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

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          Graphical abstract

          Highlights

          • During diet-induced dysbiosis the gut vascular barrier is disrupted.

          • Gut vascular barrier disruption is responsible for the translocation of bacteria or bacterial products systemically.

          • Inhibiting gut vascular barrier disruption prevents the development of non-alcoholic steatohepatitis.

          • Obeticholic acid can control gut vascular barrier disruption both in a preventive and therapeutic way.

          Abstract

          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 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 β-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.

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          Most cited references29

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          A gut-vascular barrier controls the systemic dissemination of bacteria.

          In healthy individuals, the intestinal microbiota cannot access the liver, spleen, or other peripheral tissues. Some pathogenic bacteria can reach these sites, however, and can induce a systemic immune response. How such compartmentalization is achieved is unknown. We identify a gut-vascular barrier (GVB) in mice and humans that controls the translocation of antigens into the blood stream and prohibits entry of the microbiota. Salmonella typhimurium can penetrate the GVB in a manner dependent on its pathogenicity island (Spi) 2-encoded type III secretion system and on decreased β-catenin-dependent signaling in gut endothelial cells. The GVB is modified in celiac disease patients with elevated serum transaminases, which indicates that GVB dismantling may be responsible for liver damage in these patients. Understanding the GVB may provide new insights into the regulation of the gut-liver axis.
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            Increased intestinal permeability precedes clinical onset of type 1 diabetes.

            Recent observations have shown subclinical intestinal abnormalities in human type 1 diabetes. Whether these are related to the pathogenetic process or secondary to the diabetes remains to be clarified. The aim of this study was to investigate this issue by examining intestinal permeability to sugars in subjects at different stages of type 1 diabetes: preclinical, new-onset and long-term established disease. Eighty-one subjects with islet autoimmunity (18 preclinical, 28 new-onset and 35 long-term type 1 diabetes) and 40 healthy control subjects were investigated by a lactulose-mannitol test, consisting of oral administration of the two sugars and measurement of their urinary excretion. All groups of subjects with islet autoimmunity showed an increase in intestinal permeability (p < or = 0.009 vs controls) to the disaccharide lactulose, indicative of a damaged barrier, but a similar permeability to the monosaccharide mannitol (NS vs controls), indicative of an integral surface mucosa; consequently there was an increase in the lactulose:mannitol excretion ratio (p < or = 0.025 vs controls). These findings indicate the presence of a subclinical enteropathy associated with type 1 diabetes that is already detectable before clinical onset of the disease, and suggest that the small intestine is an organ participating in the pathogenetic process of type 1 diabetes.
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              Sex and Depot Differences in Adipocyte Insulin Sensitivity and Glucose Metabolism

              OBJECTIVE To investigate how insulin sensitivity and glucose metabolism differ in adipocytes between different fat depots of male and female mice and how sex steroids contribute to these differences. RESEARCH DESIGN AND METHODS Adipocytes from intra-abdominal/perigonadal (PG) and subcutaneous (SC) adipose tissue from normal, castrated, or steroid-implanted animals were isolated and analyzed for differences in insulin sensitivity and glucose metabolism. RESULTS Adipocytes from both PG and SC depots of females have increased lipogenic rates compared with those from males. In females, intra-abdominal PG adipocytes are more insulin-sensitive than SC adipocytes and more insulin-sensitive than male adipocytes from either depot. When stimulated by low physiological concentrations of insulin, female PG adipocytes show a robust increase in Akt and extracellular signal–related kinase (ERK) phosphorylation and lipogenesis, whereas male adipocytes show activation only at higher insulin concentrations. Adipocytes from females have higher mRNA/protein levels of several genes involved in glucose and lipid metabolism. After castration, adipocytes of male mice showed increased insulin sensitivity and increased lipogenic rates, whereas adipocytes of females demonstrate decreased lipid production. Increasing estrogen above physiological levels, however, also reduced lipid synthesis in females, whereas increasing dihydrotestosterone in males had no effect. CONCLUSIONS There are major sex differences in insulin sensitivity in adipose tissue, particularly in the intra-abdominal depot, that are regulated by physiological levels of sex steroids. The increased sensitivity to insulin and lipogenesis observed in adipocytes from females may account for their lower level of insulin resistance and diabetes risk despite similar or higher fat content than in males.
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                Author and article information

                Contributors
                Journal
                J Hepatol
                J. Hepatol
                Journal of Hepatology
                Elsevier
                0168-8278
                1600-0641
                1 December 2019
                December 2019
                : 71
                : 6
                : 1216-1228
                Affiliations
                [1 ]Humanitas Clinical and Research Center – IRCCS –, via Manzoni 56, 20089 Rozzano, MI, Italy
                [2 ]Humanitas University, Department of Biomedical Sciences, Via Rita Levi Montalcini, 20090 Pieve Emanuele, MI, Italy
                [3 ]Maurice Müller Laboratories, Department for Biomedical Research, University of Bern, Bern, Switzerland
                [4 ]Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland
                [5 ]European Institute of Oncology, Department of Experimental Oncology, 20139 Milan, MI, Italy
                [6 ]Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, MI, Italy
                [7 ]Intercept Pharmaceuticals, New York, NY 10014, USA
                [8 ]Postbiotica srl, Via Rita Levi Montalcini, 20090 Pieve Emanuele, MI, Italy
                Author notes
                [* ]Corresponding author. Address: Humanitas Clinical and Research Center – IRCCS –, via Manzoni 56, 20089 Rozzano, MI, Italy. maria.rescigno@ 123456hunimed.eu
                Article
                S0168-8278(19)30471-4
                10.1016/j.jhep.2019.08.005
                6880766
                31419514
                21cb70d0-3b2e-4d85-b154-a54599f5741b
                © 2019 European Association for the Study of the Liver. Published by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 21 December 2018
                : 29 July 2019
                : 2 August 2019
                Categories
                Article

                Gastroenterology & Hepatology
                Gastroenterology & Hepatology

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