Single-cell profiling reveals monocyte mitochondrial dysfunction in patients with cirrhosis progressing to acute-on-chronic liver failure

medRxiv

Abstract

ABSTRACT Background & Aims Patients with acute decompensation (AD) of cirrhosis are at a high risk of developing acute-on-chronic liver failure (ACLF), a syndrome characterized by multi-organ failure and high short-term mortality. Prospective studies addressing the cellular mechanisms that drive the transition from AD to ACLF are lacking. In this study, we aimed to determine whether peripheral immune cell subsets at hospital admission predict the progression from AD to ACLF and to delineate underlying molecular mechanisms. Approach & Results We prospectively enrolled 63 patients with AD and 15 healthy donors across five European centers, with a 90-day follow-up. Single-cell RNA sequencing was performed on peripheral blood mononuclear cells (PBMCs) from 16 patients with distinct trajectories and 4 controls. Progression to ACLF was associated with expansion of classical monocytes, particularly subcluster “C2”, which specifically displayed impaired energy metabolism with reduced oxidative phosphorylation. Genes encoding respiratory chain Complex IV were markedly downregulated. A C2-derived gene signature was enriched in two large international whole-blood cohorts (PREDICT, n=689; ACLARA, n=521), particularly in patients with bacterial infections, those developing ACLF, and non-survivors. Functional validation by respirometry in an independent AD cohort confirmed declining monocyte Complex IV–dependent oxygen consumption in patients with pre-ACLF. Conclusions We identified and validated a distinct monocyte subpopulation with defective energy metabolism in patients with AD with poor outcomes, suggesting a mechanistic link to ACLF development.

Authors 32

1. Theresa Hildegard Wirtz Aachen Medical Department III

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Medical Department III, University Hospital RWTH Aachen, Aachen, Germany

2. Sara Palomino‐Echeverría corresponding

   University of Helsinki · Universidad Pública de Navarra (UPNA) · Complejo Hospitalario de Navarra · Navarre Institute of Health Research · Navarrabiomed · Institute for Molecular Medicine Finland · Universidad de Navarra

   Affiliation as printed

   Institute for Molecular Medicine Finland, Helsinki Institute for Life Sciences, University of Helsinki, Helsinki, Finland

   Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland

   Translational Bioinformatics Unit (TransBio), Navarrabiomed, Navarra Health Department (CHN), Public University of Navarra (UPNA), Navarra Institute for Health Research (IdiSNA), Pamplona, Spain

   Research Program in Systems Oncology, University of Helsink

3. Maike R. Pollmanns Aachen Medical Department III

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Medical Department III, University Hospital RWTH Aachen, Aachen, Germany

4. Felix Schreibing Aachen Department of Medicine 2 (Nephrology Clinical Immunology and Hypertension)

   RWTH Aachen University

   Affiliation as printed

   Department of Medicine 2 (Nephrology, Rheumatology, Clinical Immunology and Hypertension), RWTH Aachen University, Medical Faculty, Aachen, Germany

5. Johanna Reißing Aachen Medical Department III

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Medical Department III, University Hospital RWTH Aachen, Aachen, Germany

6. Cristina Sánchez-Garrido

   European Foundation for the Study of Chronic Liver Failure

   Affiliation as printed

   European Foundation for the Study of Chronic Liver Failure (EF CLIF) and Grifols Chair, Barcelona, Spain

7. Cristina López‐Vicario

   European Foundation for the Study of Chronic Liver Failure · Hospital Clínic de Barcelona · Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas · Consorci Institut D'Investigacions Biomediques August Pi I Sunyer

   Affiliation as printed

   Biochemistry and Molecular Genetics Service, Hospital Clinic-IDIBAPS, Barcelona, Spain

   CIBERehd, Madrid, Spain

   European Foundation for the Study of Chronic Liver Failure (EF CLIF) and Grifols Chair, Barcelona, Spain

   Biochemistry and Molecular Geneti

   CIBERehd, Barcelona, Spain

8. Ana María Aransay

   CIC bioGUNE · Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas

   Affiliation as printed

   CIBERehd, Madrid, Spain

   Center for Cooperative Research in Biosciences (CIC bioGUNE), Derio, Bizkaia, Spain

9. Maurizio Baldassare

   IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola · University of Bologna

   Affiliation as printed

   Unit of Semeiotics, Liver and Alcohol-related Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy

10. Giacomo Zaccherini

    IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola · University of Bologna

    Affiliation as printed

    Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum, University of Bologna, Bologna, Italy

    Unit of Semeiotics, Liver and Alcohol-related Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy

11. Enrico Pompili

    IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola · University of Bologna

    Affiliation as printed

    Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum, University of Bologna, Bologna, Italy

    Unit of Semeiotics, Liver and Alcohol-related Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy

12. Martin Schulz

    University of Münster · University Hospital Münster

    Affiliation as printed

    Department of Internal Medicine B, University Hospital Muenster, Muenster, Germany

13. Frank Erhard Uschner

    University of Münster · University Hospital Münster

    Affiliation as printed

    Department of Internal Medicine B, University Hospital Muenster, Muenster, Germany

14. Sabine Klein

    University of Münster · University Hospital Münster

    Affiliation as printed

    Department of Internal Medicine B, University Hospital Muenster, Muenster, Germany

15. Wenyi Gu

    University of Münster · University Hospital Münster

    Affiliation as printed

    Department of Internal Medicine B, University Hospital Muenster, Muenster, Germany

16. Robert Schierwagen

    University of Münster · University Hospital Münster

    Affiliation as printed

    Department of Internal Medicine B, University Hospital Muenster, Muenster, Germany

17. Shantha Ram Valainathan

    Hôpital Beaujon · Assistance Publique – Hôpitaux de Paris

    Affiliation as printed

    AP-HP, Hôpital Beaujon, Service d’Hepatologie, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Clichy, France

    AP-HP, Hopital Beaujon, Service d Hepatologie, DMU DIGEST, Centre de Reference des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Clichy, France

18. Annabelle Verbeeck

    Hôpital Beaujon · Assistance Publique – Hôpitaux de Paris

    Affiliation as printed

    AP-HP, Hôpital Beaujon, Service d’Hepatologie, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Clichy, France

    AP-HP, Hopital Beaujon, Service d Hepatologie, DMU DIGEST, Centre de Reference des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Clichy, France

19. Daniela Campion

    Azienda Ospedaliera Citta' della Salute e della Scienza di Torino

    Affiliation as printed

    Division of Gastroenterology and Hepatology, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy

    Division of Gastroenterology and Hepatology, A.O.U. Citta della Salute e della Scienza di Torino, Torino, Italy

20. Ilaria Giovo

    Azienda Ospedaliera Citta' della Salute e della Scienza di Torino

    Affiliation as printed

    Division of Gastroenterology and Hepatology, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy

    Division of Gastroenterology and Hepatology, A.O.U. Citt a della Salute e della Scienza di Torino, Torino, Italy

21. Rafael Kramann Aachen Department of Medicine 2 (Nephrology Clinical Immunology and Hypertension) Medical Department III

    Erasmus MC · Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands

    Department of Medicine 2 (Nephrology, Rheumatology, Clinical Immunology and Hypertension), RWTH Aachen University, Medical Faculty, Aachen, Germany

    Medical Department III, University Hospital RWTH Aachen, Aachen, Germany

22. Tony Bruns Aachen Medical Department III

    Karolinska Institutet · Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Medical Department III, University Hospital RWTH Aachen, Aachen, Germany

    Algorithmic Dynamics lab, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden

23. Narsis A. Kiani

    Karolinska Institutet · IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola · University of Bologna

    Affiliation as printed

    Algorithmic Dynamics lab, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden

    IRCCS Azienda Ospedaliera-Universitaria di Bologna, Bologna, Italy

    Unit of Semeiotics, Liver and Alcohol-related Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy

24. Paolo Caraceni

    Hôpital Beaujon · IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola · Assistance Publique – Hôpitaux de Paris · European Foundation for the Study of Chronic Liver Failure · University of Bologna

    Affiliation as printed

    IRCCS Azienda Ospedaliera-Universitaria di Bologna, Bologna, Italy

    Unit of Semeiotics, Liver and Alcohol-related Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy

    AP-HP, Hopital Beaujon, Service d Hepatologie, DMU DIGEST, Centre de Reference des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Clichy, Fra

    European Foundation for the Study of Chronic Liver Failure (EF CLIF) and Grifols Chair, Barcelona, Spain

25. Carlo Alessandria

    University of Münster · Azienda Ospedaliera Citta' della Salute e della Scienza di Torino · European Foundation for the Study of Chronic Liver Failure · University Hospital Münster

    Affiliation as printed

    Division of Gastroenterology and Hepatology, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy

    Department of Internal Medicine B, University Hospital Muenster, Muenster, Germany

    European Foundation for the Study of Chronic Liver Failure (EF CLIF) and Grifols Chair, Barcelona, Spain

26. Richard Moreau

    Inserm · Université Paris Cité · Hôpital Beaujon · Assistance Publique – Hôpitaux de Paris · European Foundation for the Study of Chronic Liver Failure · Hospital Clínic de Barcelona · Centre de Recherche sur l'Inflammation · Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas · Consorci Institut D'Investigacions Biomediques August Pi I Sunyer

    Affiliation as printed

    AP-HP, Hôpital Beaujon, Service d’Hepatologie, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Clichy, France

    European Foundation for the Study of Chronic Liver Failure (EF CLIF) and Grifols Chair, Barcelona, Spain

    Université Paris-Cité, Inserm, Centre de recherche sur l’inflammation, UMR 1149, Paris, France

    Biochemistry and Molecular Geneti

    Biochemistry and Molecular Genetics Service, Hospital Clinic-IDIBAPS, Barcelona, Spain

    CIBERehd, Barcelona, Spain

27. Jonel Trebicka

    University of Münster · European Foundation for the Study of Chronic Liver Failure · University Hospital Münster · Navarre Institute of Health Research · Centro de Investigación Médica Aplicada · Universidad de Navarra

    Affiliation as printed

    Department of Internal Medicine B, University Hospital Muenster, Muenster, Germany

    European Foundation for the Study of Chronic Liver Failure (EF CLIF) and Grifols Chair, Barcelona, Spain

    Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), Computational Biology Program, Instituto de Investigacion Sanitaria de Navarra (IdiSNA), Pamplona, Spain

28. Joan Clària

    Hôpital Beaujon · Assistance Publique – Hôpitaux de Paris · European Foundation for the Study of Chronic Liver Failure · Hospital Clínic de Barcelona · Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas · Consorci Institut D'Investigacions Biomediques August Pi I Sunyer · Universitat de Barcelona

    Affiliation as printed

    Biochemistry and Molecular Genetics Service, Hospital Clinic-IDIBAPS, Barcelona, Spain

    CIBERehd, Madrid, Spain

    Department of Biomedical Sciences, University of Barcelona, Spain

    European Foundation for the Study of Chronic Liver Failure (EF CLIF) and Grifols Chair, Barcelona, Spain

    AP-HP, Hopital Beaujon, Service d Hepatologie, DMU DIGEST, Centre de Reference des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Clichy, Fra

29. Núria Planell corresponding Aachen Medical Department III

    TU Dortmund University · Navarre Institute of Health Research · Universitätsklinikum Aachen · Leibniz Research Centre for Working Environment and Human Factors · Centro de Investigación Médica Aplicada · Universidad de Navarra · RWTH Aachen University

    Affiliation as printed

    Universidad de Navarra, Centro de Investigación Médica Aplicada (CIMA), Computational Biology Program, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain

    Leibniz Research Centre for Working Environment and Human Factors at the TU Dortmund (IfADo), Dortmund, Germany

    Liver Center, Department of Gastroenterology, Hepatology and GI-Onco

    Medical Department III, University Hospital RWTH Aachen, Aachen, Germany

30. Pierre‐Emmanuel Rautou corresponding

    Hôpital Beaujon · Erasmus MC · Assistance Publique – Hôpitaux de Paris · Complejo Hospitalario de Navarra · European Foundation for the Study of Chronic Liver Failure · Navarrabiomed · King Abdullah University of Science and Technology

    Affiliation as printed

    AP-HP, Hôpital Beaujon, Service d’Hepatologie, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Clichy, France

    Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands

    European Foundation for the Study of Chronic Liver Failure (EF CLIF) and Grifols Chair, Barcelona, Spain

    Biological, Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology University, Thuwal, Saudi Arabia

    Translational Bioinformatics Unit (TransBio), Navarrabiomed, Navarra Health Department (CHN), Public Universi

31. Christian Trautwein corresponding Aachen Medical Department III

    TU Dortmund University · Universitätsklinikum Aachen · Klinikum Stuttgart · Leibniz Research Centre for Working Environment and Human Factors · RWTH Aachen University

    Affiliation as printed

    Leibniz Research Centre for Working Environment and Human Factors at the TU Dortmund (IfADo), Dortmund, Germany

    Liver Center, Department of Gastroenterology, Hepatology and GI-Oncology, Klinikum Stuttgart, Stuttgart, Germany

    Medical Department III, University Hospital RWTH Aachen, Aachen, Germany

32. David Gómez-Cabrero corresponding

    Universidad Pública de Navarra (UPNA) · Complejo Hospitalario de Navarra · Navarre Institute of Health Research · Navarrabiomed · King Abdullah University of Science and Technology · Universidad de Navarra

    Affiliation as printed

    Biomedical Sciences Division, King Abdullah University of Science and Technology KAUST, Thuwal, Saudi Arabia

    Translational Bioinformatics Unit (TransBio), Navarrabiomed, Navarra Health Department (CHN), Public University of Navarra (UPNA), Navarra Institute for Health Research (IdiSNA), Pamplona, Spain