Abstract：
Drug-induced liver injury (DILI) is a common and severe adverse drug reaction that can result in acute liver failure. Previously, we have shown that Lycium barbarum L. (wolfberry) ameliorated liver damage in acetaminophen (APAP)-induced DILI. Nevertheless, the mechanism needs further clarification. Herein, we utilized APAP-induced DILI mice to investigate how wolfberry impacts the gut-liver axis to mitigate liver damage. We showed that the abundance of Akkermansia muciniphila (A. muciniphila) was decreased, and intestinal microbiota was disrupted, while the expression levels of YAP1 and FXR-mediated CYP7A1 were reduced in the liver of DILI mice. Furthermore, wolfberry increased the abundance of A. muciniphila and the number of goblet cells in the intestines, while decreasing AST, ALT, and total bile acids (TBA) levels in the serum. Interestingly, A. muciniphila promoted YAP1 and FXR expression in hepatocytes, leading to the inhibition of CYP7A1 expression and a decrease in TBA content. Notably, wolfberry did not exert the beneficial effects mentioned above after the removal of intestinal bacteria by antibiotics (ATB)-containing water. Additionally, Yap1 knockout downregulated FXR expression and enhanced CYP7A1 expression in the liver of hepatocyte-specific Yap1 knockout mice. Therefore, wolfberry stimulated YAP1/FXR activation and reduced CYP7A1 expression by promoting the balance of intestinal microbiota, thereby suppressing the overproduction of bile acids.
摘要：
药物性肝损伤（DILI）是一种常见且严重的药物不良反应，可导致急性肝衰竭。以前,我们已经证明枸杞（枸杞）改善对乙酰氨基酚（APAP）诱导的DILI的肝损伤。然而，该机制需要进一步澄清。在这里，我们利用APAP诱导的DILI小鼠研究枸杞如何影响肠-肝轴以减轻肝损伤。我们证明了阿克克曼西亚的丰度（A.粘虫)减少，肠道微生物群被破坏了，而YAP1和FXR介导的CYP7A1在DILI小鼠肝脏中的表达水平降低。此外，枸杞增加了粘虫的丰度和肠道杯状细胞的数量，在降低AST的同时，ALT,和血清中总胆汁酸（TBA）水平。有趣的是,A.黏蛋白在肝细胞中促进YAP1和FXR表达，导致CYP7A1表达抑制和TBA含量降低。值得注意的是,通过含有抗生素（ATB）的水去除肠道细菌后，枸杞没有发挥上述有益作用。此外,Yap1敲除下调FXR表达并增强肝细胞特异性Yap1敲除小鼠肝脏中CYP7A1的表达。因此,枸杞通过促进肠道菌群平衡,刺激YAP1/FXR激活,降低CYP7A1表达,从而抑制胆汁酸的过量产生。
