Causal association between 473 types of gut microbiota and neonatal bacterial sepsis: a bidirectional two-sample Mendelian randomization study

Abstract

Background: Neonatal bacterial sepsis represents a major health threat to newborns, leading to high mortality rates globally. However, the correlation between the gut microbiome and bacterial sepsis in neonates remains unclear.

Methods: This study utilized publicly available Genome-Wide Association Study data on 473 gut microbiota taxa as exposures. Instrumental variables were rigorously selected, and bidirectional two-sample Mendelian randomization (MR) analyses were performed. The MR and reverse MR analyses results were validated using Bayesian weighted MR (BWMR) analysis. Positive results from MR analysis will be validated through heterogeneity testing, evaluation of horizontal pleiotropy, and univariate sensitivity analysis.

Results: The findings revealed a significant genetic causal association between 18 gut microbial species and neonatal bacterial sepsis, including Acetobacterales (odds ratio [OR]: 159.844; p = 0.04), Campylobacter D (OR: 16.225; p = 0.029), and Firmicutes A (OR: 75.643; p = 0.025). Additionally, both MR and inverse MR analyses confirmed the absence of reverse causation (p < 1e-5), supporting the robustness of the findings (p < 0.05) across five statistical methods. Sensitivity analyses indicated high reliability without significant heterogeneity or pleiotropy (p > 0.05). Furthermore, BWMR analysis highlighted the complex roles of probiotic taxa, including Bacteroides A plebeius (OR: 0.526) and pathogenic bacteria, such as Acetobacterales (OR: 192.449), in neonatal sepsis.

Conclusions: A causal genetic association exists between gut microbiota and bacterial sepsis in neonates. These results underscore the potential of gut microbiota as biomarkers and therapeutic targets for the prevention and management of neonatal bacterial sepsis.