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

Nine microbial taxa/metabolic pathways and 18 immune traits exhibited putative causal associations with male infertility.

• Analysis used 412 gut microbial taxa/metabolic pathways and 731 immune cell phenotypes as exposures.
• Male infertility GWAS data comprised 1429 cases and 128,710 controls from FinnGen R10.
• Only exposure-mediator-outcome pairs meeting stringent pleiotropy, heterogeneity, and reverse-causality criteria were retained.
• European-ancestry genome-wide association studies were used as the data source.

The L-glutamate degradation V pathway via hydroxyglutarate was linked to reduced male infertility risk.

• Inverse-variance weighting odds ratio = 0.68 (95% CI, 0.52–0.89; P = .005).
• Bayesian weighted Mendelian randomization was used as a robustness check.
• The association survived stringent pleiotropy and heterogeneity filtering criteria.
• This pathway represents a specific microbial metabolic route connecting gut activity to reproductive outcomes.

Forward scatter area on plasmacytoid dendritic cells (pDCs) may mediate the association between L-glutamate catabolism and male infertility.

• Two-step Mendelian randomization was used to assess mediation.
• The mediation effect estimate was 0.0277 (95% CI, -0.0348 to 0.0903), indicating an imprecise effect.
• The confidence interval crossed zero, indicating the mediation finding was not statistically significant.
• Forward scatter area on pDCs was the specific immune trait identified as a potential mediator.

A 2-sample, 2-step Mendelian randomization framework was employed to investigate causal and mediation relationships between gut microbiota, immune traits, and male infertility.

• Inverse-variance weighting was used as the primary estimator.
• Bayesian weighted Mendelian randomization was applied for robustness.
• The study analyzed 412 gut microbial taxa/metabolic pathways and 731 immune cell phenotypes.
• Analyses were restricted to European-ancestry GWAS data to minimize population stratification.

The study highlights immunometabolic pathways, specifically pDC-driven glutamate catabolism, as testable targets for mechanistic validation and microbiota-directed interventions in male infertility.

• Findings are described as 'suggestive genetic evidence' rather than definitive causal proof.
• The authors propose these pathways as candidates for future mechanistic studies.
• Microbiota-directed interventions are suggested as a potential therapeutic avenue.
• The immunometabolic link involves pDCs connecting gut microbial metabolic activity to reproductive health.