{
  "abstract": "Background Bacterial translocation in cirrhosis can trigger infection and hepatic decompensation, leading to systemic inflammation, organ failure and increased mortality. These infections often originate from the gastrointestinal tract after bacteria breach the intestinal barrier and disseminate to systemic sites.Objective In this study, we explore the mechanisms underlying intestinal barrier dysfunction in cirrhosis using an experimental cirrhosis model and patient-derived intestinal biopsies.Design We developed a murine model of cirrhosis through chronic administration of carbon tetrachloride for up to 20 weeks. We investigated both the intestinal epithelial and vascular compartments and performed single-cell transcriptomic profiling of myeloid cells isolated from cirrhotic mice and from individuals with compensated and decompensated cirrhosis.Results Our findings indicate that bacterial translocation in cirrhosis is the result of failure at multiple checkpoints, including aberrant epithelial cell death, vascular barrier damage and dysfunction of gut-vascular macrophages. In a preclinical model of cirrhosis, macrophages exhibited increased levels of monocyte-attracting chemokines, reduced bacterial clearance and impaired interactions with blood vessels. Importantly, depleting vascular-lining macrophages resulted in bacterial translocation to systemic sites, even in the absence of experimental liver disease. Transcriptional profiling of macrophages from duodenal biopsies of patients with cirrhosis indicated similar dysregulation of pathways supporting blood vessels and elevated expression of chemokines.Conclusions This study emphasises the critical role of intestinal macrophages in preventing the dissemination of luminal bacteria and highlights the multifaceted breakdown of the intestinal barrier in cirrhosis and the importance of the gut-vascular barrier.",
  "authors": [
    {
      "affiliations": [
        "Laboratory of Liver Immunology, Leuven Center of Molecular Liver Sciences, Hepatology Research Unit, Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium",
        "Laboratory of Intravital Microscopy and Dynamics of Tumor Progression, Center for Cancer Biology, VIB-KU Leuven, Leuven, Belgium"
      ],
      "name": "Lena Smets"
    },
    {
      "affiliations": [
        "Laboratory for Intestinal Neuro-Immune Interaction, Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium"
      ],
      "name": "Maria Francesca Viola"
    },
    {
      "affiliations": [
        "Laboratory of Liver Immunology, Leuven Center of Molecular Liver Sciences, Hepatology Research Unit, Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium",
        "Laboratory of Reproductive Genomics, Department of Human Genetics, KU Leuven, Leuven, Belgium",
        "KU Leuven Institute for Single Cell Omics (LISCO), KU Leuven, Leuven, Belgium"
      ],
      "name": "Markus Boesch"
    },
    {
      "affiliations": [
        "Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium"
      ],
      "name": "Jana Raman"
    },
    {
      "affiliations": [
        "Laboratory of Liver Immunology, Leuven Center of Molecular Liver Sciences, Hepatology Research Unit, Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium",
        "Department of Gastroenterology and Hepatology, KU Leuven University Hospitals Leuven, Leuven, Belgium"
      ],
      "name": "Lukas Van Melkebeke"
    },
    {
      "affiliations": [
        "Intravital Imaging Expertise Center, Center for Cancer Biology, VIB-KU Leuven, Leuven, Belgium",
        "Manchester Cell-Matrix Centre, Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, UK"
      ],
      "name": "Max Nobis"
    },
    {
      "affiliations": [
        "Department of Biomedicine, Division Gastroenterology and Hepatology, University Centre for Gastrointestinal and Liver Diseases, University of Basel, Basel, Switzerland"
      ],
      "name": "Emilio Flint"
    },
    {
      "affiliations": [
        "Laboratory for Intestinal Neuro-Immune Interaction, Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium"
      ],
      "name": "Nika Pajk"
    },
    {
      "affiliations": [
        "IRCCS, Humanitas Research Hospital, Milan, Italy",
        "Department of Biomedical Sciences, Humanitas University, Milan, Italy"
      ],
      "name": "Paola Brescia"
    },
    {
      "affiliations": [
        "IRCCS, Humanitas Research Hospital, Milan, Italy"
      ],
      "name": "Alessandra Silvestri"
    },
    {
      "affiliations": [
        "Laboratory of Liver Immunology, Leuven Center of Molecular Liver Sciences, Hepatology Research Unit, Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium"
      ],
      "name": "Rita Feio-Azevedo"
    },
    {
      "affiliations": [
        "Laboratory for Intestinal Neuro-Immune Interaction, Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium"
      ],
      "name": "Elodie Modave"
    },
    {
      "affiliations": [
        "Department of Imaging and Pathology, Biomedical MRI, KU Leuven, Leuven, Belgium"
      ],
      "name": "Lander De Herdt"
    },
    {
      "affiliations": [
        "Department of Biomedicine, Division Gastroenterology and Hepatology, University Centre for Gastrointestinal and Liver Diseases, University of Basel, Basel, Switzerland"
      ],
      "name": "Annalisa Sanga"
    },
    {
      "affiliations": [
        "Department of Biomedicine, Division Gastroenterology and Hepatology, University Centre for Gastrointestinal and Liver Diseases, University of Basel, Basel, Switzerland"
      ],
      "name": "Oltin Tiberiu Pop"
    },
    {
      "affiliations": [
        "Department of Imaging and Pathology, Translational Cell and Tissue Research, University Hospitals Leuven, KU Leuven, Leuven, Belgium"
      ],
      "name": "Olivier Govaere"
    },
    {
      "affiliations": [
        "Laboratory of Liver Immunology, Leuven Center of Molecular Liver Sciences, Hepatology Research Unit, Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium",
        "Department of Gastroenterology and Hepatology, KU Leuven University Hospitals Leuven, Leuven, Belgium"
      ],
      "name": "Jef Verbeek"
    },
    {
      "affiliations": [
        "Laboratory of Mucosal Biology, Leuven Center of Molecular Liver Sciences, Hepatology Research Unit, Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium"
      ],
      "name": "Alexandre Denadai-Souza"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, KU Leuven University Hospitals Leuven, Leuven, Belgium"
      ],
      "name": "David Cassiman"
    },
    {
      "affiliations": [
        "Department of Biomedical Molecular Biology, VIB Single Cell Core, Ghent University, Ghent-Leuven, Belgium"
      ],
      "name": "Niels Vandamme"
    },
    {
      "affiliations": [
        "Laboratory for Translational Genetics, Department of Human Genetics, Center for Cancer Biology, VIB-KU Leuven, Leuven, Belgium"
      ],
      "name": "Bram Boeckx"
    },
    {
      "affiliations": [
        "Laboratory for Translational Genetics, Department of Human Genetics, Center for Cancer Biology, VIB-KU Leuven, Leuven, Belgium"
      ],
      "name": "Diether Lambrechts"
    },
    {
      "affiliations": [
        "IRCCS, Humanitas Research Hospital, Milan, Italy",
        "Department of Biomedical Sciences, Humanitas University, Milan, Italy"
      ],
      "name": "Maria Rescigno"
    },
    {
      "affiliations": [
        "Department of Biomedicine, Division Gastroenterology and Hepatology, University Centre for Gastrointestinal and Liver Diseases, University of Basel, Basel, Switzerland"
      ],
      "name": "Christine Bernsmeier"
    },
    {
      "affiliations": [
        "Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium",
        "Department of Cardiology Maastricht, University CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands"
      ],
      "name": "Elizabeth A V Jones"
    },
    {
      "affiliations": [
        "Leibniz Research Centre for Working Environment and Human Factors (IfADo), Department of Toxicology, University Dortmund, Dortmund, Germany"
      ],
      "name": "Jan G Hengstler"
    },
    {
      "affiliations": [
        "Leibniz Research Centre for Working Environment and Human Factors (IfADo), Department of Toxicology, University Dortmund, Dortmund, Germany",
        "Forensic Medicine and Toxicology Department, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt"
      ],
      "name": "Ahmed Ghallab"
    },
    {
      "affiliations": [
        "Laboratory of Intravital Microscopy and Dynamics of Tumor Progression, Center for Cancer Biology, VIB-KU Leuven, Leuven, Belgium"
      ],
      "name": "Colinda L G J Scheele"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, KU Leuven University Hospitals Leuven, Leuven, Belgium"
      ],
      "name": "Frederik Nevens"
    },
    {
      "affiliations": [
        "Laboratory of Liver Immunology, Leuven Center of Molecular Liver Sciences, Hepatology Research Unit, Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium"
      ],
      "name": "Hannelie Korf"
    },
    {
      "affiliations": [
        "Laboratory for Intestinal Neuro-Immune Interaction, Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium"
      ],
      "name": "Guy Boeckxstaens"
    },
    {
      "affiliations": [
        "Laboratory of Liver Immunology, Leuven Center of Molecular Liver Sciences, Hepatology Research Unit, Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium",
        "Department of Gastroenterology and Hepatology, KU Leuven University Hospitals Leuven, Leuven, Belgium"
      ],
      "name": "Schalk Willem Van der Merwe"
    }
  ],
  "title": "Intestinal blood vessel-associated macrophages and gut-vascular barrier dysfunction in cirrhosis",
  "uid": "ccb2241f-e257-5930-89e1-c84c7209ac9f"
}