Gut microbiota and male fertility: a two-sample Mendelian randomization study

Abstract Background Previous studies have reported that alterations in gut microbiota composition are associated with male fertility. However, it is unclear and difficult to establish whether these associations reflect a causal relationship. Objective To reveal the causal association between gut microbiota and male fertility, we conducted a two-sample Mendelian randomization (MR) analysis. Materials and Methods We assessed genome-wide association study (GWAS) summary statistics for gut microbiota and male fertility to perform MR analysis. Independent single nucleotide polymorphisms closely associated with 211 gut bacterial taxa (N = 122110) were identified as instrumental variables. The summary statistic data for male infertility (N = 733,479), abnormal spermatoz (N = 209,921) and erectile dysfunction (N = 223,805) were obtained from the latest release from the FinnGen consortium as the outcome of interest. Two-sample MR was performed to evaluate the causal effect of gut microbiota on male fertility, including inverse-variance-weighted (IVW) method, weighted median method, MR-Egger, mode-based estimation and MR-PRESSO. A series of sensitivity analyses was performed to validate the robustness of the results. The robustness of the estimation was tested by a series of sensitivity analyses including Cochran’s Q test, MR-Egger intercept analysis, leave-one-out analysis and funnel plot were used to assess the causal association. Results Combining the results from the discovery and replication stages, we identified three causal bacterial genus. Ruminiclostridm6 (OR = 0.537, 95%CI = 0.292-0.987, P = 0.045, PFDR = 0.234) was found to be closely associated with male infertility, and the decrease in its quantity increased the risk of male infertility. Decreased Prevotella9 (OR = 0.670, 95%CI = 0.452-0.992, P = 0.046, PFDR = 0.175) was found to be closely related to abnormal sperm. Lachnospiraceae NC2004 group (OR = 1.173, 95%CI = 1.008-1.366, P = 0.078, PFDR = 0.530) was found to be closely related to male erectile dysfunction, and there was a positive correlation between them. No heterogeneity and pleiotropy were detected. Conclusion This study implied a causal relationship between the Ruminiclostridm6 genus, Prevotella9 genus, Lachnospiraceae NC2004 group genus and male fertility, thus providing novel insights into the gut microbiota-mediated development mechanism of ADs. Nevertheless, future studies are warranted to dissect the underlying mechanisms of specific bacterial taxa’s role in the pathophysiology of male fertility.