Microbiota-driven gut vascular barrier disruption is a prerequisite for non-alcoholic steatohepatitis development

作者：Juliette Mouriès, Paola Brescia, Alessandra Silvestri, Ilaria Spadoni, Marcel Sorribas, Reiner Wiest, Erika Mileti, Marianna Galbiati, Pietro Invernizzi, Luciano Adorini, Giuseppe Penna, María Rescigno · 发表于：Journal of Hepatology · 年份：2019 · DOI：10.1016/j.jhep.2019.08.005 · 被引用次数：675 · 研究领域：Liver Disease Diagnosis and Treatment、Gut microbiota and health、Barrier Structure and Function Studies

BACKGROUND & AIMS: Fatty liver disease, including non-alcoholic 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/β-catenin signaling pathway, as shown by genetic intervention driving β-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 β-catenin activation in endothelial cells. Accordingly, pharmacologic intervention with OCA protects ag...