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Journal Articles Journal of Hepatology Year : 2020

Blood metabolomics uncovers inflammation-associated mitochondrial dysfunction as a potential mechanism underlying ACLF

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Richard Moreau
  • Function : Author
Joan Clària
  • Function : Author
Ferran Aguilar
  • Function : Author
Juan José Lozano
  • Function : Author
Benoit Colsch
Paolo Caraceni
  • Function : Author
Jonel Trebicka
Marco Pavesi
  • Function : Author
Carlo Alessandria
  • Function : Author
Frederik Nevens
  • Function : Author
Faouzi Saliba
  • Function : Author
Tania Welzel
  • Function : Author
Agustin Albillos
  • Function : Author
Thierry Gustot
  • Function : Author
Javier Fernández
  • Function : Author
Christophe Moreno
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Maurizio Baldassarre
  • Function : Author
Giacomo Zaccherini
  • Function : Author
Salvatore Piano
  • Function : Author
Sara Montagnese
  • Function : Author
Victor Vargas
  • Function : Author
Joan Genescà
  • Function : Author
Elsa Solà
  • Function : Author
William Bernal
  • Function : Author
Christian Jansen
  • Function : Author
Christian Steib
  • Function : Author
Daniela Campion
  • Function : Author
Raj Mookerjee
  • Function : Author
Miguel Rodríguez-Gandía
  • Function : Author
German Soriano
  • Function : Author
François Durand
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Daniel Benten
  • Function : Author
Rafael Bañares
  • Function : Author
Rudolf Stauber
  • Function : Author
Henning Gronbaek
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Minneke Coenraad
  • Function : Author
Pere Ginès
  • Function : Author
Alexander Gerbes
  • Function : Author
Rajiv Jalan
  • Function : Author
Mauro Bernardi
  • Function : Author
Vicente Arroyo
  • Function : Author
Paolo Angeli
  • Function : Author

Abstract

Background & Aims: Acute-on-chronic liver failure (ACLF), which develops in patients with cirrhosis, is characterized by intense systemic inflammation and organ failure(s). Because systemic inflammation is energetically expensive, its metabolic costs may result in organ dysfunction/failure. Therefore, we aimed to analyze the blood metabolome in patients with cirrhosis, with and without ACLF.Methods: We performed untargeted metabolomics using liquid chromatography coupled to high-resolution mass spectrometry in serum from 650 patients with AD (acute decompensation of cirrhosis, without ACLF), 181 with ACLF, 43 with compensated cirrhosis, and 29 healthy individuals.Results: Of the 137 annotated metabolites identified, 100 were increased in patients with ACLF of any grade, relative to those with AD, and 38 comprised a distinctive blood metabolite fingerprint for ACLF. Among patients with ACLF, the intensity of the fingerprint increased across ACLF grades, and was similar in patients with kidney failure and in those without, indicating that the fingerprint reflected not only decreased kidney excretion but also altered cell metabolism. The higher the ACLF-associated fingerprint intensity, the higher the plasma levels of inflammatory markers, tumor necrosis factor α, soluble CD206, and soluble CD163. ACLF was characterized by intense proteolysis and lipolysis; amino acid catabolism; extra-mitochondrial glucose metabolism through glycolysis, pentose phosphate, and D-glucuronate pathways; depressed mitochondrial ATP-producing fatty acid β-oxidation; and extra-mitochondrial amino acid metabolism giving rise to metabotoxins.Conclusions: In ACLF, intense systemic inflammation is associated with blood metabolite accumulation and profound alterations in major metabolic pathways, in particular inhibition of mitochondrial energy production, which may contribute to the development of organ failures.Lay summary: Acute-on-chronic liver failure (ACLF), which develops in patients with cirrhosis, is characterized by intense systemic inflammation and organ failure(s). Because systemic inflammation is energetically expensive, its metabolic costs may result in organ dysfunction/failure. We identified a 38-metabolite blood fingerprint specific for ACLF that revealed mitochondrial dysfunction in peripheral organs. This may contribute to organ failures.
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Dates and versions

hal-03350315 , version 1 (22-08-2022)

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Attribution - NonCommercial - CC BY 4.0

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Richard Moreau, Joan Clària, Ferran Aguilar, François Fenaille, Juan José Lozano, et al.. Blood metabolomics uncovers inflammation-associated mitochondrial dysfunction as a potential mechanism underlying ACLF. Journal of Hepatology, 2020, 72 (4), pp.688-701. ⟨10.1016/j.jhep.2019.11.009⟩. ⟨hal-03350315⟩
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