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. 2025 May 23;16(1):877.
doi: 10.1007/s12672-025-02618-9.

Circulating metabolic biomarkers mediated causal relationship between gut microbiota and bladder cancer: a two-step mendelian randomization study

Fa-Ye Wei  1 , Qi-Huan He  1 , Bin-Tong Yin  1 , Jia-Wen Zhao  1 , Yu-Tong Zhao  1 , Zheng-Shu Wei  2 , Yu-Jian Li  1 , Hai-Qi Liang  1 , Min Qin  3 , Ji-Wen Cheng  4
Affiliations

Circulating metabolic biomarkers mediated causal relationship between gut microbiota and bladder cancer: a two-step mendelian randomization study

Fa-Ye Wei et al. Discov Oncol. .

Abstract

Background: Dysbiosis of the gut microbiota (GM) has been reported to be associated with cancers, including bladder cancer (BLCA). However, the specific causal relationship between GM and BLCA, as well as the mediating role of circulating metabolic biomarkers (CMBs), has remained unclear. Therefore, we aimed to elucidate the causal relationship among GM, CMBs, and BLCA, through a mendelian randomization (MR) approach.

Method: The summary statistics of 473 GM (n = 5959) and 233 CMBs (n = 136,016) from the NHGRI-EBI GWAS Catalog, and BLCA (cases n = 2053 and controls n = 287,137) from the FinnGen study were leveraged for our research. Bidirectional MR analysis was conducted to investigate the causal link between GM and BLCA, and two-step MR (TSMR) was employed to identified potential mediating CMBs. The inverse-variance weighted (IVW) was primarily utilized for effect estimation. Additionally, the Cochrane's Q test was used to evaluate heterogeneity, and the MR-Egger method was employed to evaluate pleiotropy.

Result: The study revealed that 15 GM and 12 CMBs were causally associated with BLCA (p < 0.05). Specially, dorea was found to significantly increase the risk of developing BLCA (OR = 2.20, 95% CI: 1.29-3.75). Furthermore, TSMR analysis indicated that total cholesterol levels in small HDL and cholesterol esters in small HDL mediate the causal relationship between dorea and BLCA, with mediated proportions of 2.46% and 2.14%, respectively.

Conclusion: The findings of this study provide compelling evidence supporting the mediating role of CMBs in the causal relationship on GM and BLCA.

Keywords: Bladder cancer; Circulating metabolic biomarkers; Gut microbiota; Mendelian randomization; TSMR.

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Conflict of interest statement

Declarations. Competing interests: We declare that there are no conflicts of interests. Informed consent: Ethical approval does not apply to this article. Statement for institutional email: Because some authors are not formal hospital employees, so we cannot provide institutional email addresses for all authors.

Figures

Fig. 1
Fig. 1
Design of our study. In our MR hypothesis, genetic variants as the instrumental variables are strongly associated with the exposure (GM) and related to the outcome (BLCA) solely through GM, without confounding factors. For two-step MR study, the causal relationship between GM and the mediator (CMBs) was constructed. Finally, the mediating role of CMBs in the connection of GM and BLCA was demonstrated. β: the causal effect estimates of GM on BLCA; β1: the causal effect estimates of GM on CMBs; β2: the causal effect of CMBs on BLCA. MR, mendelian randomization; GM, gut microbiota; BLCA, bladder cancer; CMBs, circulating metabolic biomarkers. The figure was drawn by Figdraw
Fig. 2
Fig. 2
Forest plot to identified the GM related to BLCA. By MR analysis, 15 GM were revealed to be related to BLCA (p < 0.05). Specially, dorea abundance in stool was found to significantly elevate the risk of BLCA with a larger OR (2.20, 95% CI: 1.29–3.75). MR, mendelian randomization; GM, gut microbiota; BLCA, bladder cancer; OR, odds ratio
Fig. 3
Fig. 3
Forest plot to infer the causal relationship among CMBs and BLCA. 12 CMBs were identified to be associated with BLCA (p < 0.05). Among them, the lactate levels and metabolites associated with HDL were major kind of CMBs. CMBs, circulating metabolic biomarkers; BLCA, bladder cancer; HDL, high-density lipoprotein
See this image and copyright information in PMC

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