Causal association between gastroesophageal reflux disease and sepsis, and the mediating role of gut bacterial abundance, a Mendelian randomization study

Gastroesophageal reflux disease (GERD), akin to sepsis, is mediated by inflammatory reactions and exhibits a strong correlation with intestinal dysbiosis. We sought to examine whether these associations reflect causality using the Mendelian randomization (MR) mediation analysis. Genetic data were obtained from genome-wide association studies. Two-sample MR were performed to evaluate the causal association, accompanied by sensitivity analyses. Reverse direction MR was undertaken to assess the potential for reverse causation. Then, mediation analysis was performed to evaluate the mediating effect of gut bacterial pathway abundance in this relationship. Genetic predisposition to GERD was significantly associated with sepsis [inverse variance weighting: odds ratio = 1.366, P = 2.13E-09, 95% confidence interval [CI] 1.233-1.513] and sepsis-related 28-day mortality (inverse variance weighting: odds ratio = 1.412, P = 6.64E-03, 95% CI 1.101-1.812). There is no convincing evidence for reverse causation. Gut bacterial pathway abundance (ARO.PWY..chorismate.biosynthesis.I) mediates the effect of GERD on sepsis (β = 0.036, 95% CI 0.004-0.067, P = .025), accounting for 11.406% of the total effect; Gut bacterial pathway abundance (PWY.7219..adenosine.ribonucleotides.de.novo.biosynthesis) mediates the effect of GERD on sepsis (β = 0.026, 95% CI -0.003 to 0.056, P = .083), accounting for 8.486% of the total effect; gut bacterial pathway abundance (ARO.PWY..chorismate.biosynthesis.I) mediates the effect of GERD on sepsis (28-day death) (β = 0.079, 95% CI 0.005-0.153, P = .036), accounting for 22.890% of the total effect; gut bacterial pathway abundance (TRNA.CHARGING.PWY..tRNA.charging) mediates the effect of GERD on sepsis (28-day death) (β = -0.066, 95% CI -0.140 to 0.007, P = .078), accounting for -19.171% of the total effect. The present MR study supported GERD as a causal risk factor of sepsis and sepsis-related 28-day mortality. Three specific gut bacterial pathway abundances were identified that played a partial mediating role in the aforementioned causal relationship between GERD and sepsis.