Pentosan polysulfate alleviates cyclophosphamide-induced interstitial cystitis/bladder pain syndrome in mice by modulating gut microbiota and bile acid metabolism
ZHU Yuexuan
ZHU Zhangrui
WU Peng
Abstract：Objective To investigate the therapeutic efficacy and mechanism of pentosan polysulfate(PPS)for cyclophosphamide(CYP)-induced interstitial cystitis/bladder pain syndrome(IC/BPS)in mice.Methods Female C57BL/6 mice(6-8 weeks old)were randomized into control group,PPS treatment(25 mg/kg via gavage for 3 weeks)group,CYP treatment(3 separate intraperitoneal injections at 50 mg/kg in week 4),and CYP+PPS treatment group.Gut microbiota alterations of the mice were analyzed using 16S rDNA sequencing and non-targeted metabolomics.Fecal microbiota transplantation(FMT)was performed in CYP-treated recipient mice and those treated with both CYP and PPS.In the in vitro experiment,LPS-stimulated human bladder epithelial cells(SV-HUC-1)were used to assess the effects of deoxycholic acid(DCA)and TGR5 signaling inhibitor SBI-115 on barrier functions of bladder epithelial cells.Results PPS treatment significantly improved the mechanical pain thresholds,restored the urodynamic parameters,and attenuated bladder inflammation and barrier dysfunction in CYP-treated mice.Mechanistically,PPS enriched the abundance of Eubacterium xylanophilum and increased DCA levels in the intestines of CYP-treated mice.FMT experiments confirmed microbiota-dependent therapeutic effects of PPS,shown by reduced bladder pathology in the recipient mice treated with both CYP and PPS.In SV-HUC-1 cells,DCA obviously alleviated LPS-induced inflammation and barrier disruption,and treatment with SBI-115 abolished these protective effects of DCA.Conclusion PPS ameliorates IC/BPS in mice by remodeling gut microbiota to enhance DCA production and activate TGR5 signaling,suggesting a novel microbiota-bile acid-TGR5 axis that mediates the therapeutic effect of PPS and a therapeutic strategy for IC/BPS by targeting gut-bladder crosstalk.
Keywords：interstitial cystitis/bladder pain syndromepentosan polysulfatecyclophosphamidegut microbiotabile acids
Publication Date：2025-06-20
Online Publishing Date：2025-08-15(First online date of this platform, not the publication date of the document)
Pages：10( 1270-1279 )