目的 基于干酵母混悬液诱导的发热大鼠模型，评价牛胆汁的解热效果，并进一步通过基于UPLC-MS/MS的代谢组学方法探索其潜在的作用机制。方法 40只SD大鼠随机分为对照组、模型组、对乙酰氨基酚（200 mg/kg）组、牛胆汁（10 mL/kg）组及猪胆汁（10 mL/kg）组，以背部sc 20%干酵母混悬液的方式构建发热大鼠模型，分别于造模前0.5 h及造模后3.5 h对各给药组大鼠给予药物干预，并于造模后第0、4、5、6、7、8小时测量大鼠肛温，收集造模后8 h大鼠血清及脑组织，采用ELISA法检测大鼠血清中肿瘤坏死因子-α（tumor necrosis factor α，TNF-α）、白细胞介素-1β（interleukin-1β，IL-1β）、IL-6及下丘脑中前列腺素E₂（prostaglandin E₂，PGE₂）、环磷酸腺苷（cyclic adenosine monophosphate，cAMP）的含量；采用超高效液相色谱-四极杆飞行时间质谱（UPLC-Q-TOF-MS）对大鼠的血清及下丘脑进行代谢组学分析，探究其潜在的生物标志物，结合血清及下丘脑代谢组学的相关分析结果及ELISA指标，共同阐释牛胆汁的解热作用机制。结果 造模4 h后模型组大鼠肛温显著升高（P＜0.01），牛胆汁组大鼠肛温显著低于模型组（P＜0.01），牛胆汁能够显著抑制发热导致的TNF-α、IL-1β、IL-6、PGE₂、cAMP含量增加（P＜0.01）。代谢组学结果表明干酵母致大鼠发热后血清及下丘脑的代谢轮廓发生了显著的变化，分别从其中鉴定得到24、18种内源性代谢物，给予牛胆汁干预后其含量均显著回调，主要影响花生四烯酸代谢、甘油磷脂代谢、丙酮酸代谢、柠檬酸循环、鞘脂代谢、嘧啶代谢、氨基酸代谢、糖代谢等途径。结论 牛胆汁对干酵母所致发热大鼠模型具有显著的解热作用，其作用机制可能与抑制内源性致热源的释放及调节机体的脂质代谢、氨基酸代谢、糖代谢有关，具有多靶点、多途径的特征。

Objective To evaluate the antipyretic effect of bovine bile through a fever rat model induced by dry yeast suspension and further explore its potential mechanism through metabolomics based on UPLC-MS/MS. Methods A total of 40 SD rats were randomly divided into control group, model group, acetaminophen (200 mg/kg) group, bovine bile (10 mL/kg) group and pig bile (10 mL/kg) group. Fever rat model was constructed by subcutaneous injection of 20% dry yeast suspension into the back. Drug was orally administrated to each treated group of rats 0.5 h before and 3.5 h after modeling, and the rectal temperature of rats were monitored at 0, 4, 5, 6, 7 and 8 h after modeling. The serum and brain tissue of rats were collected 8 h after modeling. The contents of tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), IL-6 in serum and prostaglandin E₂ (PGE₂), cyclic adenosine monophosphate (cAMP) in hypothalamus were detected using ELISA method. Metabolomics analysis was conducted on the serum and hypothalamus of rats through ultra high performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) to explore their potential biomarkers. Then, the antipyretic mechanism of bovine bile was elucidated combined with relevant analysis results of serum and hypothalamic metabolomics and ELISA indicators. Results The rectal temperature of rats in model group was significantly increased after 4 h of modeling compared with control rats (P < 0.01), while the temperature of bovine bile group was significantly lower than that in model group (P < 0.01). Besides, the increasing contents of TNF-α, IL-1β, IL-6, PGE₂, cAMP resulted from fever rats were reversed by oral administration of bovine bile (P < 0.01). The metabolomics results revealed the significant changes of metabolic profiles from serum and hypothalamus in fever rats, 24 and 18 endogenous metabolites were identified, respectively. Their contents were significantly reversed after intervention with bovine bile, mainly affecting pathways such as arachidonic acid metabolism, glycerophospholipid metabolism, pyruvate metabolism, citric acid cycle, sphingolipid metabolism, pyrimidine metabolism, amino acid metabolism and sugar metabolism. Conclusion The bovine bile exerts a significant antipyretic action on a dry yeast induced fever rat model, and its underlying mechanism may be related to inhibiting the release of endogenous heat sources and regulating the lipid metabolism, amino acid metabolism and sugar metabolism, with the characteristics of multiple targets and pathways.

R285.5

国家重点研发计划项目（2018YFC1707100）；中药传承与创新“百千万”人才工程——岐黄工程首席科学家项目（国中医药人教函[2021]7号）；2022年全国名老中医药专家传承工作室建设项目（国中医药人教函[2022]75号）；第七批全国老中医药专家学术经验继承工作项目（国中医药人教函[2022]76号）；黑龙江省“头雁”团队支持项目（黑龙江省头雁行动领导小组文件[2019]5号）