Paeoniflorin alleviates CKD-associated constipation by modulating TPH1/AHR-related signaling and suppressing NLRP3/GSDMD-mediated pyroptosis.

Abstract

<p>INTRODUCTION: Constipation is a common complication of chronic kidney disease (CKD) and contributes to a vicious cycle linking intestinal dysfunction and renal injury, yet effective targeted therapies remain limited. Paeoniflorin (PF), a major bioactive constituent of Paeonia lactiflora Pall., has reported renoprotective and gastrointestinal regulatory effects, but its role in CKD-associated constipation remains unclear. METHODS: In this study, we investigated the therapeutic effects and underlying mechanisms of PF in an adenine-induced mouse model of CKD-associated constipation. Constipation-related phenotypes, renal function, renal and colonic histopathology, intestinal barrier markers, TPH1/AHR-related signaling, renal NLRP3/GSDMD-mediated pyroptosis, gut microbial composition, PCS-related metabolic alterations, and molecular docking with key enzymes involved in the tyrosine-p-cresol-PCS pathway were assessed. RESULTS: PF dose-dependently improved constipation-related phenotypes and renal dysfunction, and the high-dose PF group was selected for subsequent mechanistic analyses. High-dose PF attenuated renal fibrosis, restored colonic mucosal architecture, and increased the expression of tight junction proteins. Mechanistically, PF upregulated TPH1 and AHR expression, suggesting modulation of TPH1/AHR-related signaling. In renal tissues, PF suppressed NLRP3/GSDMD-mediated pyroptosis and improved the expression of KCNK3 and OAT3. PF also selectively reshaped gut microbial composition and was associated with microbial functional changes related to amino acid metabolism and inflammatory signaling. In addition, PF was associated with PCS-related metabolic alterations and showed potential interactions with key enzymes involved in the tyrosine-p-cresol-PCS pathway. DISCUSSION: These findings indicate that PF alleviated CKD-associated constipation and improved renal injury, possibly through integrated modulation of intestinal barrier integrity, gut microbial composition, TPH1/AHR-related signaling, and renal pyroptosis-related signaling. PF may therefore represent a potential pharmacological candidate for CKD-associated constipation.</p>