Erectile dysfunction (ED) is a common male condition characterized by the inability of the penis to achieve or maintain a sufficient erection for satisfactory sexual activity, lasting for at least 3 months (Salonia et al., 2021). ED significantly affects the physical and mental well-being of patients, creating immense pressure on family harmony and stability (Wang et al., 2023). Research indicates that ED is associated with various complications and related risk factors such as aging, smoking, obesity, cardiovascular diseases, and depression (Zeleke et al., 2021; Castela and Costa, 2016; Liu et al., 2018). Currently, phosphodiesterase type 5 inhibitors are the first-line treatment for ED, but the results are not satisfactory (Kang et al., 2023). With the development of technology, emerging targeted technologies such as stem cell therapy, protein therapy and low-intensity extracorporeal shockwave therapy (Li-ESWT), as well as intestinal probiotic therapies, are being utilized for the treatment of ED. However, emerging treatments are still in their infancy, and their pharmacological pathways and specific mechanisms have not yet been fully discovered (Kang et al., 2023; Chung et al., 2023).

Gut microbiota is a collective of a large number of bacteria that exist in the human gut. There are over 1,000 species of microbiota in the intestines of adults, with a total count exceeding 3.8 × 10¹³, roughly equivalent to the number of human cells (Sender et al., 2016). The gut microbiota exerts various effects on the host, including nutrient metabolism, immune regulation, and tumorigenesis (Durack and Lynch, 2019). Studies have also indicated that the gut microbiota can affect male fertility through mediating inflammation, substance metabolism, and psychological factors (Gorman and Golovanov, 2022; Zhang et al., 2022; Bear et al., 2021). In a cross-sectional study in Japan, a total of 192 male participants were enrolled and divided into two groups based on the International Index of Erectile Function (IIEF-5), and fecal 16S rRNA gene sequencing was performed on both groups. The result showed that the relative abundance of Alistipes and Clostoridium XVIII was significantly different between the two groups. Multivariate logistic analysis demonstrated that the relative abundance of Clostridium XVIII (OR, 2.06; 95% CI, 1.20–3.55, p = 0.009) and Alistipes (OR, 0.81; 95% CI, 0.66–0.99, p = 0.040), as well as the IPSS ≥8, were independent factors for low IIEF-5 (Okamoto et al., 2020). In another study, male mice that routinely consumed purified Lactobacillus initially isolated from human milk had enlarged testes and elevated serum testosterone levels. Mice with Lactobacillus neutrophils added to their drinking water showed a significant increase in the cross-sectional profile of the seminiferous tubules, spermatogenesis, and the number of Leydig cells per testis (Poutahidis et al., 2014). The current observational study found a strong relationship between ED and gut microbes, however, due to confounding factors and reverse causation, previous studies have not determined the exact causal relationship.

Mendelian randomization (MR) analysis MR utilized genetic variants significantly associated with exposure as instrumental variables (IVs) to infer causal relationships between exposure and outcome. The genotype corresponding to an individual’s IV locus reflects the level of exposure, while the parental allele is randomly assigned to the offspring during the deceleration period; thus, the MR approach, also known as a “natural randomized controlled trial,” avoids confounding bias and reverse causation, which are common in observational studies (Bowden and Holmes, 2019). Currently, The MR study by professor Fu found Desulfovibrionales and nine other bacteria to be associated with CKD, thus confirming that the gut microbiota plays an important role in the pathogenesis of CKD (Luo et al., 2023), while the study by Luo professor found a causal relationship between nine gut microbial taxa and cholelithiasis (Li et al., 2023). In our study, we initially explored the causal relationship between gut microbiota and ED through MR analysis.

ED is very common in adult men and increases with age. As society ages, the prevalence of ED is on the rise. It is estimated that there are nearly 150 million ED patients worldwide, and this number may reach 350 million in the near future (Burnett et al., 2018). The cause of ED is unclear and may be due to organic (vascular, neurogenic, hormonal, etc.) factors, psychosomatic or mixed causes (Bovijn et al., 2019). In this study, we investigated the causal relationship between gut microbiota and male ED using MR analysis. Our findings revealed a positive causal association between the genus Lachnospiraceae NC2004 group, genus Oscillibacte, genus Tyzzerella3, and the family Lachnospiraceae, and male ED. On the other hand, we observed a negative causal relationship between the genus Ruminococcaceae UCG013 and ED. These results suggest that different gut microbial communities may have different effects on male ED. This research provides the first conclusive evidence of a causal relationship between gut microbiota and ED, and provides a new direction for future interventions targeting the gut microbiota in the treatment of ED.

The gut microbiota includes commensal, opportunistic and pathogenic bacteria in the human gastrointestinal tract. The gut microbiota contains more than 100 times the amount of genes as the human genome, and has therefore been referred to as the “second genome” and “eighth organ” of the human body (Baquero and Nombela, 2012). The gut microbiota plays a crucial role in human health and diseases. It has been found that gut microbiota and its metabolites, such as short-chain fatty acids and amino acids, can affect glucose and lipid metabolism through a variety of pathways, which in turn can affect the function of penile vascular endothelial cells (Wu et al., 2021; Mitidieri et al., 2020). Some studies have also found that gut microbiota imbalance will affect the content of NO, Lactobacillus and Bifidobacterium were the most efficient NO-producing strains, whereas Escherichia coli and Bacteroides polymorphicus may deplete NO (Sobko et al., 2006; Vermeiren et al., 2009). NO, in turn, had an important impact on the brain’s libido, the blood supply to the testes, and the release of sex hormones. This suggested that gut microbiota can affect erectile function in men through a variety of ways. Our results suggest that modulation of the gut microbiota may be a potential approach to treat or improve ED, and that gut microbial markers may also have the potential to predict the development of ED and serve as effective indicators for ED prevention. In the future, the gut flora of ED patients can be effectively improved in various ways, such as gut flora transplantation, to restore the patient’s intestinal microcosm, which in turn can have a therapeutic effect.

Lachnospiraceae is one of the core gut microbiota, which exists in the gut of most healthy individuals and is involved in the metabolism of various carbohydrates, producing acetate and butyrate through fermentation to provide energy to the host (Stackebrandt, 2014). However, controversy still exists regarding whether Lacinospora is a beneficial or harmful microorganism, possibly due to the different roles played by its various components at different stages and environments (Vacca et al., 2020). In the Canadian Healthy Infant Longitudinal Development (CHILD) study, a decrease in the relative abundance of Lachnospiraceae at 3 months of age was found to be associated with asthma. Moreover, the ratio of Lachnospira/Clostridium was identified as a potential biomarker for predicting asthma development (Stiemsma et al., 2016). Another study discovered that Lachnospira multipara and Eubacterium eligens consistently decreased throughout the progression from early to advanced stages of colon cancer (Zhang et al., 2023). Research by Shen et al. (2017) revealed a significant increase in the abundance of Lachnospiraceae in populations with non-alcoholic liver cirrhosis and severe liver fibrosis. Other studies also found a positive relationship (p < 0.05) between Lachnospiraceae and severe major depressive disorder (MDD) (Vacca et al., 2020). Similarly, our study identified a positive causal relationship (OR = 1.264, p < 0.05) between Lachnospiraceae and ED. Subgroups within Lachnospiraceae, namely genus Lachnospiraceae NC2004 group and genus Tyzzerella3 also showed positive causal relationships with ED, with OR of 1.189 and 1.213, respectively. These findings suggest that Lachnospiraceae may play a crucial role in male ED, but the specific mechanisms need to be further investigated.

Ruminococcaceae is also one of the cornerstone bacteria in the gut, playing a significant role in metabolism and normal physiological activities. A meta-analysis revealed a significant decrease in the abundance of Ruminococcaceae in populations with cognitive impairments and Alzheimer’s disease (Chen et al., 2023). Another meta-analysis similarly found a significant decrease in the abundance of Ruminococcus ruminococcus in a bipolar disorder population (Nguyen et al., 2021). Feng et al. (2022) found that Ruminococcaceae_UCG-013 was positively correlated with serum HDL cholesterol levels and negatively correlated with serum total cholesterol, total cholesterol, and LDL cholesterol levels. In our study, we found a negative causal relationship between Ruminococcaceae_UCG-013 and ED (OR = 0.761, 95% CI 0.626–0.926). This suggests that Ruminococcaceae_UCG-013 may affect erectile through lipid metabolism pathway.

However, our study also has several limitations. Firstly, all the GWAS data involved in our research were obtained from European populations. Therefore, further validation is needed to assess the applicability of our research findings to other racial and ethnic groups. Secondly, the sample size in our study was relatively small, which may introduce biases and chance effects, and therefore needs to be validated by larger population-based GWAS studies. Finally, when selecting SNPs for exposure factor, we used a more relaxed threshold (p < 1 × 10⁻⁵) than the traditional threshold (p < 5 × 10^–8). This may have led to the inclusion of SNPs with weaker correlations. However, we found that each instrumental variable was greater than 10 through F-test.

We comprehensively assessed the causal relationship between gut microbiota and ED in men. Our findings indicated that four gut microbiota were positively causally associated with ED and one gut microbiota was negatively causally associated with ED. Our study provides new insights into the involvement of gut microbiota in the occurrence and development of ED.