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Treatment With Simvastatin and Rifaximin Restores the Plasma Metabolomic Profile in Patients With Decompensated Cirrhosis

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

DOI

  • Elisa Pose, University of Barcelona, Barcelona
  • ,
  • Elsa Solà, University of Barcelona, Barcelona
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  • Juan J Lozano, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas
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  • Adrià Juanola, University of Barcelona, Barcelona
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  • Julia Sidorova, Instituto de Tecnología del Conocimiento
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  • Giacomo Zaccherini, University of Bologna, Bologna, Italy.
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  • Koos de Wit, Academic Centre for Dentistry Amsterdam, University of Amsterdam and and VU University Amsterdam, Amsterdam
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  • Frank Uschner, Univ Hosp Frankfurt, Goethe University Frankfurt, Goethe University Frankfurt Hospital
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  • Marta Tonon, University of Padova, Padova, Italy
  • ,
  • Konstantin Kazankov
  • Cesar Jiménez, Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona and CIBERehd, Barcelona, Spain.
  • ,
  • Daniela Campion, Department of Psychology, University of Turin & Neuroscience Institute of Turin, University of Turin
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  • Laura Napoleone, University of Barcelona, Barcelona
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  • Ann T Ma, University of Barcelona, Barcelona
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  • Marta Carol, University of Barcelona, Barcelona
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  • Manuel Morales-Ruiz, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS)
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  • Carlo Alessandria, Department of Psychology, University of Turin & Neuroscience Institute of Turin, University of Turin
  • ,
  • Ulrich Beuers, Academic Centre for Dentistry Amsterdam, University of Amsterdam and and VU University Amsterdam, Amsterdam
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  • Paolo Caraceni, University of Bologna, Bologna, Italy.
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  • Claire Francoz, Univ Paris Diderot, PRES University Sorbonne Paris Cite, University of Paris Diderot - Paris VII
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  • François Durand, Univ Paris Diderot, PRES University Sorbonne Paris Cite, University of Paris Diderot - Paris VII
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  • Rajeshwar P Mookerjee, Institute for Liver and Digestive Health, University College London and Royal Free Medical School, London, UK., Department of Public Health and Clinical Medicine, Division of Medicine, and Division of Respiratory Medicine, Umeå University, Umeå, Sweden., Royal Free Hospital, London, University College London
  • ,
  • Jonel Trebicka, Univ Hosp Frankfurt, Goethe University Frankfurt, Goethe University Frankfurt Hospital
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  • Victor Vargas, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas
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  • Salvatore Piano, University of Padova, Padova, Italy
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  • Hugh Watson
  • Juan G Abraldes, Univ Alberta, University of Alberta, Dept Psychiat
  • ,
  • Patrick S Kamath, Division of Gastroenterology and Hepatology
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  • Mark M Davis, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA; Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
  • ,
  • Pere Ginès, University of Barcelona, Barcelona
  • ,
  • investigators of the LIVERHOPE Consortium

Patients with decompensated cirrhosis, particularly those with acute-on-chronic liver failure (ACLF), show profound alterations in plasma metabolomics. The aim of this study was to investigate the effect of treatment with simvastatin and rifaximin on plasma metabolites of patients with decompensated cirrhosis, specifically on compounds characteristic of the ACLF plasma metabolomic profile. Two cohorts of patients were investigated. The first was a descriptive cohort of patients with decompensated cirrhosis (n = 42), with and without ACLF. The second was an intervention cohort from the LIVERHOPE-SAFETY randomized, double-blind, placebo-controlled trial treated with simvastatin 20 mg/day plus rifaximin 1,200 mg/day (n = 12) or matching placebo (n = 13) for 3 months. Plasma samples were analyzed using ultrahigh performance liquid chromatography-tandem mass spectroscopy for plasma metabolomics characterization. ACLF was characterized by intense proteolysis and lipid alterations, specifically in pathways associated with inflammation and mitochondrial dysfunction, such as the tryptophan-kynurenine and carnitine beta-oxidation pathways. An ACLF-specific signature was identified. Treatment with simvastatin and rifaximin was associated with changes in 161 of 985 metabolites in comparison to treatment with placebo. A remarkable reduction in levels of metabolites from the tryptophan-kynurenine and carnitine pathways was found. Notably, 18 of the 32 metabolites of the ACLF signature were affected by the treatment. Conclusion: Treatment with simvastatin and rifaximin modulates some of the pathways that appear to be key in ACLF development. This study unveils some of the mechanisms involved in the effects of treatment with simvastatin and rifaximin in decompensated cirrhosis and sets the stage for the use of metabolomics to investigate new targeted therapies in cirrhosis to prevent ACLF development.

Original languageEnglish
JournalHepatology communications
Volume6
Issue5
Pages (from-to)1100-1112
Number of pages13
ISSN2471-254X
DOIs
Publication statusPublished - May 2022

    Research areas

  • Acute-On-Chronic Liver Failure, Carnitine/therapeutic use, Humans, Kynurenine/therapeutic use, Liver Cirrhosis/drug therapy, Metabolomics, Rifaximin/therapeutic use, Simvastatin/therapeutic use, Tryptophan/therapeutic use

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