Gut microbiota, inflammatory cytokines and gastro-esophageal reflux disease: A Mendelian randomization analysis

Gut microbiota has been recognized as an extrahepatic manifestation of gastro-esophageal reflux disease (GERD) in observational studies. However, the directionality and causality of the association and whether cytokines act as a mediator remain unclear. We aim to estimate the casual relationship between gut microbiota, inflammatory cytokines and GERD using a 2-sample Mendelian randomization method. Gut microbiota, cytokines, and GERD were identified using summary data from the genome-wide association studies and the FinnGen consortium. The primary method for causal estimation was the inverse-variance weighted approach, complemented by a range of sensitivity analyses aimed at assessing heterogeneity, horizontal pleiotropy, and the robustness of the findings. Furthermore, mediation analysis was conducted to evaluate the association between gut microbiota and GERD, with 5 cytokines, and to calculate the mediated proportions. We found 3 positive and 3 negative causal associations observed between genetic predisposition in gut microbiota and GERD. Additionally, 2 positive and 3 negative causal associations were identified between cytokines and GERD. Our analysis unveiled that TNF-related apoptosis-inducing ligand levels (TRAIL) mediated the causal relationships between the genera Family XIII UCG001 and Senegalimassilia, and GERD. We identified causal effects between 6 bacterial traits, 5 inflammatory cytokines, and GERD. Notably, we furnished causal evidence linking TRAIL levels to a substantial proportion of the risk attributed to genus Family XIII UCG001 and genus Senegalimassilia, thereby mediating the risk of GERD. These findings offer novel avenues for therapeutic interventions targeting individuals with GERD.