OBJECTIVES: 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. CONCLUSIONS 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.
Animals ; Cystitis, Interstitial/drug therapy* ; Gastrointestinal Microbiome/drug effects* ; Pentosan Sulfuric Polyester/therapeutic use* ; Cyclophosphamide/adverse effects* ; Mice, Inbred C57BL ; Female ; Mice ; Bile Acids and Salts/metabolism* ; Urinary Bladder ; Fecal Microbiota Transplantation ; Humans

BACKGROUND: Airway responsiveness after acute inhalation of ozone is related to the concentration and duration of ozone exposure. Using barometric whole-body plethysmography and increase in enhanced pause (Penh) as an index of airway obstruction, we measured the response of BALB/c mice to acute ozone inhalation to study the time course change of pulmonary function after ozone exposure. METHODS: Penh was measured before and after exposure to filtered air or 0.12, 0.5, 1, or 2 ppm ozone for 3 hr (n=6/group). In addition, Penh was measured 24, 48 and 72 hr after ozone exposure. Bronchoalveolar lavage (BAL) and histopathologic examinations were performed. RESULTS: The increase in Penh after ozone exposure was significantly higher in the 0.12, 0.5, 1 and 2 ppm groups compared with the control group (all p< 0.01). Increases in Penh 24 hr after ozone exposure were significantly lower than those immediately after acute ozone exposure; however, increases in Penh 72 hr after ozone exposure were significantly higher than those in the control group (each p< 0.01). The proportion of neutrophils in BAL fluid was significantly higher in the group exposed to 2 ppm ozone than in the groups exposed to filtered air or 0.12 ppm ozone (both p< 0.01). CONCLUSION: These results indicate that airway obstruction is induced following ozone exposure in a concentration-dependent manner and persists for at least 72 hr.
Airway Obstruction/*etiology/*pathology ; Animals ; Animals, Newborn ; Bronchoalveolar Lavage Fluid/cytology ; Disease Models, Animal ; Female ; Mice ; Mice, Inbred BALB C ; Plethysmography, Whole Body/*methods ; Probability ; Reference Values ; Respiratory Function Tests ; Risk Assessment ; Sensitivity and Specificity ; Statistics, Nonparametric ; Sulfuric Acids/*adverse effects