effect of s_Paraprevotella_clara on CTS, with an effect size of 0.0018, corresponding to 4.10% of the total effect. Moreover, CD8 on CD28+ CD45RA- CD8+ T cells mediated the association between s_Bacteroides_massiliensis and CTS, with a mediating effect of -0.0096, representing 10.49% of the total effect. The risk of CTS has been linked causally to gut microbiota, with 4 distinct immunophenotypes acting as potential mediators in this relationship. The role of gut microbiota in modulating immune cells, thereby influencing CTS, may offer novel therapeutic strategies and management approaches.