Casual roles of gut microbiota, immune cells, and inflammatory cytokines in acute respiratory distress syndrome: A Mendelian randomization study

Gut dysbiosis and aberrant immune activation are increasingly recognized as critical determinants of acute respiratory distress syndrome (ARDS). However, the causal contributions of specific gut taxa, immune-cell phenotypes, and their interactive pathways remain incompletely understood. In this study, we conducted a comprehensive two-sample Mendelian randomization (MR) analysis to elucidate the individual and combined effects of the gut microbiome and immune milieu on ARDS susceptibility. Using 5 combined methodologies, the primary causal estimates were primarily derived through the Inverse-Variance Weighted approach. Heterogeneity was evaluated using Cochrane's Q test, while horizontal pleiotropy was assessed via the MR-Egger intercept, and robustness was confirmed through leave-one-out and reverse MR analyses. Following adjustments for the false discovery rate (FDR), our findings indicated that, although the overall effects of exposures on ARDS were not statistically significant (PFDR < 0.2), there were causal associations identified for 12 gut microbiota taxa, 24 immune cells, and 6 circulating inflammatory cytokines with ARDS (P < .05). Initial mediation analyses indicated that EIF4EBP1, caspase-8, IL-6, and IL-8 might partly mediate these effects, but 1000 BCa bootstrap iterations rejected all indirect pathways. These findings underscore the pivotal roles of gut microbiota and immune factors, both individually and interactively, in the pathogenesis of ARDS, offering a genetically informed basis for future treatments targeting the microbiome and immune system.