{
  "abstract": "Background Neutrophils guarantee a prompt and robust host response to pathogens. Yet, overshooting neutrophil activation leads to tremendous collateral damage in tissues. In advanced chronic liver disease (ACLD), neutrophils are exposed to the highly immunogenic milieu of the portal circulation prior to entering the liver sinusoids. In alcohol-related liver disease (ALD), neutrophils occupy a central role and therefore mechanisms regulating neutrophil activity pose a possible therapeutic target.Objective Evaluate the impact of the portal milieu on neutrophils in ACLD with portal hypertension.Design We conducted a prospective study of patients undergoing transjugular intrahepatic portosystemic shunt placement. Paired blood samples were obtained from the portal vein (PV) and superior vena cava (SVC); the neutrophil phenotype was assessed by spectral flow cytometry; plasma was analysed by cytokine quantification, reporter assays and metabolomics. Effects of tryptophan supplementation on neutrophil function and phenotype were tested in isolated neutrophils.Results Patients with ALD but not non-ALD showed highly activated CD10 highCD11bhigh neutrophils in the portal circulation. PV plasma induced this phenotype in SVC neutrophils. Analysis of portal plasma revealed no differences in cytokines or toll-like receptor (TLR)/nucleotide-binding oligomerisation domain-containing protein (NOD) ligands but decreased local tryptophan concentrations in patients with ALD. In vitro supplementation of tryptophan ameliorated activation of isolated neutrophils.Conclusion Our findings identify portal tryptophan as a local regulator of neutrophil activation in ACLD. The link between low tryptophan levels and heightened neutrophil reactivity, especially in ALD, underscores the role of the gut–liver metabolic crosstalk in immune modulation and highlights a potential therapeutic target for mitigating neutrophil-driven liver injury.",
  "authors": [
    {
      "affiliations": [
        "Institute of Experimental Pathology, Center of Molecular Biology of Inflammation (ZMBE), University of Münster, Münster, Germany",
        "Department of Internal Medicine B, University Hospital Münster, Münster, Germany"
      ],
      "name": "Sara Reinartz Groba"
    },
    {
      "affiliations": [
        "Institute of Experimental Pathology, Center of Molecular Biology of Inflammation (ZMBE), University of Münster, Münster, Germany"
      ],
      "name": "Mathis Richter"
    },
    {
      "affiliations": [
        "Institute of Experimental Pathology, Center of Molecular Biology of Inflammation (ZMBE), University of Münster, Münster, Germany",
        "Department of Cardiology I - Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital Münster, Münster, Germany"
      ],
      "name": "Dennis Schwarz"
    },
    {
      "affiliations": [
        "Institute of Pharmaceutical Sciences, Pharmaceutical (Bio-)Analysis, University of Tübingen, Tübingen, Germany"
      ],
      "name": "Philipp Seyfried"
    },
    {
      "affiliations": [
        "Institute of Pharmaceutical Sciences, Pharmaceutical (Bio-)Analysis, University of Tübingen, Tübingen, Germany",
        "current address: Institut de Recherche Expérimentale et Clinique (IREC) Metabolomics Core, UCLouvain, Woluwé-Saint-Lambert, Belgium"
      ],
      "name": "Kristian Serafimov"
    },
    {
      "affiliations": [
        "Institute of Pharmaceutical Sciences, Pharmaceutical (Bio-)Analysis, University of Tübingen, Tübingen, Germany",
        "current address: School of Medicine, Shanghai University, Shanghai, People's Republic of China"
      ],
      "name": "Xiaoqing Fu"
    },
    {
      "affiliations": [
        "Institute of Experimental Pathology, Center of Molecular Biology of Inflammation (ZMBE), University of Münster, Münster, Germany"
      ],
      "name": "Luca Farinola"
    },
    {
      "affiliations": [
        "Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany",
        "current address: Department of Anaesthesiology and Intensive Care Medicine, University Hospital Essen, Essen, Germany"
      ],
      "name": "Jan-Niklas Heming"
    },
    {
      "affiliations": [
        "Clinic for Radiology, University Hospital Münster, Münster, Germany"
      ],
      "name": "Max Masthoff"
    },
    {
      "affiliations": [
        "Clinic for Radiology, University Hospital Münster, Münster, Germany"
      ],
      "name": "Michael Köhler"
    },
    {
      "affiliations": [
        "Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany"
      ],
      "name": "Alexander Zarbock"
    },
    {
      "affiliations": [
        "Department of Cardiology I - Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital Münster, Münster, Germany"
      ],
      "name": "Yahya Sohrabi"
    },
    {
      "affiliations": [
        "Department of Internal Medicine B, University Hospital Münster, Münster, Germany"
      ],
      "name": "Michael Praktiknjo"
    },
    {
      "affiliations": [
        "Institute of Medical Biochemistry, Center for Molecular Biology of Inflammation (ZMBE), University of Münster, Münster, Germany"
      ],
      "name": "Angelika S. Rambold"
    },
    {
      "affiliations": [
        "Institute of Experimental Pathology, Center of Molecular Biology of Inflammation (ZMBE), University of Münster, Münster, Germany"
      ],
      "name": "Raphael Chevre"
    },
    {
      "affiliations": [
        "Institute of Pharmaceutical Sciences, Pharmaceutical (Bio-)Analysis, University of Tübingen, Tübingen, Germany"
      ],
      "name": "Michael Lämmerhofer"
    },
    {
      "affiliations": [
        "Department of Internal Medicine B, University Hospital Münster, Münster, Germany",
        "European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain"
      ],
      "name": "Jonel Trebicka"
    },
    {
      "affiliations": [
        "Institute of Experimental Pathology, Center of Molecular Biology of Inflammation (ZMBE), University of Münster, Münster, Germany"
      ],
      "name": "Oliver Soehnlein"
    }
  ],
  "title": "Tryptophan depletion generates hyper-reactive portal neutrophils in alcoholic liver disease",
  "uid": "638145a7-e975-55b3-b42b-2c024b0c23ce"
}