Genetically Predicted Immune Cells Mediate the Association Between Gut Microbiota and Gastroesophageal Reflux Disease

Background: Recent evidence increasingly acknowledges the close interrelationship between immunity and gut microbiota (GM) in humans. Furthermore, previous studies have demonstrated a strong correlation between GM and gastroesophageal reflux disease (GERD). However, the specific impact of GM on immune factors in GERD remains largely unexplored. Therefore, we conducted the Mendelian randomization (MR) analysis to investigate the precise causal relationships and underlying mechanisms linking GM, immunity, and GERD.Method: We employed the mediation MR utilizing summary statistics derived from Genome-Wide Association Study (GWAS) data to investigate the causal effects of 207 taxa and 205 bacterial pathways on GERD. The analysis concentrated on 731 immune cell traits as potential mediators. The inverse variance weighted (IVW) approach was the primary analytical method. To ensure robustness, we employed additional MR methods, including Bayesian weighted MR (BWMR), MR-Egger, Weighted Median, Weighted Mode, and Simple Mode. Furthermore, a series of sensitivity analyses, such as the Cochran's Q test, leave-one-out test, MR-Egger intercept analysis, and MR-PRESSO test, were conducted to ensure the reliability and consistency of the findings.Results: The study identified three taxa and eight bacterial pathways that exhibited a negative correlation with GERD. Mediation MR analyses indicated that four bacterial pathways influence GERD through four immune cell types acting as mediators. For instance, the "arginine, ornithine, and proline interconversion" pathway was implicated in reducing the risk of GERD via "PDL-1 on CD14- CD16+ monocyte" cells, with a total effect of -0.0484 and a mediation effect of -0.0093. Sensitivity analyses provided additional validation for the reliability of the MR findings.Conclusion: Our study contributes evidence to the close causal relationship between the GM and GERD, emphasizing the possible role of immune cells as mediators. Future research should focus on developing microbiome-oriented therapeutic approaches for managing GERD.