Intestinal Epithelial Cell-Derived Extracellular Vesicles Modulate Hepatic Injury via the Gut-Liver Axis During Acute Alcohol Injury
Frontiers in Pharmacology, vol. 11, pp. 603771
Abstract
Binge drinking, i.e., heavy episodic drinking in a short time, has recently become an alarming societal problem with negative health impact. However, the harmful effects of acute alcohol injury in the gut-liver axis remain elusive. Hence, we focused on the physiological and pathological changes and the underlying mechanisms of experimental binge drinking in the context of the gut-liver axis. Eight-week-old mice with a C57BL/6 background received a single dose (p.o.) of ethanol (EtOH) [6 g/kg b.w.] as a preclinical model of acute alcohol injury. Controls received a single dose of PBS. Mice were sacrificed 8 h later. In parallel, HepaRGs and Caco-2 cells, human cell lines of differentiated hepatocytes and intestinal epithelial cells intestinal epithelial cells (IECs), respectively, were challenged in the presence or absence of EtOH [0–100 mM]. Extracellular vesicles (EVs) isolated by ultracentrifugation from culture media of IECs were added to hepatocyte cell cultures. Increased intestinal permeability, loss of zonula occludens-1 (ZO-1) and MUCIN-2 expression, and alterations in microbiota—increased Lactobacillus and decreased Lachnospiraceae species—were found in the large intestine of mice exposed to EtOH. Increased TUNEL-positive cells, infiltration of CD11b-positive immune cells, pro-inflammatory cytokines (e.g., tlr4 , tnf , il1β ), and markers of lipid accumulation (Oil Red O, srbep1 ) were evident in livers of mice exposed to EtOH, particularly in females. In vitro experiments indicated that EVs released by IECs in response to ethanol exerted a deleterious effect on hepatocyte viability and lipid accumulation. Overall, our data identified a novel mechanism responsible for driving hepatic injury in the gut-liver axis, opening novel avenues for therapy.
Authors 18
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Universidad Complutense de Madrid · Research Institute Hospital 12 de Octubre
Affiliation as printed
12 de Octubre Health Research Institute (imas12), Madrid, Spain
Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain
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Spanish National Centre for Cardiovascular Research · Hospital General Universitario Gregorio Marañón · Centro de Investigación Biomédica en Red de Salud Mental · Instituto de Investigación Sanitaria Gregorio Marañón · Universidad Carlos III de Madrid
Affiliation as printed
Bioengineering and Aerospace Engineering Department, Universidad Carlos III de Madrid, Madrid, Spain
Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
Centro de Investigación Biomédico en Red de Salud Mental (CIBERSAM), Madrid, Spain
Servicio de Aparato Digestivo del Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
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Universidad Complutense de Madrid
Affiliation as printed
Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain
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Universitätsklinikum Knappschaftskrankenhaus Bochum · Ruhr University Bochum
Affiliation as printed
Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany
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University Hospital Magdeburg · Otto-von-Guericke-Universität Magdeburg
Affiliation as printed
Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto von Guericke University Hospital Magdeburg, Magdeburg, Germany
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Hospital General Universitario Gregorio Marañón · Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas · Instituto de Investigación Sanitaria Gregorio Marañón
Affiliation as printed
Centre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, Spain
Servicio de Aparato Digestivo del Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
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Universidad Complutense de Madrid · Shanghai Jiao Tong University · Ruijin Hospital · Research Institute Hospital 12 de Octubre
Affiliation as printed
12 de Octubre Health Research Institute (imas12), Madrid, Spain
Department of General Surgery, Hepatobiliary Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain
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Universidad Complutense de Madrid · Research Institute Hospital 12 de Octubre · Zhongda Hospital Southeast University · Southeast University
Affiliation as printed
12 de Octubre Health Research Institute (imas12), Madrid, Spain
Department of Anesthesiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain
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Universidad Complutense de Madrid · Research Institute Hospital 12 de Octubre
Affiliation as printed
12 de Octubre Health Research Institute (imas12), Madrid, Spain
Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain
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Universidad Complutense de Madrid · Centro de Investigación Biomédica en Red de Enfermedades Respiratorias · Universitätsklinikum Knappschaftskrankenhaus Bochum · Centro de Investigación Biomédica en Red · Ruhr University Bochum
Affiliation as printed
Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany
Department of Pharmacology and Toxicology, Complutense University School of Medicine and Centre for Biomedical Research, Network on Respiratory Diseases (CIBERES), Madrid, Spain
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Universidad Complutense de Madrid · Centro de Investigación Biomédica en Red de Enfermedades Respiratorias · Universitätsklinikum Knappschaftskrankenhaus Bochum · Centro de Investigación Biomédica en Red · Ruhr University Bochum
Affiliation as printed
Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany
Department of Pharmacology and Toxicology, Complutense University School of Medicine and Centre for Biomedical Research, Network on Respiratory Diseases (CIBERES), Madrid, Spain
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Universidad Complutense de Madrid · Research Institute Hospital 12 de Octubre
Affiliation as printed
12 de Octubre Health Research Institute (imas12), Madrid, Spain
Department of Cell Biology, Complutense University School of Medicine, Madrid, Spain
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Universitätsklinikum Knappschaftskrankenhaus Bochum · Ruhr University Bochum
Affiliation as printed
Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany
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Universidad Complutense de Madrid · Research Institute Hospital 12 de Octubre
Affiliation as printed
12 de Octubre Health Research Institute (imas12), Madrid, Spain
Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain
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Hospital General Universitario Gregorio Marañón · Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas · Instituto de Investigación Sanitaria Gregorio Marañón
Affiliation as printed
Centre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, Spain
Servicio de Aparato Digestivo del Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
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Hospital General Universitario Gregorio Marañón · Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas · Instituto de Investigación Sanitaria Gregorio Marañón
Affiliation as printed
Centre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, Spain
Servicio de Aparato Digestivo del Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
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Universidad Complutense de Madrid · Research Institute Hospital 12 de Octubre · Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
12 de Octubre Health Research Institute (imas12), Madrid, Spain
Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain
Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
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Francisco Javier Cubero corresponding
Universidad Complutense de Madrid · Research Institute Hospital 12 de Octubre
Affiliation as printed
12 de Octubre Health Research Institute (imas12), Madrid, Spain
Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain
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