红景天苷抑制PPARα改善失重模型导致的小鼠肠道稳态失衡作用机制

During the space flight, astronauts are prone to intestinal homeostasis imbalance due to long-term exposure to weightlessness and are susceptible to intestinal infectious diseases. Therefore, it is of great scientific significance to explore the molecular mechanism of intestinal homeostasis imbalance in weightlessness environment and to find effective methods of intestinal steady state protection. . In our pervious study, we used the hindlimb unloading (HU) mouse model to simulate a weightlessness condition. Compared with ground controls (Ctrls), the intestinal microbiota composition and diversity changed in HU mice, with a profile that was characterized by the expansion of Firmicutes and decrease of Bacteroidetes. The HU mice showed decreased colonic goblet cell numbers and reduced epithelial cell turnover. As a result, the susceptibility to epithelial injury induced by dextran sulfate sodium was increased in HU mice.. We recently found that PPARα may be involved in regulating the homeostasis of intestinal epithelial cells in HU mice, and more importantly, we also found that the traditional Chinese herbal ingredients salidroside can relieve the intestinal homeostasis imbalance in the HU mice. Therefore, this project intends to further clarify the protective effect of salidroside on intestinal homeostasis in HU mice, and to analyze the role of PPARα in the intestinal homeostasis imbalance of HU mice. Furthermore, we hope to elucidate the molecular mechanism of salidroside in maintaining the homeostasis of intestinal epithelial cells through PPARα. This project will enrich our understanding of the mechanism of intestinal homeostasis imbalance in HU mice, and provide a new strategy for intervention and treatment of intestinal homeostasis caused by weightlessness.

在空间飞行过程中，航天员因长期暴露于失重环境，容易发生肠道稳态失衡，易感肠道感染性疾病。因此，探究失重环境下肠道稳态失衡的分子机制，寻找有效的肠道稳态保护措施具有重要的科学意义。我们前期利用小鼠尾吊模型模拟失重效应，首次发现尾吊小鼠出现肠上皮细胞的更新减慢、肠上皮细胞防御功能相关基因表达异常、肠道菌群改变以及对化学诱导性肠炎的易感性增加。新近发现PPARα可能参与调控尾吊小鼠肠上皮细胞稳态；更重要的是，我们还发现传统中药成分红景天苷能够缓解尾吊小鼠肠道稳态失衡。因此，本项目拟进一步明确红景天苷对尾吊小鼠肠道稳态失衡的保护性效应，解析肠上皮细胞中的PPARα在尾吊小鼠肠道稳态失衡中的作用机制，进一步阐明红景天苷通过PPARα维护肠上皮细胞稳态的分子机制。本项目的完成将丰富我们对失重环境下肠道稳态失衡机制的认识，并为干预和治疗失重导致的肠道稳态失衡提供新的策略。

在空间飞行过程中，航天员因长期暴露于失重环境，容易发生肠道稳态失衡，探究失重环境下肠道稳态失衡的分子机制，寻找有效的肠道稳态保护措施具有重要的科学意义。我们在本项目的研究中发现PPARα可能通过其下游的脂代谢途径和炎症反应调控功能参与尾吊小鼠肠上皮细胞稳态调控，可能是尾吊小鼠肠上皮异常的关键调控分子；更重要的是，我们发现传统中药提取物红景天苷能缓解尾吊小鼠肠道稳态失衡，改善尾吊小鼠肠上皮异常，包括杯状细胞减少和肠上皮更新的减慢，但不显著影响肠道转运速率和肠道菌群。红景天苷调控肠上皮的作用可能与其抑制PPARα的表达相关。本项目的完成丰富了我们对失重环境下肠道稳态失衡机制的认识，并为干预和治疗失重导致的肠道稳态失衡提供新的策略，也为红景天苷用于肠道炎症性疾病的治疗提供可能依据。