FXR modulates the gut-vascular barrier by regulating the entry sites for bacterial translocation in experimental cirrhosis
FXR modulates the gut-vascular barrier by regulating the entry sites for bacterial translocation in experimental cirrhosis
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DOI：
10.1016/j.jhep.2019.06.017
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发表时间：
2019-12-01
影响因子：
25.7
通讯作者：
Wiest, Reiner
中科院分区：
文献类型：
--
作者：
Sorribas, Marcel;Jakob, Manuel O.;Wiest, Reiner
背景与目的：肝硬变的病理性细菌易位是自发性细菌感染的标志，可使死亡率增加数倍。尽管粘液层的作用尚未详细阐述，但已知肠道通透性增加与肝硬变的PBT有关。肠腔细菌移位的明确途径尚未确定，但我们假设最近描述的肠-血管屏障(GVB)在实验性门静脉高压症中受到损害，导致血管腔内细菌移位的可达性增加。材料：使用胆管结扎(BDL)和CCL4诱导小鼠模型肝硬变。门静脉部分结扎(PPVL)诱导肝前性门脉高压。结果：健康和肝前性门静脉高压症(PPVL)小鼠缺乏FITC-葡聚糖和GFP-E的易位。BDL和CCl4诱导的肝硬变小鼠表现出病理性移位，这种移位不会因之前的胸导管结扎而改变。肝硬变小鼠的粘液层厚度减少，杯状细胞减少，Muc2染色和表达减少，但PPVL小鼠没有。这些变化与内粘液层细菌过度生长和GFP-E的病理性移位有关。大肠埃希氏菌通过回肠上皮。大体积150 kDa-FITC-葡聚糖回肠渗出的BDL和CCl4小鼠的GVB发生了深刻的改变，但在PPVL小鼠中只有轻微的改变。肝硬变小鼠内皮细胞的这种病理性通透性和可达性与肠道血管中PV1的表达增强有关。OCA而不是非沙拉明可以稳定GVB，而两种FXR激动剂都能改善GFP-E的肠道到肝脏易位。结论：门静脉高压症本身不是门脉高压，而是肝硬变严重损害了血管内皮细胞和粘膜上皮屏障，促进了PBT对门静脉循环的作用。这两种屏障似乎都是FXR调节的，FXR激动剂通过门静脉途径减少PBT。Lay概要：肠道细菌要进入体循环，它们必须穿过粘液和上皮层，以及肠血管屏障。肝硬变破坏了所有这三个屏障，使细菌能够进入门静脉循环，从而进入肠道-肝轴。随着FXR激动剂减少细菌通过门静脉途径进入肝脏，管腔胆汁酸的可获得性降低、肝硬变以及与之相关的法尼类X受体(FXR)信号的减少似乎至少部分地介导了这些变化。(C)2019年欧洲肝脏研究协会。爱思唯尔出版，版权所有。
Background & Aims: Pathological bacterial translocation (PBT) in cirrhosis is the hallmark of spontaneous bacterial infections, increasing mortality several-fold. Increased intestinal permeability is known to contribute to PBT in cirrhosis, although the role of the mucus layer has not been addressed in detail. A clear route of translocation for luminal intestinal bacteria is yet to be defined, but we hypothesize that the recently described gut-vascular barrier (GVB) is impaired in experimental portal hypertension, leading to increased accessibility of the vascular compartment for translocating bacteria.Materials: Cirrhosis was induced in mouse models using bileduct ligation (BDL) and CCl4. Pre-hepatic portal-hypertension was induced by partial portal vein ligation (PPVL). Intestinal permeability was compared in these mice after GFP-Escherichia coli or different sized FITC-dextrans were injected into the intestine.Results: Healthy and pre-hepatic portal-hypertensive (PPVL) mice lack translocation of FITC-dextran and GFP-E. coli from the small intestine to the liver, whereas BDL and CCl4-induced cirrhotic mice demonstrate pathological translocation, which is not altered by prior thoracic-duct ligation. The mucus layer is reduced in thickness, with loss of goblet cells and Muc2-staining and expression in cirrhotic but not PPVL mice. These changes are associated with bacterial overgrowth in the inner mucus layer and pathological translocation of GFP-E. coli through the ileal epithelium. GVB is profoundly altered in BDL and CCl4-mice with Ileal extravasation of large-sized 150 kDa-FITC-dextran, but only slightly altered in PPVL mice. This pathological endothelial permeability and accessibility in cirrhotic mice is associated with augmented expression of PV1 in intestinal vessels. OCA but not fexaramine stabilizes the GVB, whereas both FXR-agonists ameliorate gut to liver translocation of GFP-E. coli.Conclusions: Cirrhosis, but not portal hypertension per se, grossly impairs the endothelial and muco-epithelial barriers, promoting PBT to the portal-venous circulation. Both barriers appear to be FXR-modulated, with FXR-agonists reducing PBT via the portal-venous route.Lay summary: For intestinal bacteria to enter the systemic circulation, they must cross the mucus and epithelial layer, as well as the gut-vascular barrier. Cirrhosis disrupts all 3 of these barriers, giving bacteria access to the portal-venous circulation and thus, the gut-liver axis. Diminished luminal bile acid availability, cirrhosis and the associated reduction in farnesoid x receptor (FXR) signaling seem, at least partly, to mediate these changes, as FXR-agonists reduce bacterial translocation via the portal-venous route to the liver in cirrhosis. (C) 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.