Abstract：
Etomidate (ETO) is used as an anesthetic in surgery, but it is being abused in some populations. The damage caused by long-term intake of ETO to intestinal and brain functions is not yet clear, and it remains to be determined whether the drug affects the central nervous system through the gut-brain axis. This study aimed to investigate the neurotoxic and gastrointestinal effects of ETO at doses of 1 mg/kg and 3 mg/kg in mice over 14 consecutive days. The results showed that long-term injection of ETO led to drug resistance in mice, affecting their innate preference for darkness and possibly inducing dependence on ETO. The levels of 5-hydroxytryptamine in the brain, serum, and colon decreased by 37%, 51%, and 42% respectively, while the levels of γ-aminobutyric acid reduced by 38%, 52%, and 41% respectively. H&E staining revealed that ETO reduced goblet cells in the colon and damaged the intestinal barrier. The expression of tight junction-related genes Claudin4 and ZO-1 was downregulated. The intestinal flora changed, the abundance of Akkermansia and Lactobacillus decreased by 33% and 14%, respectively, while Klebsiella increased by 18%. TUNEL results showed that high-dose ETO increased apoptotic cells in the brain. The expression of Claudin1 in the brain was downregulated. Untargeted metabolomics analysis of the colon and brain indicated that ETO caused abnormalities in glycerophospholipid metabolism. Abnormal lipid metabolism might lead to the production or accumulation of lipotoxic metabolites, causing central nervous system diseases. ETO induced changes in the intestinal flora and metabolism, further affecting the central nervous system through the gut-brain axis. The study unveiled the detrimental effects on the brain and gastrointestinal system resulting from long-term intake of ETO, which holds significant implications for comprehending the adverse impact of ETO abuse on human health.
摘要：
依托咪酯（ETO）在手术中用作麻醉剂，但它在某些人群中被滥用。长期摄入ETO对肠道和大脑功能的损害尚不清楚,该药物是否通过肠-脑轴影响中枢神经系统仍有待确定。本研究旨在研究ETO在1mg/kg和3mg/kg剂量下连续14天对小鼠的神经毒性和胃肠道作用。结果表明,长期注射ETO导致小鼠耐药,影响他们对黑暗的天生偏好，并可能诱导对ETO的依赖。大脑中5-羟色胺的水平，血清,结肠减少了37%,51%,分别为42%，而γ-氨基丁酸的水平降低了38%，52%,分别为41%。H&E染色显示ETO减少结肠中的杯状细胞并破坏肠屏障。紧密连接相关基因Claudin4和ZO-1的表达下调。肠道菌群发生了变化,Akkermansia和乳酸杆菌的丰度分别下降了33%和14%，分别,而克雷伯菌则增加了18%。TUNEL结果显示高剂量ETO增加脑中的凋亡细胞。大脑中Claudin1的表达下调。结肠和大脑的非靶向代谢组学分析表明，ETO引起甘油磷脂代谢异常。脂质代谢异常可能导致脂毒性代谢物的产生或积累，引起中枢神经系统疾病。ETO诱导肠道菌群和代谢的变化，通过肠脑轴进一步影响中枢神经系统。该研究揭示了长期摄入ETO对大脑和胃肠道系统的有害影响，这对理解滥用ETO对人类健康的不利影响具有重大影响。
