Benign prostatic hyperplasia (BPH) is a common disease affecting middle-aged and elderly men; the clinical symptoms include frequent urination, urgent urination, and increased nocturia (Berry et al., 1984). The incidence of BPH gradually increases with age. The clinical prevalence of BPH in men aged >50 years is 50–75%, which increases with age. The prevalence of BPH in men aged > 70 years is >80% (Wang et al., 2020). The disease course seriously affects the quality of life of middle-aged and elderly men. Many studies have been conducted on the pathogenesis of BPH; however, its etiology has not yet been clarified. Currently, the accepted risk factors for the pathogenesis of BPH include functional testis and aging (Braeckman and Denis, 2017). Additionally, there are other theories, such as the role of androgen and its receptors (Carson and Rittmaster, 2003), imbalance between cell proliferation and apoptosis (Rho et al., 2019; Yuan et al., 2020), role of growth factor neurotransmitters (La Vignera et al., 2016), prostate interstitial glandular epithelial interaction (Timme et al., 1995), and inflammatory factors (Kohnen and Drach, 1979). Smoking, obesity, alcoholism, family history, race, and geographical environment are also associated with BPH occurrence (Bushman, 2009; Vuichoud and Loughlin, 2015). In recent years, many studies have shown that changes in the gut microbiota (GM) are of great significance for the diagnosis, prevention, and treatment of BPH (An et al., 2023; Russo et al., 2023).

The GM comprises a genome of microbiota that inhabits the gastrointestinal tract and works symbiotically with the host to maintain health (Connelly et al., 2019). According to recent publications, the human GM contains trillions of microorganisms, including bacteria, fungi, protists, archaea, and viruses (Yatsunenko et al., 2012). The human GM is viewed across age and geography. The composition of each individual’s GM is influenced by several factors, including age, diet, lifestyle, and drug intake (Yatsunenko et al., 2012; Goodrich et al., 2014). The GM has become a research hotspot in recent years. There have been many reports on the relationship between GM and various diseases, confirming that GM plays an important role in the occurrence and progression of diseases. The relationship between GM dysbiosis and several diseases has been established; some examples include periodontal disease, cancer, obesity, diabetes, and chronic fatigue syndrome (Ditto et al., 2021). However, a growing number of studies have shown that differences between healthy and bio-imbalanced microbiota may be associated with prostate diseases, such as chronic prostatitis, BPH, prostate cancer, and other prostate diseases (Fernandes et al., 2022). Tsai et al. observed significant differences in the microbial composition of urine samples between patients with BPH and healthy controls (Tsai et al., 2022). Li et al. used intestinal samples from BPH rats and healthy control rats, and the GM composition was analyzed using 16S rDNA sequencing and liquid chromatography-tandem mass spectrometry. BPH may affect the GM and gut metabolites in a variety of ways, including changing the proportion of GM through the nervous and psychological systems. This regulates the body’s metabolism and hormone synthesis and mediates the inflammatory response of the host and immune system to regulate the changes in GM. Consequently, GM and gut metabolites are affected (Li et al., 2022). BPH can cause complications such as prostatitis, renal damage, and metabolic syndrome, which are associated with GM (Tang et al., 2015; Bishehsari et al., 2020; Liu et al., 2021). In the present study, we explored the relationship between GM and BPH.

Currently, a few high-quality randomized controlled trials (RCTs) have investigated the relationship between the GM and BPH. Furthermore, observational studies cannot completely eliminate the influence of confounding factors and are susceptible to recall bias and reverse causation. Mendelian randomization (MR) is a contemporary method for examining the correlation between GM and BPH. MR employs instrumental variables (IVs), in which genetic variants serve as instruments. During pregnancy, alleles are randomly assigned, a process akin to the randomization of treatment and control groups in RCTs (Li et al., 2023), and common confounding factors have no impact on the correlation between genetic variations and outcomes (Davey and Hemani, 2014). To date, MR has been extensively employed for assessing potential causal links between exposure and disease, as mentioned in reference (Shu et al., 2019). In this research, we conducted a two-sample MR analysis to evaluate the potential connection between GM and BPH. Summary statistics from genome-wide association study (GWAS) conducted by the MiBioGen and FinnGen consortiums were utilized for this purpose.

In recent years, the human GM has been extensively studied. GM evolved with the evolution of the host, and the flora obtained at birth developed with the development of the host (Adak and Khan, 2019). GM dynamically colonizes the intestinal mucous layer of the human body. The total number of GM is approximately 10 times that of human cells, and the total number of genomes is approximately 150 times that of human genes. It is often called the “virtual organ” of the human body (Mu et al., 2017) and the “second genome” that affects human health. There is a two-way interaction between the host and GM, which is affected by the diversity and abundance of GM, and it has a certain effect on the health of the host body (Dominguez-Bello et al., 2010). It plays important roles in the regulation of digestion, nutrient absorption, energy metabolism, fat metabolism, and immunity (Farre et al., 2020). Studies have shown that an imbalance in GM is related to cardiovascular (Wang and Zhao, 2018), neurological (Socala et al., 2021), respiratory (Chunxi et al., 2020) and metabolic (Fan and Pedersen, 2021) diseases, malignant tumors (Long et al., 2023), and other diseases (Gomaa, 2020).

BPH may affect GM and gut metabolites in many ways. BPH can cause complications such as prostatitis, renal damage, and metabolic syndrome, which have been found to be associated with GM (Li et al., 2022). To date, the effect of GM on the occurrence and development of BPH is unclear, and there are few related studies. Jinho et al. found that changes in the GM induced by BPH and finasteride treatment were closely related to the regulation of prostate morphology, hormones, and prostate cell apoptosis. Therefore, intestinal microorganisms can be used as indicators and therapeutic measures (An et al., 2023).

In our study, a two-sample MR analysis was conducted to investigate the potential causal relationship between GM and BPH. This study marks an initial extensive MR study into the causal association between GM and BPH at the gene prediction level, employing a significant volume of GWAS data. The findings of this study may provide valuable insights for future management of BPH by highlighting the relevance of GM to the condition. Specifically, this study found that Eisenbergiella and Ruminococcaceae (UCG009) exhibited protective effects against BPH, whereas Escherichia shigella showed the opposite effects.

Eisenbergiella is a proposed genus of Spirillaceae, which includes Eisenbergiella tayi, an anaerobic bacterium. Butyric acid is the primary fermentation end product and energy source of colonic cells (Jousimies-Somer, 2002) and is involved in the maintenance of colonic mucosal health (Amir et al., 2014). Although the biological function information of this genus is very limited, Eisenbergiella belongs to Lachnospiraceae. Studies have shown that an increase in Lachnospiraceae may be related to the occurrence of metabolic diseases, such as diabetes (Kameyama and Itoh, 2014). However, few studies have examined the relationship between Eisenbergiella and BPH. Escherichia shigella is a conditional pathogen. Its DNA is closely related to that of Escherichia coli and can cause acute gastrointestinal infections. It is one of the most important pathogenic bacteria in the human body and is balanced with other bacteria in the intestinal tract. Escherichia shigella has two important roles in the human body: first, it plays an important role in inducing intestinal inflammation; second, in an inflammatory environment, it can gain a stronger survival advantage by secreting enterosin and aggravating the disorder of intestinal microecology (Singh et al., 2015). Lee et al. recruited 77 BPH patients and 30 controls who had not recently taken antibiotics. They found that there was a significant difference in the abundance of Escherichia shigella between the BPH and control groups (Lee et al., 2021). Ruminococcaceae (UCG009) is an anti-inflammatory bacterium found in the cecum and colon. As one of the producers of short-chain fatty acids, it is responsible for the degradation of various indigestible polysaccharides and fibers (Hooda et al., 2012; Donaldson et al., 2016). However, there are limited studies on the effects of Ruminococcaceae (UCG009) on BPH.

This study had several strengths. In this research, MR analysis was conducted to explore the causal link between GM and BPH in humans, eliminating the influence of confounding variables. The GM summary statistics were sourced from the most extensive GWAS meta-analysis conducted by the MiBioGen consortium, while the BPH summary statistics came from the FinnGen consortium’s R8 release data. This provided robustness to the instruments and incorporated the most up-to-date information in the MR analysis. The MR-PRESSO and MR-Egger regression intercept-term tests were employed to identify and rule out horizontal pleiotropy. Furthermore, cML-MA was used to exclude bias from both linked and independent pleiotropies. Non-overlapping exposure and result summary-level data were employed in this MR study to prevent bias.

Nonetheless, the interpretation of the study’s outcomes must take several limitations into account. First, we could not study the non-linear correlations because the analysis was conducted on aggregated numbers instead of raw data. Second, the GWAS analysis of GM did not confined only to male subjects. Although this analysis considers sex differences and ignores any genetic variation in male and female chromosomes, it cannot avoid any potential bias caused by sex (Verbanck et al., 2018). Third, our study was limited to European patients; therefore, the exclusive focus on European patients raises questions regarding the applicability of the findings to non-European populations, due to inherent genetic distinctions among ethnic groups. Finally, because only generic-level exposure data were available, it was impossible to further explore the connection between GM and BPH at the species level.

The outcomes of this two-sample MR study indicate that Eisenbergiella and Ruminococcaceae (UCG009) may confer protective effects against BPH, whereas Escherichia shigella may have a positive relationship with the risk of BPH. Further research is needed to obtain a more comprehensive understanding of the possible beneficial or harmful impacts of these GM on BPH and the mechanisms behind them. Although there is a dearth of evidence demonstrating the impact of BPH on GM, it is possible that an effect may exist, this possibility calls for more research to ascertain the truth.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

Ethical approval was not provided for this study on human participants because this research has been conducted using published studies and consortia providing publicly available summary statistics. All original studies have been approved by the corresponding ethical review board. In addition, no individual-level data was used in this study. Therefore, no new ethical review board approval was required.

Conception and design: DX, JW, and XZ. Data collection and assembly: DX, JW, XZ, TS, and LL. Data analysis and interpretation: DX, JW, XZ, TS, and LL. Manuscript writing: DX. Final approval of the manuscript: All authors. DX and JW are the co-first authors who made equal contributions to this study. All authors contributed to the article and approved the submitted version.