Association between gut microbiota and male infertility: a two-sample Mendelian randomization study

Abstract

Abstract Purpose: Previous research has confirmed the significant association between gut microbiota (GM) and male infertility (MI), but the causality between them remains unclear. This study aims to investigate the causal relationship between GM and MI using Mendelian randomization (MR) and provide supplementary information for the optimization of future randomized controlled trials (RCTs). Materials and Methods: Instrumental variables for 211 GM taxa were obtained from genome-wide association studies (GWAS), and inverse variance weighted (IVW) method was used as the main analysis method for two-sample MR analysis to assess the impact of GM on the risk of MI using FinnGen GWAS data (1,128 cases and 110,070 controls). Four methods were used to test for horizontal pleiotropy and heterogeneity of MR results to ensure the reliability of the MR findings. Results: A total of 50 single nucleotide polymorphisms (SNPs) closely related to GM were included, and we found that family-Bacteroidaceae was significantly associated with MI (odds ratio [OR] = 0.54, 95% confidence interval [CI]: 0.31–0.96, P = 0.035). Furthermore, we used four MR methods to evaluate the causality, and the results supported these findings. The leave-one-out analysis showed stable results with no instrumental variables exerting strong influence on the results. The causal direction indicated a positive effect, and the effects of heterogeneity and horizontal pleiotropy on the estimation of causal effect were minimized. Conclusions: We confirmed a causal relationship between GM taxa and MI, providing new insights into the mechanisms underlying GM-mediated MI. Further comprehensive and larger sample studies are needed to explore the relationship between GM and MI for identification of novel biomarkers and targeted prevention strategies for MI in future research.