Plasmacytoid dendritic cell-mediated L-glutamate catabolism links gut microbiota to male infertility.

Emerging evidence suggests that gut microbiota composition influences male reproductive health; however, the immunometabolic mechanisms underlying this association remain insufficiently characterized. We investigated whether specific immune cell-mediated metabolic pathways, particularly plasmacytoid dendritic cell (pDC)-driven L-glutamate catabolism via the hydroxyglutarate pathway, contribute to the causal link between gut microbiota and male infertility. We conducted a 2-sample, 2-step Mendelian randomization (MR) analysis using inverse-variance weighting as the primary estimator and Bayesian weighted MR for robustness. Exposure data comprised 412 gut microbial taxa/metabolic pathways and 731 immune cell phenotypes from large European-ancestry genome-wide association studies. Male infertility genome-wide association studies data (1429 cases; 128,710 controls) were obtained from FinnGen R10. Only exposure-mediator-outcome pairs meeting stringent pleiotropy, heterogeneity, and reverse-causality criteria were retained for mediation analysis. Nine microbial taxa/metabolic pathways and 18 immune traits exhibited putative causal associations with male infertility. The L-glutamate degradation V pathway via hydroxyglutarate was linked to reduced infertility risk (inverse-variance weighting odds ratio [OR] = 0.68; 95% confidence interval, 0.52-0.89; P = .005). Two-step MR suggested that forward scatter area on pDCs may mediate this association, although the mediation effect was imprecise (effect = 0.0277; 95% confidence interval, -0.0348 to 0.0903). This study provides suggestive genetic evidence that pDC-mediated glutamate catabolism may connect gut microbial metabolic activity to male infertility. These findings highlight immunometabolic pathways as testable targets for mechanistic validation and microbiota-directed interventions.