Mechanistic study of swertiamarin in treating ulcerative colitis by regulating YAP-mediated Wnt and Notch pathways for intestinal stem cell repair

BACKGROUND: Ulcerative colitis (UC) is a chronic immune-mediated inflammatory disease. In 2024, the American Gastroenterological Association updated its guidelines for UC patients, shifting the treatment goal from "clinical remission" to "mucosal healing" and "histological healing." This highlights the vital role of the interaction between intestinal stem cells (ISCs) and immune cells in maintaining and repairing intestinal tissue homeostasis. However, effective regulatory approaches targeting ISC-immune crosstalk are lacking in current clinical practice. The traditional Chinese medicine Qinjiao, which is widely used in clinical prescriptions for treating UC, contains many iridoid compounds, but whether they can promote tissue healing by regulating the ISC immune microenvironment remains to be clarified. METHODS: UHPLC-MS and an ISC injury organoid model were applied to identify and screen the four major iridoid compounds in Qinjiao. Then, the pharmacodynamic effects of swertiamarin (SW) on UC mice, the proliferation and differentiation of colonic ISCs, and the related status of Wnt, Notch, and Hippo-YAP signaling pathways were analyzed using RT-qPCR and other methods. Finally, the mechanism in organoids was verified using the YAP inhibitor Verteporfin. RESULTS: This study found that SW, a bioactive iridoid compound from Qinjiao, alleviated weight loss, mitigated colon atrophy, and reduced DAI scores in UC mice. SW also restored the proliferation and differentiation of ISCs. It mitigated immune-inflammatory responses and repaired the mucosal barrier by modulating YAP nuclear translocation to activate Wnt/β-catenin signaling and downregulate Notch signaling, enhancing ISC proliferation and differentiation. CONCLUSION: This study revealed that iridoid compounds, represented by SW, are the primary active components in Qinjiao for treating UC by restoring mucosal barrier integrity through enhanced ISC proliferation and differentiation.