Large-scale mediator Mendelian randomization analysis identifies multiple immune cells mediating the causal link between gut microbes and chronic graft-versus-host disease risk.

Disorders of gut microbiota and immune cells have been observed to be involved in the occurrence of chronic graft-versus-host disease (cGVHD), but their causal connections have yet to be fully understood. This study utilized Mendelian randomization (MR), integrating genome-wide association study (GWAS) meta-analyses from the MiBioGen consortium (microbial taxa), the SardiNIA project (immune traits), and disease data from the Fred Hutchinson Cancer Research Center (FHCRC) cohort to investigate their relationships. The aim was to explore the causal effects of microbiota and immune traits on the incidence of cGVHD, using mediation analysis to identify which immune traits might mediate the effects of microbiota on this condition. The main analysis observed significant causal associations of 3 specific microbial taxa with cGVHD: Lactococcus.id.1851 (odds ratio [OR] = 1.989, 95% confidence interval [CI] = 1.311-3.019, p = 0.001), Ruminiclostridium9.id.11357 (OR = 3.273, 95% CI = 1.604-6.679, p = 0.001), and Intestinimonas.id.2062 (OR = 0.400, 95% CI = 0.230-0.697, p = 0.001). Sensitivity analysis and multivariable MR analysis ruled out possible horizontal pleiotropy and bias. Additionally, 10 immune traits, predominantly covering regulatory T cells (Tregs) and B cells, were identified as influencing cGVHD risk. The two-step mediation MR analysis presented the effect of identified microbial taxa on Tregs and B cells and detailed the pathways through which Intestinimonas impacts cGVHD via CD27 on memory B cells (proportion mediated = 4.2%). Similarly, the role of interactions between Ruminiclostridium9 and effector memory double-negative T cells in mediating cGVHD was quantified, accounting for 9.5% of the total effect.