Pentosan polysulfate alleviates interstitial cystitis/bladder pain syndrome by modulating bile acid metabolism and activating the TGR5 receptor through gut microbiota regulation.

BACKGROUND

The disrupted gut microbiome has been found to be implicated in the development of interstitial cystitis/bladder pain syndrome (IC/BPS). Pentosan polysulfate (PPS) is an oral medication used for treating IC/BPS, acting as both an anti-inflammatory agent and a bladder barrier protector. However, the precise mechanisms by which the PPS-mediated modulation of the gut microbiome alleviates IC/BPS are not fully understood.

OBJECTIVE

This study aimed to identify the key gut microbiota species and metabolites involved in PPS's protective effects against IC/BPS.

METHODS

We employed a multifaceted approach, including 16S rDNA gene sequencing, antibiotic treatment, and fecal microbiota transplantation, to validate the dependency of PPS's protective effects on the gut microbiome. Furthermore, we performed a comprehensive metabolomic profiling using non-targeted metabolomics and liquid chromatography-tandem mass spectrometry.

RESULTS

PPS significantly elevated the abundance of the xylan-degrading bacteria, Eubacterium xylanophilum group, which, through its interaction with the gut microbiome, markedly reduced inflammation and barrier damage induced by cyclophosphamide in IC/BPS. In addition, PPS significantly increased the level of ursodeoxycholic acid (UDCA), a secondary bile acid, demonstrating a strong correlation with the abundance of the E. xylanophilum group. Ex vivo supplementation with UDCA mitigated lipopolysaccharide-induced inflammation and barrier disruption in SV-HUC-1 cells by activating the TGR5 receptor.

CONCLUSION

PPS exerts its protective effects against IC/BPS by modulating the gut microbiome and its metabolites.