鼠李糖乳杆菌
法尼甾体X受体
内分泌学
牛磺酸
胆汁酸
鹅去氧胆酸
FGF19型
内科学
肝损伤
肠道菌群
胆酸
医学
生物
受体
乳酸菌
生物化学
成纤维细胞生长因子
核受体
氨基酸
发酵
基因
转录因子
作者
Yunhuan Liu,Kefei Chen,Fengyuan Li,Zelin Gu,Qi Liu,Liqing He,Tuo Shao,Qing Song,Fenxia Zhu,Lihua Zhang,Mengwei Jiang,Yun Zhou,Shirish Barve,Xiang Zhang,Craig J. McClain,Wenke Feng
出处
期刊:Hepatology
[Wiley]
日期:2020-03-16
卷期号:71 (6): 2050-2066
被引量:186
摘要
Background and Aims Cholestatic liver disease is characterized by gut dysbiosis and excessive toxic hepatic bile acids (BAs). Modification of gut microbiota and repression of BA synthesis are potential strategies for the treatment of cholestatic liver disease. The purpose of this study was to examine the effects and to understand the mechanisms of the probiotic Lactobacillus rhamnosus GG (LGG) on hepatic BA synthesis, liver injury, and fibrosis in bile duct ligation (BDL) and multidrug resistance protein 2 knockout ( Mdr2−/− ) mice. Approach and Results Global and intestine‐specific farnesoid X receptor (FXR) inhibitors were used to dissect the role of FXR. LGG treatment significantly attenuated liver inflammation, injury, and fibrosis with a significant reduction of hepatic BAs in BDL mice. Hepatic concentration of taurine‐β‐muricholic acid (T‐βMCA), an FXR antagonist, was markedly increased in BDL mice and reduced in LGG‐treated mice, while chenodeoxycholic acid, an FXR agonist, was decreased in BDL mice and normalized in LGG‐treated mice. LGG treatment significantly increased the expression of serum and ileum fibroblast growth factor 15 (FGF‐15) and subsequently reduced hepatic cholesterol 7α‐hydroxylase and BA synthesis in BDL and Mdr2−/− mice. At the molecular level, these changes were reversed by global and intestine‐specific FXR inhibitors in BDL mice. In addition, LGG treatment altered gut microbiota, which was associated with increased BA deconjugation and increased fecal and urine BA excretion in both BDL and Mdr2−/− mice. In vitro studies showed that LGG suppressed the inhibitory effect of T‐βMCA on FXR and FGF‐19 expression in Caco‐2 cells. Conclusion LGG supplementation decreases hepatic BA by increasing intestinal FXR–FGF‐15 signaling pathway–mediated suppression of BA de novo synthesis and enhances BA excretion, which prevents excessive BA‐induced liver injury and fibrosis in mice.
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