Duan Zhicheng, Yang Tingting, Li Lin, Wang Xue, Wei Chujing, Xia Ziyin, Chai Yuanyuan, Huang Xin, Zhang Luyong, Jiang Zhenzhou
New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China.
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China.
J Steroid Biochem Mol Biol. 2022 Jun;220:106100. doi: 10.1016/j.jsbmb.2022.106100. Epub 2022 Mar 25.
Bile acids (BAs) were selected as biomarkers for the diagnosis and prevention of multiple liver diseases, and they were also considered as an important signal transductor via "liver-gut" axis. As important factors for maintaining the normal function and tissue morphology, BA homeostasis throughout the enterohepatic circulation system was guaranteed by BA synthases and transporters, nuclear receptors (NRs) and gut microbiota, all of which presented significant species differences. Thus, we simultaneously quantify BA profiles in the enterohepatic circulation of SD rats and C57BL/6 mice to reveal the species differences of BA homeostasis between these two main rodents of preclinical studies. Our results showed that BA profiles of mice plasma, bile and liver were most dissimilar from these of rats. Meanwhile, BAs profiles also presented obvious species differences in the intestine of mice and rats, especially small intestine. Unlike rats, taurine-conjugated bile acids (T-BAs) were predominant in mice small intestine content and tissue, in which taurocholic acid (TCA) was the most prominent BAs. BAs dynamic analysis showed that compared with rats, mice showed stranger taurine and glycine de-conjugations in lager intestine. However, both the ratios of unconjugated bile acids (Un-BAs) to conjugated BAs, and secondary BAs to primary BAs in mice small content and tissue were all much lower than these in rats. Furthermore, ileum BAs profiles also showed significantly separation trend between rats and mice, whether content or tissue. Our data revealed that the patterns of BAs homeostasis in mice enterohepatic circulation system were significantly different from these in rats (especially in intestine), suggesting that more cautious should be paid to the selection of BAs as biomarkers for disease diagnosis or/and drug induced toxicity, and the certain role and mechanism of individual BA in the pathological process of BA-related diseases via "liver-gut" axis should be verified by using of multiple species.
胆汁酸（BAs）被选为多种肝脏疾病诊断和预防的生物标志物，并且它们还被视为通过“肝-肠”轴的重要信号转导分子。作为维持正常功能和组织形态的重要因素，整个肠肝循环系统中的胆汁酸稳态由胆汁酸合成酶和转运体、核受体（NRs）以及肠道微生物群保证，所有这些都呈现出显著的物种差异。因此，我们同时定量分析了SD大鼠和C57BL/6小鼠肠肝循环中的胆汁酸谱，以揭示这两种临床前研究中主要啮齿动物之间胆汁酸稳态的物种差异。我们的结果表明，小鼠血浆、胆汁和肝脏中的胆汁酸谱与大鼠的最为不同。同时，胆汁酸谱在小鼠和大鼠的肠道中也呈现出明显的物种差异，尤其是在小肠中。与大鼠不同，牛磺酸结合型胆汁酸（T-BAs）在小鼠小肠内容物和组织中占主导地位，其中牛磺胆酸（TCA）是最突出的胆汁酸。胆汁酸动态分析表明，与大鼠相比，小鼠在大肠中表现出更强的牛磺酸和甘氨酸去结合作用。然而，小鼠小肠内容物和组织中未结合胆汁酸（Un-BAs）与结合胆汁酸的比例以及次级胆汁酸与初级胆汁酸的比例均远低于大鼠。此外，无论内容物还是组织，回肠胆汁酸谱在大鼠和小鼠之间也呈现出明显的分离趋势。我们的数据表明，小鼠肠肝循环系统中胆汁酸稳态模式与大鼠显著不同（尤其是在肠道中），这表明在选择胆汁酸作为疾病诊断或/和药物诱导毒性的生物标志物时应更加谨慎，并且应通过多种物种验证单个胆汁酸在胆汁酸相关疾病病理过程中通过“肝-肠”轴的特定作用和机制。
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