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. 2025 Dec 3.
doi: 10.1186/s40168-025-02267-8. Online ahead of print.

Modulating the gut-bladder axis: fecal transplantation protects antibiotic-treated mice from E. coli cystitis via the Ahr/Prg4 pathway

Yi Yang #  1   2   3   4   5 , Haoran Chen #  1   2 , Jianjuan Lu #  1   2 , Ning Yang #  1   2 , Lingrui Liu  1   2 , Qinyue Zhang  1   2 , Mingyang Tang  1   2 , Xufeng Li  1   2 , Bao Meng  1   2 , Yasheng Li  1   2   3   4   5 , Liang Yu  1   2   3   4   5 , Long Gao  1   2 , Hui Zhang  1   2 , Ting Wu  1   2 , Yahong Zheng  1   2 , Yanyan Liu  6   7   8   9   10 , Yuxian Shen  11   12 , Jiabin Li  13   14   15   16   17
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Free article

Modulating the gut-bladder axis: fecal transplantation protects antibiotic-treated mice from E. coli cystitis via the Ahr/Prg4 pathway

Yi Yang et al. Microbiome. .
Free article

Abstract

Background: Bacterial cystitis, caused by Escherichia coli (E. coli), is a common urinary tract infection that frequently recurs and seriously affects patient health. Although it is known that gut dysbiosis increases susceptibility to recurrent urinary tract infections, its impact on non-complicated bacterial cystitis-the most common and primary form of urinary tract infection-remains uncertain.

Results: This study found that bacterial infection can cause long-term alterations in gut microbiota structure and affect the production of metabolites. Depletion of the gut microbiota worsens the inflammatory response to bacterial infection, disrupts the epithelial barrier of the bladder, and increases E. coli retention in the bladder and bloodstream. Fecal microbiota transplantation was found to significantly alleviate these excessive inflammatory responses. The study also identified that several tryptophan derivatives derived from the gut microbiota were significantly altered during bacterial microbiota depletion and bacterial infection, with indole-3-propionic acid (IPA) exhibiting the most significant alleviating effect on the excessive inflammatory response during infection. Additionally, the study demonstrated that transcriptional activation of the immune-inhibitory protein Prg4 is regulated by the IPA receptor AhR, which is expressed in bladder urothelial cells. Knockout of AhR in bladder urothelial reduced Prg4 expression and overactivated NF-κB signaling, resulting in the loss of the IPA-alleviating effect. This study suggests that the normal gut microbiota can activate AhR in bladder urothelial cells through its metabolite IPA, regulating the transcription of Prg4 and subsequently modulating the inflammatory response to bacterial cystitis caused by E. coli infection.

Conclusions: These findings provide a theoretical foundation for the clinical diagnosis and treatment of bacterial cystitis by leveraging the gut microbiota and their metabolites as promising therapeutic targets. Video Abstract.

Keywords: Escherichia coli; Bacterial cystitis; Gut microbiota; Indole-3-propionic acid; Proteoglycan 4; Tryptophan derivatives.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: Clinical specimens were obtained from the First Affiliated Hospital of Anhui Medical University, Hefei, China, in accordance with the principles of the Declaration of Helsinki. This study was approved by the Ethics Committee of the Anhui Medical University (approval no. PJ2023-01–52). Supplementary Table 3 provides basic patient information. All the participants provided written informed consent. Animal experiments were conducted in strict accordance with the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines for the care and use of laboratory animals. This study was approved by the Animal Experimentation Ethics Committee of the Anhui Medical University (approval no. LLSC20230023). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

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