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Probiotic LGG prevents liver fibrosis through inhibiting hepatic bile acid synthesis and enhancing bile acid excretion in mice.
益生菌 LGG 通过抑制小鼠肝胆汁酸合成和增强胆汁酸排泄预防肝纤维化。
Mdr2-/- Bile-duct ligation Cholestatic liver disease FXR/FGF-15 Probiotics
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摘要

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 bile acid synthesis, liver injury and fibrosis in bile-duct ligation (BDL) and Mdr2-/- mice. Global and intestinal specific 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 T-βMCA, an FXR antagonist, was markedly increased in BDL mice and reduced in LGG-treated mice, while chenodeoxycholic acid (CDCA), an FXR agonist, was decreased in BDL mice and normalized in LGG-treated mice. LGG treatment significantly increased the expression of serum and ileum FGF15 and subsequently reduced hepatic CYP7A1 and BA synthesis in BDL and Mdr2-/- mice. At the molecular level, these changes were reversed by global and intestinal specific FXR inhibitors in BDL mice. In addition, LGG treatment altered gut microbiota, which was associated with increased BA de-conjugation and increased fecal and urine BA excretion both in BDL and Mdr2-/- mice. In vitro studies showed that LGG suppressed the inhibitory effect of T-βMCA on FXR and FGF19 expression in Caco-2 cells. Conclusion: LGG supplementation decreases hepatic BA by increasing intestinal FXR/FGF15 signaling pathway-mediated suppression of BA de novo synthesis and enhances BA excretion, which prevents excessive BA-induced liver injury and fibrosis in mice.

译文

胆汁淤积性肝病的特征是肠道生态失调和过量的中毒性肝胆汁酸 (BAs)。肠道菌群的改变和 BA 合成的抑制是治疗胆汁淤积性肝病的潜在策略。本研究的目的是检验益生菌鼠李糖乳杆菌 GG (LGG) 对肝胆汁酸合成的影响并了解其机制, 胆管结扎 (BDL) 和 Mdr2-/-小鼠的肝损伤和纤维化。全局和肠道特异性 FXR 抑制剂用于剖析 FXR 的作用。LGG 治疗显著减轻了 BDL 小鼠的肝脏炎症、损伤和纤维化,并显著减少了肝脏 BAs。T-β mca (一种 FXR 拮抗剂) 的肝脏浓度在 BDL 小鼠中显著增加,在 LGG 处理的小鼠中减少,而鹅去氧胆酸 (CDCA),一种 FXR 激动剂, 在 BDL 小鼠中降低,在 LGG 处理的小鼠中正常化。LGG 处理显著增加了 BDL 和 Mdr2-/-小鼠血清和回肠 FGF15 的表达,随后减少了肝脏中 CYP7A1 和 BA 的合成。在分子水平上,这些变化被 BDL 小鼠的全局和肠道特异性 FXR 抑制剂逆转。此外,LGG 治疗改变了肠道菌群,这与 BDL 和 Mdr2-/-小鼠体内 BA 脱附增加以及粪便和尿液 BA 排泄增加有关。体外研究表明,LGG 抑制 T-β mca 对 Caco-2 细胞中 FXR 和 FGF19 表达的抑制作用。结论: 补充 LGG 通过增加肠道 FXR/FGF15 信号通路介导的 BA 从头合成抑制和增强 BA 排泄来降低肝 BA, 防止过量 BA 引起的小鼠肝损伤和纤维化。

liver fibrosis

消化 疾病病理状态 临床研究术语
概述  :  

肝硬化是各种慢性肝病进展为肝纤维化的必然过程,肝纤维化程度的准确评估对其可逆性治疗具有重要的临床意义。肝穿刺活组织检查一直是肝纤维化评估的“金标准”,然而因其具有侵入性、局限性、取样误差等缺点不易被患者和临床医生接受。因此,越来越多肝穿刺活组织检查的替代方法在临床工作中得到了重视和发展。目前,肝移植仍是治疗终末期肝硬化的唯一手段。   随着血清学技术和影像学技术的发展和改进,肝穿刺活组织检查在肝纤维化诊断中的应用已经逐渐减少。早期观点认为肝纤维化和

liver 英 /ˈlɪvə(r)/  美 /ˈlɪvər/

释义   n. 肝脏

例句   Her life was finally extinguished by the onset of liver complaint. 她的生命之火终因肝病发作而被掐灭了。

 

fibrosis 英 /faɪ'brəʊsɪs/  美 /faɪ'brosɪs/

释义   n. [医] 纤维化,[病理] 纤维变性

例句   A few diseases, such as cystic fibrosis and sickle cell anemia, are caused by a single SNP.一些疾病,比如囊肿性纤维化和镰状细胞性贫血是由一种SNP引起的。

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