Microbiota-driven gut vascular barrier disruption is a prerequisite for non-alcoholic steatohepatitis development
Microbiota-driven gut vascular barrier disruption is a prerequisite for non-alcoholic steatohepatitis development
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DOI：
10.1016/j.jhep.2019.08.005
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发表时间：
2019-12-01
影响因子：
25.7
通讯作者：
Rescigno, Maria
中科院分区：
文献类型：
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作者：
Mouries, Juliette;Brescia, Paola;Rescigno, Maria
背景和目标：脂肪肝疾病，包括非酒精性脂肪肝（NAFLD）和脂肪性肝炎（NASH），与肠道屏障通透性增加和细菌或细菌产物易位到血液循环中有关。在这项研究中，我们的目的是解开在NAFLD/NASHdevelopment.Methods的肠道屏障的完整性和微生物群的作用：C57 BL/6 J小鼠喂食高脂肪饮食（HFD）或蛋氨酸胆碱缺乏饮食1周或更长的时间，以概括NASH的方面（脂肪变性，炎症，胰岛素抵抗）。遗传和药理学策略，然后用于调节肠屏障integrity.Results：我们表明，破坏肠上皮屏障和肠血管屏障（GVB）是NASH发病机制的早期事件。喂食HFD仅1周的小鼠经历饮食诱导的生态失调，其驱动GVB损伤和细菌移位到肝脏中。将来自HFD喂养小鼠的粪便微生物群移植到无特定病原体的受体中诱导GVB损伤和附睾脂肪组织增大。GVB破坏依赖于对WNT/β-连环蛋白信号传导途径的干扰，如通过仅在内皮细胞中驱动β-连环蛋白活化的遗传干预所示，从而防止GVB破坏和NASH发展。胆汁酸类似物和法尼醇X受体激动剂奥贝胆酸（OCA）驱动内皮细胞中的β-连环蛋白激活。因此，用OCA进行药物干预可作为预防剂和治疗剂防止GVB破坏。重要的是，我们发现上调的GVB泄漏标记物在结肠NASH.Conclusions患者：我们已经确定了一个新的球员在NASH的发展，GVB，其损害导致细菌或细菌产物易位到血液循环。在美国，脂肪肝的发病率已达到流行病的水平，超过30%的成年人患有NAFLD（非酒精性脂肪肝），这可能会发展为更严重的非酒精性脂肪性肝炎（NASH）。在此，我们发现肠上皮屏障和肠血管屏障的破坏是NASH发展的早期事件。我们表明，药物奥贝胆酸可防止屏障破坏，从而防止NASH的发展，为其用于预防或治疗NASH提供了进一步的证据。(C)2019年欧洲肝脏研究协会。由爱思唯尔公司出版
Background & Aims: Fatty liver disease, including nonalcoholic fatty liver (NAFLD) and steatohepatitis (NASH), has been associated with increased intestinal barrier permeability and translocation of bacteria or bacterial products into the blood circulation. In this study, we aimed to unravel the role of both intestinal barrier integrity and microbiota in NAFLD/NASH development.Methods: C57BL/6J mice were fed with high-fat diet (HFD) or methionine-choline-deficient diet for 1 week or longer to recapitulate aspects of NASH (steatosis, inflammation, insulin resistance). Genetic and pharmacological strategies were then used to modulate intestinal barrier integrity.Results: We show that disruption of the intestinal epithelial barrier and gut vascular barrier (GVB) are early events in NASH pathogenesis. Mice fed HFD for only 1 week undergo a diet-induced dysbiosis that drives GVB damage and bacterial translocation into the liver. Fecal microbiota transplantation from HFD-fed mice into specific pathogen-free recipients induces GVB damage and epididymal adipose tissue enlargement. GVB disruption depends on interference with the WNT/beta-catenin signaling pathway, as shown by genetic intervention driving beta-catenin activation only in endothelial cells, preventing GVB disruption and NASH development. The bile acid analogue and farnesoid X receptor agonist obeticholic acid (OCA) drives beta-catenin activation in endothelial cells. Accordingly, pharmacologic intervention with OCA protects against GVB disruption, both as a preventive and therapeutic agent. Importantly, we found upregulation of the GVB leakage marker in the colon of patients with NASH.Conclusions: We have identified a new player in NASH development, the GVB, whose damage leads to bacteria or bacterial product translocation into the blood circulation. Treatment aimed at restoring beta-catenin activation in endothelial cells, such as administration of OCA, protects against GVB damage and NASH development.Lay summary: The incidence of fatty liver disease is reaching epidemic levels in the USA, with more than 30% of adults having NAFLD (non-alcoholic fatty liver disease), which can progress to more severe non-alcoholic steatohepatitis (NASH). Herein, we show that disruption of the intestinal epithelial barrier and gut vascular barrier are early events in the development of NASH. We show that the drug obeticholic acid protects against barrier disruption and thereby prevents the development of NASH, providing further evidence for its use in the prevention or treatment of NASH. (C) 2019 European Association for the Study of the Liver. Published by Elsevier B.V.