The host genes influencing infection and the potential role of intestinal Lactobacillus acidophilus: a Mendelian randomization and animal model study.

Introduction: infection (CDI) poses a significant clinical burden due to its high recurrence rate and life-threatening complications. While gut dysbiosis is central to CDI pathogenesis, mechanisms underlying microbiota-mediated host defense remain underexplored.

Methods: This study integrated summary-data-based Mendelian randomization (SMR) of cis-expression quantitative trait loci (cis-eQTLs) from blood, transverse colon, and sigmoid colon tissues with CDI genome-wide association study (GWAS) data to identify host genes influencing CDI susceptibility. Bayesian co-localization was employed to validate relationships. Then a germ-free (GF) mice model colonized with (LA) was used to investigate LA-mediated regulation of possible gene expression and phenotypic changes in the host.

Results: SMR analysis identified 14 genes associated with CDI risk, primarily clustered in the major histocompatibility complex (MHC) region. Notably, THOC5 exhibited robust associations (P < 0.05 in all tissues) and co-localization evidence (posterior probability = 82.6%). In GF mice, LA colonization significantly upregulated colonic expression in two independent experiments (fold change = 5.19/5.00, P = 0.034/0.031). Subsequent immunofluorescence experiments revealed that LA colonisation enhanced macrophage activation in the colonic tissue.

Discussion: These findings reveal key host genes, particularly THOC5, that influence susceptibility to CDI, providing new targets for future prevention and treatment research. Additionally, the study suggests a potential mechanism by which host intestinal LA protects against CDI, highlighting the interaction between probiotics and host transcriptional networks in CDI resistance. These insights offer valuable directions for further investigation.