Yu Jiayu, Wang Zixu, Chen Yaoxing, Dong Yulan
National Key Laboratory of Veterinary Public Health Security, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
Int J Mol Sci. 2025 Apr 24;26(9):4021. doi: 10.3390/ijms26094021.
Stress may aggravate the development of inflammatory bowel disease and irritable bowel syndrome, in which the number of enterochromaffin (EC) cells and 5-hydroxytryptamine (5-HT) levels are abnormal, but the underlying mechanism remains largely unresolved. In this study, we discovered that restraint stress triggered the expression of Tph1, which led to 5-HT production. The 5-HT signaling then increased intestinal permeability, downregulated the expression of tight junction proteins, reduced the number of goblet cells and their ability to secrete mucin, promoted the expression of inflammatory cytokines, and ultimately damaged the intestinal mucosal barrier. Mechanistically, the 5-HT receptor HTR7 was highly expressed in the intestine. It interacted with 5-HT to initiate the Wnt/β-catenin signaling pathway, inducing an increase in intestinal EC cells and further promoting 5-HT secretion. Additionally, the activation of the Wnt/β-catenin signaling pathway could initiate the NF-κB signaling pathway and induce the expression of inflammatory cytokines. Blocking the 5-HT signal in mice inhibited the activation of the Wnt/β-catenin signal, thereby alleviating intestinal inflammation. Our findings revealed a novel role for 5-HT in intestinal inflammatory diseases and represent a potential new therapeutic target.
压力可能会加剧炎症性肠病和肠易激综合征的发展，在这些疾病中，肠嗜铬（EC）细胞的数量和5-羟色胺（5-HT）水平是异常的，但其潜在机制在很大程度上仍未得到解决。在本研究中，我们发现束缚应激会触发色氨酸羟化酶1（Tph1）的表达，从而导致5-HT的产生。然后，5-HT信号通路增加肠道通透性，下调紧密连接蛋白的表达，减少杯状细胞的数量及其分泌粘蛋白的能力，促进炎性细胞因子的表达，并最终破坏肠道黏膜屏障。从机制上讲，5-HT受体HTR7在肠道中高表达。它与5-HT相互作用以启动Wnt/β-连环蛋白信号通路，导致肠道EC细胞增加并进一步促进5-HT分泌。此外，Wnt/β-连环蛋白信号通路的激活可启动NF-κB信号通路并诱导炎性细胞因子的表达。在小鼠中阻断5-HT信号可抑制Wnt/β-连环蛋白信号的激活，从而减轻肠道炎症。我们的研究结果揭示了5-HT在肠道炎性疾病中的新作用，并代表了一个潜在的新治疗靶点。
