A Mendelian randomization study between air pollutants and benign prostatic hyperplasia

Abstract

An increasing number of studies have investigated the relationship between air pollution and human health, yielding significant findings. However, few studies have explored the relationship between air pollution and prostate health. Mendelian randomization was employed to evaluate the causal relationships between 5 major air pollutants and benign prostatic hyperplasia. Univariate Mendelian randomization (UVMR) was used to test the primary causal relationships, whereas multivariate Mendelian randomization (MVMR) was applied to construct risk-adjusted models, enhancing the robustness of the causal inference. Finally, we further assessed the potential mediating role of the gut microbiome in the relationships identified. We found a significant positive causal association between NO₂ and benign prostatic hyperplasia (OR = 2.39, 95% CI = 1.17–4.91, P = .01). The results of the MVMR analysis are consistent with UVMR (OR = 2.01, 95% CI = 1.05–3.85, P = .03). Additionally, we identified significant positive associations between several gut microbial species and benign prostatic hyperplasia. However, further mediated Mendelian randomization analyses did not reveal a mediating effect in the causal relationship between NO₂ and benign prostatic hyperplasia. Mendelian randomization analysis showed that there is a genetic causal relationship between air pollution and benign prostatic hyperplasia, and high exposure to NO₂ will increase the risk of benign prostatic hyperplasia.

1. Introduction

Air pollution refers to the presence of harmful substances in the atmosphere that exceed the self-purification capacity of the environment, adversely affecting human health and the ecological environment and its main air pollutants include particulate matter (PM) and nitrogen oxides (NOx).^[1] According to the Global Burden of Disease Report, in 2019, air pollution is ranked as the fourth leading risk factor for premature death globally, after unhealthy diet, smoking and hypertension.^[2] Severe air pollution already places a huge economic burden on public health systems. Globally, a growing body of research evidence suggests a risk relationship between air pollution and a variety of diseases, particularly affecting cardiovascular, respiratory and neurological health.^[3,4] Although research on air pollution has gained increasing attention over the past few decades, this progress has been driven primarily by technological advancements in developed countries.^[5] Moreover, research on the effects of air pollution has focused on some specific body systems, and the effects on other systems have not been fully explored.^[6] Benign prostatic hyperplasia (BPH) is a common nonmalignant enlargement of the prostate gland that affects aging men worldwide. It is characterized by lower urinary tract symptoms such as urinary frequency, urgency, and incomplete bladder emptying, which significantly impair quality of life.^[7] The prevalence of BPH increases with age, with over 50% of men affected by the age of 60.^[8] Despite its high prevalence, the etiology of BPH remains incompletely understood, and identifying modifiable risk factors is crucial for prevention and management. There is limited research on the relationship between air pollution and BPH. An ecological study conducted by Sung Ryul Shim et al from 2010 to 2013 on the Korean population reported a relationship between air pollution and BPH, and found that the risk of BPH increased significantly with increasing concentrations of air pollutants (OR = 2.23; 95% CI: 1.55–3.21).^[9] Notably, nitrogen oxides showed a dose-dependent relationship in their study (OR = 1.73; 95% CI: 1.25–2.39). A Chinese cohort study of middle-aged and older adults found that PM2.5 (OR = 1.04, 95% CI: 1.01–1.07) and PM2.5–10 (OR = 1.06, 95% CI: 1.02–1.10) significantly increased the incidence of BPH. Most existing studies on the relationship between air pollution and BPH are observational in nature and thus prone to confounding, reverse causation, and measurement errors. These limitations hinder our ability to infer a causal relationship. Therefore, a more robust approach is needed to clarify whether air pollution has a direct causal effect on the development of BPH.

The human gut microbiome is a vast community of microorganisms that plays a crucial role in human health.^[10] As research progresses, it has become increasingly evident that dysbiosis of the gut microbiome can have detrimental effects on human health, contributing to the development of various chronic diseases, including BPH.^[11,12]

Although the results of these studies suggest that both air pollutants and the gut microbiome can influence the onset and progression of BPH, these methods do not directly demonstrate a causal relationship. Therefore, there is a need for a research methodology to determine if there is a causal relationship between air pollutants, gut microbiome and BPH. Mendelian randomization is a research method that uses genetic variation as an instrumental variable to explore causal relationships. Its advantage lies in its ability to effectively mitigate the impact of confounding factors while avoiding reverse causation, thereby enhancing the robustness of research findings.^[13] In this study, our objective was to assess the causal relationships between 5 major air pollutants (including PM₂.₅, PM₂.₅–10, PM₁₀, NO_x, and NO₂) and BPH through univariate Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR). In addition, we used mediation Mendelian randomization (MMR) to explore whether the gut microbiome potentially mediates the association between air pollution and BPH.

2. Methods

2.1. Study design overview

Our MR analysis was conducted in strict accordance with the STROBE-MR guidelines to ensure rigor throughout the research process.^[14] It is important to emphasize that MR analysis must meet 3 fundamental assumptions to ensure its validity^[15]: the relevance assumption: the genetic instrumental variables must have a strong association with the exposure; the independence assumption: the genetic instrumental variables are independent of any confounding variables; and the exclusion restriction assumption: the genetic instrumental variables influence the outcome only through the exposure and not through other pathways. Building on this foundation, we employed UVMR to seek robust evidence of a causal relationship between air pollution and BPH. Previous studies have shown that traditional mediators such as smoking, alcohol consumption, and body mass index (BMI) may increase the risk of BPH.^[16,17] Therefore, to improve the reliability of the findings, we used MVMR to adjust for statistically significant results. The corrected risk factors included smoking, alcohol consumption, and BMI. Finally, we conducted MMR to explore whether the gut microbiome had a mediation effect. The flowchart of the study design is shown in Figure 1.

Figure 1.

Flowchart of a MR study. MR = Mendelian randomization.

2.2. Data source

We obtained genetic instrumental variables for air pollution from the IEU Open GWAS project (https://gwas.mrcieu.ac.uk) with all populations of European ancestry. Fine particulate pollutants primarily include PM_2.5, PM_2.5–10, and PM₁₀, with a sample size of 423,796 for PM_2.5 and PM_2.5–10, 455,314 for PM₁₀ and the sample size for NO_x and NO₂ is 456,380.^[18] The gut microbiome dataset was obtained from the MiBioGen Consortium (https://mibiogen.gcc.rug.nl/). After excluding 15 unknown microbial taxa, 196 microbial taxa were included in our final analysis.^[19] For outcome data, we selected the latest version of the FinnGen 11 dataset (https://r11.finngen.fi).^[20] The BPH data included 36,601 cases and 141,300 controls. Our data come from 3 publicly available databases, avoiding the problem of overlapping samples. Table 1 provides detailed information about the exposure and outcome variables as well as their sources.

Table 1.

Detailed data sources of exposures and outcomes.

Characteristics	GWAS ID	Consortium	Samples	Source
PM2.5	ukb-b-11,312	MRC-IEU	423,796	https://gwas.mrcieu.ac.uk/
PM2.5–10	ukb-b-12,963	MRC-IEU	423,796	https://gwas.mrcieu.ac.uk/
PM10	ukb-b-589	MRC-IEU	455,314	https://gwas.mrcieu.ac.uk/
NO2	ukb-b-2618	MRC-IEU	456,380	https://gwas.mrcieu.ac.uk/
NOx	ukb-b-12,417	MRC-IEU	456,380	https://gwas.mrcieu.ac.uk/
Past smoking	ukb-a-17	Neale Lab	310,749	https://gwas.mrcieu.ac.uk
Past alcohol consumption	ukb-a-352	Neale Lab	21,894	https://gwas.mrcieu.ac.uk/
BMI	ieu-a-1089	UK Biobank	120,286	https://gwas.mrcieu.ac.uk/
Gut microbiome	NA	MiBioGen Consortium	18,340	https://mibiogen.gcc.rug.nl/
BPH	NA	FinnGen	36,601/ 141,300	https://r11.finngen.fi/

BMI = body mass index, BPH = benign prostatic hyperplasia, NO₂ = nitrogen dioxide air pollution, NOx = Nitrogen oxides air pollution_, PM₁₀ = particulate matter with aerodynamic diameters ≤10 μm, PM_2.5 = particulate matter with aerodynamic diameters ≤2.5 μm, PM_2.5–10 = particulate matter with aerodynamic diameters 2.5–10 μm.

All of the above data were obtained from publicly available databases and have been obtained with the written informed consent of the participant, eliminating the need for additional ethical approval.

2.3. Genetic instrument variable selection

To ensure the reliability of SNPs, we established several selection criteria. In Mendelian randomization analyses, a P-value of < 5 × 10⁻⁸ is considered the gold standard for selection.^[21] However, using this threshold did not yield a sufficient number of SNPs for our analysis. Therefore, we ultimately decided to use a P-value threshold of < 1 × 10⁻⁷ for our selection criteria.^[22,23] We controlled for linkage disequilibrium effects by employing the PLINK clustering method, with an LD r² threshold of <0.001 and a clustering window of 10,000 kb.^[24] Finally, we excluded potential horizontal pleiotropy as well as nonsignificant and palindromic SNPs.

2.4. Statistical analysis

In our study, we selected inverse variance weighting (IVW) as the primary method for validating causal relationships because it produces robust causal estimates while accounting for pleiotropic effects.^[25] To enhance the reliability of the IVW results, we performed sensitivity analyses using the MR-Egger regression, the weighted median, weighted mode, and simple mode.^[25,26] Moreover, we conducted Cochran Q-test and MR-Egger intercept analysis to assess the presence of heterogeneity and horizontal pleiotropy among all SNPs.^[26,27] We also utilized leave-one-out analysis and MR-PRESSO to identify and exclude any outliers.^[28] To avoid the confounding effects of traditional mediators, we used MVMR to adjust for statistically significant results. Correcting factors include smoking, alcohol consumption, and BMI. The information of data sources for MVMR and MMR is also shown in Table 1. For MMR, we used a 2-step MR, which is similar to the coefficient product method. MMR estimates are calculated: the causal effect of exposure on the mediator; and the causal effect of the mediator on the outcome.^[29,30] The 2 estimates were then multiplied to estimate the mediating effect confidence intervals. All statistical analyses were conducted using the “TwoSampleMR” package (version 5.6) in R software (version 4.3.1).

3. Result

All data are rigorously screened, and detailed statistics are provided in Supplementary Material 1, Supplemental Digital Content, https://links.lww.com/MD/P954. The F-statistics for all genetic instrumental variables exceeded 10, indicating a low likelihood of a weak instrument bias and enhancing the credibility of the data. In the UVMR we found that NO₂ significantly increased the risk of BPH (OR = 2.39, 95% CI = 1.17–4.91, P = .01) (Fig. 2). We did not find significant evidence to establish a causal relationship between other air pollutants and BPH (Fig. 2). Figure 3 is a scatter plot of the results of the analysis. Figure 4 shows the results of the test of the leave-one-out method. In the leave-one-out method, rs12462492 was found to be a potential outlier and was therefore excluded from the analysis. In the sensitivity analysis, the results of the Q-test did not indicate the presence of heterogeneity (all P-values were >0.05) and all MR-Egger intercept results showed no evidence of potential horizontal pleiotropy (all intercept P-values were >.05) (Table 2). After adjusting for the risk factors of smoking, alcohol consumption, and BMI in the causal relationship between NO₂ and BPH, the IVW results from MVMR were consistent with those from UVMR (Table 3).

Figure 2.

Forest plot of the causal association between Air pollutants and BPH. BPH = benign prostatic hyperplasia, NO₂ = nitrogen dioxide air pollution, NOx = nitrogen oxides air pollution, PM₁₀ = particulate matter with aerodynamic diameters ≤10 μm, PM_2.5 = particulate matter with aerodynamic diameters ≤ 2.5 μm, PM_2.5–10 = particulate matter with aerodynamic diameters 2.5–10 μm, SNP = single-nucleotide polymorphism.

Figure 3.

Causal association between air pollutants and BPH. (A) Scatter plot for PM_2.5; (B) scatter plot for PM_2.5–10; (C) scatter plot for PM₁₀; (D) scatter plot for NO₂; (E) scatter plot for NO_x. BPH = benign prostatic hyperplasia, NO₂ = nitrogen dioxide air pollution, NO_x = nitrogen oxides air pollution, PM10 = particulate matter with aerodynamic diameters ≤10 μm, PM2.5 = particulate matter with aerodynamic diameters ≤2.5μm, PM2.5–10 = particulate matter with aerodynamic diameters 2.5–10 μm, SNP = single-nucleotide polymorphism.

Figure 4.

Causal association between air pollutants and BPH. (A) leave-one-out test for PM_2.5; (B) leave-one-out test for PM_2.5–10; (C) leave-one-out test for PM₁₀; (D) leave-one-out test for NO₂; (E) leave-one-out test for NO_x. BPH = benign prostatic hyperplasia, NO₂ = nitrogen dioxide air pollution, NO_x = nitrogen oxides air pollution, PM10 = particulate matter with aerodynamic diameters ≤10 μm, PM2.5 = particulate matter with aerodynamic diameters ≤2.5μm, PM2.5–10 = particulate matter with aerodynamic diameters 2.5–10 μm.

Table 2.

Details of heterogeneity and pleiotropy check in the MR analysis.

Exposure	Outcome	Heterogeneity				Horizontal pleiotropy		MR-PRESSO
		IVW		MR-Egger
		Q	P	Q	P	Egger intercept	P	RSSobs	P-value
PM2.5	BPH	3.86	.69	3.81	.57	0.003021	.82	5.64	.68
PM2.5–10	BPH	3.86	.11	46.91	.18	−0.021525	.36	2.32	.89
PM10	BPH	1.51	.91	0.46	.97	−0.004239	.29	42.31	.33
NO2	BPH	3.88	.56	3.72	.44	−0.011025	.71	5.94	.58
NOx	BPH	9.15	.42	7.86	.44	0.026035	.28	11.57	.42

BPH = benign prostatic hyperplasia, MR = Mendelian randomization, NO₂ = nitrogen dioxide air pollution, NO_x = nitrogen oxides air pollution, PM₁₀ = particulate matter with aerodynamic diameters ≤10μm, PM_2.5 = particulate matter with aerodynamic diameters ≤2.5 μm, PM_2.5–10 = particulate matter with aerodynamic diameters 2.5–10 μm, IVW = inverse variance weighting.

Table 3.

Results of MVMR.

Exposure	Outcome	SNP	OR (95%)	P
NO2	BPH	6	2.39 (1.16–4.91)	.01
Model 1		59	2.03 (1.09–3.79)	.02
Model 2		7	2.21 (1.02–4.79)	.04
Model 3		6	2.27 (1.09–4.72)	.02
Model 4		60	2.01 (1.05–3.85)	.03

BMI = body mass index, BPH = benign prostatic hyperplasia, MVMR = multivariate Mendelian randomization, NO₂ = nitrogen dioxide air pollution.

Model 1: NO₂ adjusted by past smoking; Model 2: NO₂ adjusted by past alcohol consumption; Model 3: NO₂ adjusted by BMI; Model 4: NO₂ adjusted by past smoking; past alcohol consumption and BMI.

In the analysis of the gut microbiome, we identified 14 gut microbial populations associated with BPH, of which 5 significantly increased the risk of the disease (Fig. 5). These include the genera Ruminiclostridium9, Genus Family XIII AD3011 group, Lachnospiraceae UCG008, Lachnospiraceae UCG010, and Ruminococcaceae UCG003. Mendelian randomization analysis showed a significant positive causal association between NO₂ and the abundance of gut microbiota Lachnospiraceae UCG008 (OR = 4.69, 95% CI = 1.45–15.12, P = .01) (Table 4). Additionally, there was a significant positive association between the gut microbiome of the Genus Lachnospiraceae UCG008 and BPH incidence. Therefore, we propose that the gut microbiome of the Genus Lachnospiraceae UCG008 is a potential mediator of the relationship between NO2 and BPH. In the coefficient product test for the MMR, our P-test (P = .11) indicated no statistical significance. The results of the mediation analysis can be found in Table 4.

Figure 5.

Risk relationship between gut microbiome and BPH. BPH = benign prostatic hyperplasia, SNP = single-nucleotide polymorphism.

Table 4.

Mediating effects of gut microorganisms between NO₂ and BPH.

Exposure/outcome	Mediators	Exposure to mediators		Mediators to outcome		Total effect	Direct effect	Mediation effect	P-tests
		OR (95%)	P	OR (95%)	P
NO2/BPH	Genus. Ruminiclostridium9	0.78 (0.25–2.43)	.67	1.16 (1.02–1.32)	.01	0.872	0.909	−0.037	.68
NO2/BPH	Genus. Family XIII AD3011 group	1.04 (0.81–1.34)	.70	1.10 (1.01–1.21)	.03	0.872	0.867	0.004	.71
NO2/BPH	Genus. Lachnospiraceae UCG008	4.69 (1.45–15.12)	.01	1.07 (1.01–1.15)	.03	0.872	0.758	0.113	.11
NO2/BPH	Genus. Lachnospiraceae UCG010	0.52 (0.14–1.93)	.33	1.12 (1.01–1.24)	.03	0.872	0.944	−0.07	.37
NO2/BPH	Genus. Ruminococcaceae UCG003	1.20 (0.53–2.70)	.65	1.11 (1.01–1.22)	.03	0.872	0.853	0.018	.66

BPH = benign prostatic hyperplasia, NO₂ = nitrogen dioxide air pollution, OR = odds ratio.

4. Discussion

Air pollution is an important environmental issue that severely affects human health. Increasing evidence suggests that air pollution is associated with various human diseases.^[31] BPH is the primary urinary system disorders in men, and its prevalence is increasing in middle-aged and older people. Although a growing number of research is investigating the causal relationship between air pollution and various diseases, there is limited evidence to establish a causal link between air pollution and BPH. In this study, we employed UVMR and MVMR to investigate the causal relationships between 5 major air pollutants (PM_2.5, PM_2.5–10, PM₁₀, NO₂, and NO_X) and BPH. Ultimately, we found that NO₂ exposure significantly increased the risk of BPH, with the results remaining consistent after multivariable adjustment. Our findings demonstrate a significant causal relationship between NO2 exposure and BPH. However, we did not find no significant evidence to establish causal links between other major air pollutants and BPH.

The occurrence of BPH is associated with various factors such as testosterone levels, chronic inflammation, and oxidative stress.^[32] As early as a long time ago, Berry et al demonstrated through castration and testosterone replacement therapy experiments in animals that testosterone levels influence the occurrence of BPH.^[33] On the other hand, chronic inflammation can lead to damage to prostate tissue and prolonged wound healing, which in turn promotes an increase in prostate volume, ultimately resulting in BPH.^[34] The oxidative stress response activated by various cytokines also plays a crucial role in BPH pathogenesis. Due to the rapid turnover of cells and the low levels of DNA repair enzymes, the prostate tissue is highly susceptible to oxidative damage.^[35] This oxidative stress triggers compensatory cell proliferation, thereby contributing to the development of BPH. In prostate cells, disruptions in the redox homeostasis between ROS and antioxidants can accelerate the progression of prostate diseases, such as BPH.^[36] Liu et al discovered that STEAP4 regulates the proliferation and apoptosis of prostate cells through the AKT/mTOR signaling pathway, thereby influencing the occurrence of BPH using qRT-PCR and immunofluorescence staining techniques.^[37] Chang et al analyzed urine and blood samples from patients with BPH and found that sex hormones and oxidative stress could promote the occurrence of BPH by mediating phthalates.^[38] In air pollution research, scientists have found that exposure to NO₂ can trigger mechanisms such as oxidative stress and chronic inflammation,^[39] and can also cause some degree of endocrine disruption in the body.^[40] NO₂ itself exhibits strong oxidizing properties and can directly generate reactive oxygen species (ROS) through reactions with biomolecules such as lipids, proteins, and DNA.^[41] These ROS include superoxide anion (O₂⁻), hydrogen peroxide (H₂O₂), and hydroxyl radicals (OH⁻). Furthermore, ROS generated by NO₂ can activate antioxidant transcription factors or stimulate the NADPH oxidase (NOX) family, such as NOX2 and NOX4, via the pentose phosphate pathway.^[42,43] This activation enhances electron leakage from the electron transport chain, leading to a surge in superoxide anion (O₂⁻) production, thereby further amplifying intracellular ROS generation in prostate cells. Animal experiments conducted by Chan Lu et al demonstrated that NO₂ exposure significantly increased lipid peroxidation product malondialdehyde (MDA) and 8-hydroxy-2’-deoxyguanosine (8-OHdG), indicating the accumulation of oxidative damage under nitrogen dioxide exposure.^[44] Moreover, the study further demonstrated that NO₂ exposure inhibits the activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione (GSH), disrupting redox homeostasis,^[45] which would accelerate apoptosis in prostate tissue. ROS induced by NO₂ can further activate IκB kinase (IKK), promoting the nuclear translocation of NF-κB and driving the release of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β, ultimately triggering chronic inflammation in the body.^[46] Notably, inflammation serves as a critical pathological basis for the development of BPH. Therefore, NO₂ can activate multiple pathways, thereby increasing the risk of developing BPH.

Additionally, in our exploration of the causal relationship between gut microbiome and BPH, we found 5 types of gut microorganisms that were positively associated with the risk of BPH, whereas 9 types of gut microorganisms exhibited a negative associated with BPH. The human gut microbiome is a vast community of microorganisms that has been found in recent years to be associated with various chronic diseases owing to dysbiosis within its populations.^[11] Consistent with our results, the experimental findings of Makoto Matsushita and colleagues demonstrated that short-chain fatty acids produced by gut microbiota stimulate the production of IGF1, which in turn activates local MAPK and PI3K signaling pathways in the prostate, thereby influencing prostate growth. This supports the existence of the gut microbiome-prostate axis.^[47] In a review published by Cao et al, the authors elaborated on how the gut microbiome influences the occurrence of prostate disease.^[48] They discussed various mechanisms, including the modulation of inflammation, immune response, and metabolic pathways, which contribute to the development and progression of conditions such as BPH and PCa. This underscores the significance of the gut microbiome in prostate health and disease. In our further MMR, we found that genus. Lachnospiraceae UCG008 is influenced by NO₂. On the other hand, genus. lachnospiraceae UCG008 was significantly and positively associated with the risk of developing BPH. Therefore, we propose that genus. Lachnospiraceae UCG008 serves as a mediating bridge in the causal relationship between NO₂ and BPH development. However, the final statistical test of the coefficients did not show statistical significance, so the positive causal association of the genus Lachnospiraceae UCG008 with BPH indicates that it is an independent risk factor for the development of BPH. In conclusion, our findings indicate that there is no mediating effect of gut microbiome in the positive causal relationship between NO₂ and BPH. Nevertheless, our research provides new avenues for future clinical treatment of BPH, highlighting the potential of targeting gut microbiota as a therapeutic strategy.

4.1. Strength and limitation

To the best of our knowledge, this is the first study to explore the causal relationship between air pollution and BPH using Mendelian randomization. This approach advances our understanding of the effects of air pollution on the urinary system. Compared with cohort studies or meta-analyses, Mendelian randomization is better at mitigating the effects of confounding factors and reverse causation, making the assessment of causal relationships more reliable. In addition, other studies have often lacked consistent and accurate methods for measuring air pollutants. Our research approaches the evaluation of air pollutants from a genetic perspective, which highlights the superiority of our methodology. This genetic approach allows for a more reliable assessment of the causal relationship, reducing the measurement bias associated with traditional exposure assessment methods.

However, we must also recognize the limitations of this study. First, our study included only European populations, which requires further validation before generalizing the results to other populations. Caution is needed in applying our findings to different population groups, as genetic, environmental and lifestyle factors can vary greatly. Previous studies have indicated a strong association between prostate disease and age.^[49] Unfortunately, the Mendelian randomization approach we employed was not stratified by age, which represents an inherent limitation of this research method. Similarly, some studies have suggested that there may be a nonlinear relationship between air pollution and disease incidence.^[50] However, the Mendelian randomization approach may not fully capture the nuances of such nonlinear relationships. Despite these limitations, our study provides a valid assessment of the positive causal association between nitrogen dioxide exposure and the development of BPH.

In the future, we recommend further research into the relationship between air pollution and prostate health. On the one hand it is important to study whether the same causal relationship still exists between different populations. On the other hand, the specific mechanisms by which air pollution causes BPH have not been fully elucidated. Therefore, these investigations are essential, whether through molecular biology studies, animal experiments or other experimental studies.

5. Conclusion

In conclusion, our study found a positive causal association between NO₂ and BPH, which suggests that high NO₂ exposure increases the chances of BPH. Improving air quality through measures such as utilizing cleaner energy sources and continuous monitoring of air quality is essential for prostate health. Furthermore, our results suggest that there is also a positive causal relationship between intestinal flora and BPH. This provides new avenues for future clinical prevention and treatment of BPH and highlights the potential of targeting the gut microbiome as a therapeutic strategy.

Acknowledgments

The authors thank the consortium for providing the data for our research and all the participants and researchers for their participation in this MR study.

Author contributions

Conceptualization: Long Xia, Ying Liu, Binglei Jiang.

Data curation: Long Xia, Yongbo Zheng, Ben Wang.

Formal analysis: Long Xia, Ying Liu, Li Wang.

Writing – original draft: Long Xia, Ying Liu.

Writing – review & editing: Binglei Jiang, Ping-Yu Zhu.

Supplementary Material

medi-104-e44548-s001.xlsx ^{(16.3KB, xlsx)}