Deciphering the gut microbiota's role in infection risk: Mendelian randomization analysis of microbial taxa and infectious outcomes

Abstract

Background Observational studies have linked the gut microbiota (GM) to infectious diseases, but confounding, reverse causation, and disease-related microbiome changes limit causal interpretation. We combined Mendelian randomization (MR) with focused experimental analyses to investigate microbiota–infection relationships. Methods Two-sample MR evaluated genetically predicted microbial taxa across 75 infectious outcomes. Inverse-variance weighted (IVW) estimates were used as the primary analysis, with weighted-median and MR-Egger estimates as complementary methods. Benjamini–Hochberg false discovery rate (FDR) and Bonferroni corrections were applied across all IVW tests. Instrument strength, Cochran's Q, MR-Egger intercepts, leave-one-out analysis, MR-PRESSO, and Steiger directionality testing were used to assess robustness. Exploratory association patterns were used to prioritize a Coriobacteriia-related respiratory signal for experimental investigation using Collinsella aerofaciens cell-free supernatant and A549 epithelial cells. Results Among 15,728 IVW tests, 659 associations had nominal P < 0.05. After global correction, three taxonomically related associations with urinary tract infection (UTI) remained significant. Higher genetically predicted abundance of genus Bifidobacterium was associated with lower UTI risk (odds ratio [OR] 0.29, 95% confidence interval [CI] 0.17–0.49; FDR-adjusted P = 0.029), while order Bifidobacteriales and family Bifidobacteriaceae showed similar estimates (both OR 0.25, 95% CI 0.14–0.45) and met the Bonferroni threshold. Sensitivity analyses showed no significant heterogeneity or MR-PRESSO-detected outliers, and leave-one-out and Steiger analyses were supportive, although MR-Egger intercepts suggested possible directional pleiotropy. Exploratory analyses identified clustering between Coriobacteriia-lineage taxa and respiratory outcomes. C. aerofaciens cell-free supernatant altered 993 genes and enriched inflammatory pathways in A549 cells. qPCR supported increased CSF2, CXCL8, and CCL20 expression, while ELISA detected IL-8 and MIP-3α but not quantifiable GM-CSF. Untargeted metabolomics identified 201 differential metabolites between bacterial supernatant samples and matched BHI controls. Conclusion The corrected Bifidobacterium-related UTI association was the principal MR finding, while the broader analysis identified exploratory microbiota–infection patterns. The C. aerofaciens model linked extracellular metabolic remodeling during bacterial growth with epithelial transcriptional and inflammatory responses, providing focused directions for further investigation.