Genetically predicted immune cell-mediated causal associations between 473 gut microbiome species and...

Neurodevelopmental disorders (NDD) are a class of complex diseases whose underlying pathogenesis has not been fully elucidated. Previous observational studies have reported that gut microbiota dysbiosis may be one of the potential risk factors for the development of NDD, however, causal relationships and the potential mediating role of immune cells have yet to be established.

Bidirectional two-sample Mendelian randomization (TSMR) and two-step Mendelian randomization (two-step MR) methods, mainly using inverse variance weighting (IVW), were used to explore the potential associations between gut microbiota and NDD, as well as the mediating role of immune cells in the causal pathway. Bayesian weighted Mendelian randomization (BWMR) method was additionally used to validate positive causality. Sensitivity analyses under different statistical assumptions were conducted to assess association robustness.

Based on the IVW and BWMR methods, we identified 5 and 4 gut microbiota taxonomic units exhibiting significant causal associations with ADHD and ASD, respectively. These included the negative modifying effect of family Syntrophorhabdaceae abundance on ADHD risk (OR: 0.4440, 95 % CI = 0.2620-0.7523, P = 0.0025), the significant protective effect of species ER4 sp002437735 on ASD (OR: 0.2996, 95 % CI = 0.1504-0.5968, P = 0.0004) and the stimulatory effect of species Agathobacter sp000434275 on ASD (OR: 1.7426, 95 % CI = 1.1496-2.6415, P = 0.0089). P values derived from Cochran's Q test, Egger's regression intercept test, and global test for pleiotropy and outliers did not suggest statistical significance. Further two-step MR revealed that Syntrophorhabdaceae could reduce the risk of ADHD, with Unswitched memory B cell %lymphocyte mediating 6.35 %. Additionally, 2.49 % and 1.91 % of the causal associations between ER4 sp002437735 and Agathobacter sp000434275 with ASD were mediated by BAFF-R⁺ switched memory B cells and activated/secreting CD4 regulatory T cell percentage of CD4 regulatory T cells, respectively.

Our study reveals direct evidence that NDD is influenced by specific gut microbiota, while its causal effects may be mediated by immune cell traits.