背景:非甾体抗炎药(NSAIDs)是目前使用最广泛的抗炎药,但是它们的长期使用会对胃肠道(GIT)造成损害。GIT损伤的危险因素之一是暴露于高海拔低氧环境,这可能导致肠粘膜屏障受损。在高海拔低氧环境中服用NSAIDs可加剧GIT损伤并影响肠道微生物群。本研究的目的是探讨在高原低氧环境中白藜芦醇(RSV)干预减轻NSAID引起的肠损伤的机制。以及它在调节肠道微生物群中的作用。
方法:大鼠口服阿司匹林,构建NSAIDs致肠损伤大鼠模型。在诱导肠道损伤后,大鼠通过管饲法给予RSV,和TLR4,NF-κB的表达水平,通过蛋白质印迹评估不同处理组中的IκB以及ZonulaOccludens-1(ZO-1)和Occludin蛋白。此外,炎症因子IL-10、IL-1β的表达,使用Elisa.16sRNA测序用于研究肠道微生物群的变化。
结果:HCk组TLR4/NF-κB/IκB通路蛋白表达升高,促炎因子IL-1β和TNF-α的表达增加,抗炎因子IL-10的表达降低,肠黏膜屏障蛋白ZO-1和Occludin的表达降低。在高原低氧环境中施用NSAIDs药物会加剧肠道炎症和肠粘膜屏障的损伤。RSV干预治疗后,TLR4/NF-κB/IκB信号通路蛋白表达降低,从而降低HAsp组炎症因子的表达。HE染色成果直接显示RSV介入后肠的毁伤和肠粘膜的修复。16sRNA测序结果显示,在Ruminococus中存在显著差异(P<0.05),Facklamia,Parasutterilla,无节虫,球菌,HCk组和Ck组之间的嗜冷杆菌。与HCk组相比,HAsp组Facklamia表现出显著差异(P<0.05),无节虫,罗斯布里亚,嗜冷杆菌,和Alloprevotella.RSV干预后,与HAsp组相比,严格梭菌细菌显着增加。
结论:白藜芦醇可通过调节TLR4/NF-κB/IκB信号通路和肠道菌群组成,减轻高原低氧环境下NSAIDs给药引起的肠道损伤。
BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are currently the most widely used anti-inflammatory medications, but their long-term use can cause damage to the gastrointestinal tract(GIT). One of the risk factors for GIT injury is exposure to a high-altitude hypoxic environment, which can lead to damage to the intestinal mucosal barrier. Taking NSAIDs in a high-altitude hypoxic environment can exacerbate GIT injury and impact gut microbiota. The aim of this study is to investigate the mechanisms by which resveratrol (RSV) intervention alleviates NSAID-induced intestinal injury in a high-altitude hypoxic environment, as well as its role in regulating gut microbiota.
METHODS: Aspirin was administered orally to rats to construct a rat model of intestinal injury induced by NSAIDs. Following the induction of intestinal injury, rats were administered RSV by gavage, and the expression levels of TLR4, NF-κB,IκB as well as Zonula Occludens-1 (ZO-1) and Occludin proteins in the different treatment groups were assessed via Western blot. Furthermore, the expression of the inflammatory factors IL-10, IL-1β, and TNF-α was evaluated using Elisa.16sRNA sequencing was employed to investigate alterations in the gut microbiota.
RESULTS: The HCk group showed elevated expression of TLR4/NF-κB/IκB pathway proteins, increased expression of pro-inflammatory factors IL-1β and TNF-α, decreased expression of the anti-inflammatory factor IL-10, and expression of intestinal mucosal barrier proteins ZO-1 and Occludin. The administration of NSAIDs drugs in the plateau hypoxic environment exacerbates intestinal inflammation and damage to the intestinal mucosal barrier. After treatment with RSV intervention, the expression of TLR4/NF-κB/IκB signaling pathway proteins would be reduced, thereby lowering the expression of inflammatory factors in the HAsp group. The results of HE staining directly show the damage to the intestines and the repair of intestinal mucosa after RSV intervention. 16sRNA sequencing results show significant differences (P<0.05) in Ruminococcus, Facklamia, Parasutterella, Jeotgalicoccus, Coprococcus, and Psychrobacter between the HCk group and the Ck group. Compared to the HCk group, the HAsp group shows significant differences (P<0.05) in Facklamia, Jeotgalicoccus, Roseburia, Psychrobacter, and Alloprevotella. After RSV intervention, Clostridium_sensu_stricto bacteria significantly increase compared to the HAsp group.
CONCLUSIONS: Resveratrol can attenuate intestinal damage caused by the administration of NSAIDs at high altitude in hypoxic environments by modulating the TLR4/NF-κB/IκB signaling pathway and gut microbiota composition.