Abstract
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. We assessed genome-wide association study summary statistics for gut microbiota and male fertility to perform MR analysis. Independent single nucleotide polymorphisms closely associated with 211 gut bacterial taxa (N = 122,110) were identified as instrumental variables. The summary statistic data for male infertility (N = 733,479), abnormal spermatozoa (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. Combining the results from the discovery and replication stages, we identified 3 causal bacterial genus. Ruminiclostridm6 (OR = 0.537, 95%CI = 0.292-0.987, P = .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 = .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 = .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. 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.