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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Probiotic Lactobacillus rhamnosus Lactobacillus rhamnosus GG Prevents Liver Fibrosis Through Inhibiting Hepatic Bile Acid Synthesis and Enhancing Bile Acid Excretion in Mice
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Probiotic Lactobacillus rhamnosus Lactobacillus rhamnosus GG Prevents Liver Fibrosis Through Inhibiting Hepatic Bile Acid Synthesis and Enhancing Bile Acid Excretion in Mice

机译：益生菌乳酸杆菌乳菌乳杆菌GG通过抑制肝胆酸合成并增强小鼠的胆汁酸排泄来防止肝纤维化

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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.
机译：背景和AIMS胆汁淤积性肝病的特征在于肠道脱泻和过量有毒的肝胆汁酸（BAS）。肠道微生物的改性和BA合成的抑制是治疗胆汁淤泥肝病的潜在策略。本研究的目的是检查肝脏BA合成，肝损伤和胆管结扎（BDL）和多药抗性蛋白2敲除（MDR2）的肝脏BA合成，肝损伤和纤维化的益生菌乳杆菌菌株GG（LGG）的效果和理解效果。 /？ ） 老鼠。方法和结果全局和肠特异性法呢X受体（FXR）抑制剂用于剖析FXR的作用。 LGG治疗显着减弱了肝脏炎症，损伤和纤维化，在BDL小鼠中显着减少了肝族。在BDL小鼠中，牛磺酸-β-杂色酸（T-βMCA）的肝细胞浓度明显增加，并且在宜曲处理的小鼠中减少，而ChenodeOxycholic酸是FXR激动剂，在BDL小鼠中降低并在LGG中归一化 - 治疗的小鼠。 LGG治疗显着增加了血清和回肠成纤维细胞生长因子15（FGF-15）的表达，随后在BDL和MDR2中减少了肝胆固醇7α-羟化酶和BA合成的β-/？老鼠。在分子水平下，通过BDL小鼠的全球和肠特异性FXR抑制剂逆转这些变化。此外，LGG治疗改变了肠道微生物肿，这与BA剥皮增加的增加和BDL和MDR2中的粪便和尿液BA排泄增加了？/？老鼠。体外研究表明，LGG抑制了T-βMCA对Caco-2细胞中FXR和FGF-19表达的抑制作用。结论LGG补充通过增加肠FXR-FGF-15信号通路介导的BA de Novo合成的抑制来降低肝BA，并增强BA排泄，这防止了小鼠的过度BA诱导的肝损伤和纤维化。

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