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 and was downregulated. The intestinal flora changed, the abundance of and decreased by 33% and 14%, respectively, while increased by 18%. TUNEL results showed that high-dose ETO increased apoptotic cells in the brain. The expression of 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.

中文翻译：

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长期使用依托咪酯会破坏小鼠肠道稳态和神经系统

依托咪酯 (ETO) 在手术中用作麻醉剂，但在某些人群中被滥用。长期摄入ETO对肠道和大脑功能造成的损害尚不清楚，该药物是否通过肠-脑轴影响中枢神经系统还有待确定。本研究旨在研究连续 14 天服用 1 mg/kg 和 3 mg/kg 剂量的 ETO 对小鼠的神经毒性和胃肠道影响。结果表明，长期注射ETO会导致小鼠产生耐药性，影响其对黑暗的先天偏好，并可能诱发对ETO的依赖。大脑、血清和结肠中的5-羟色胺水平分别降低了37%、51%和42%，而γ-氨基丁酸水平分别降低了38%、52%和41%。 H&E 染色显示，ETO 减少了结肠中的杯状细胞并破坏了肠道屏障。紧密连接相关基因的表达下调。肠道菌群发生变化， 和 的丰度分别下降了33%和14%，而增加了18%。 TUNEL 结果显示，高剂量 ETO 增加了大脑中的凋亡细胞。大脑中的表达下调。对结肠和大脑的非靶向代谢组学分析表明，ETO 导致甘油磷脂代谢异常。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 引起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对大脑和胃肠系统的有害影响，这对于理解ETO滥用对人类健康的不利影响具有重要意义。