Blood metabolomics uncovers inflammation-associated mitochondrial dysfunction as a potential mechanism underlying ACLF
Por:
Moreau, R, Claria, J, Aguilar, F, Fenaille, F, Lozano, JJ, Junot, C, Colsch, B, Caraceni, P, Trebicka, J, Pavesi, M, Alessandria, C, Nevens, F, Saliba, F, Welzel, TM, Albillos, A, Gustot, T, Fernandez, J, Moreno, C, Baldassarre, M, Zaccherini, G, Piano, S, Montagnese, S, Vargas, V, Genesca, J, Sola, E, Bernal, W, Butin, N, Hautbergue, T, Cholet, S, Castelli, F, Jansen, C, Steib, C, Campion, D, Mookerjee, R, Rodriguez-Gandia, M, Soriano, G, Durand, F, Benten, D, Banares, R, Stauber, RE, Gronbaek, H, Coenraad, MJ, Gines, P, Gerbes, A, Jalan, R, Bernardi, M, Arroyo, V, Angeli, P
Publicada:
1 abr 2020
Resumen:
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 alpha, soluble CD206, and soluble CD163. ACLF was characterizedbyintense proteolysis andlipolysis; aminoacid catabolism; extra-mitochondrial glucose metabolism through glycolysis, pentose phosphate, and D-glucuronate pathways; depressed mitochondrial ATP-producing fatty acid beta-oxidation; and extramitochondrial 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. (C) 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Filiaciones:
Moreau, R:
EASL CLIF Consortium & Grifols Chair, EF Clif, Barcelona, Spain
Univ Paris, CRI, INSERM, U1149,UMRS1149, Clichy, France
Claria, J:
EASL CLIF Consortium & Grifols Chair, EF Clif, Barcelona, Spain
Univ Barcelona, Hosp Clin IDIBAPS, Barcelona, Spain
CIBEREHD, Barcelona, Spain
Aguilar, F:
EASL CLIF Consortium & Grifols Chair, EF Clif, Barcelona, Spain
Fenaille, F:
Univ Paris Saclay, Lab Etud Metabol Medicaments, SPI, CEA,INRA,MetaboHUB, F-91191 Gif Sur Yvette, France
Lozano, JJ:
CIBEREHD, Barcelona, Spain
Junot, C:
Univ Paris Saclay, Lab Etud Metabol Medicaments, SPI, CEA,INRA,MetaboHUB, F-91191 Gif Sur Yvette, France
Colsch, B:
Univ Paris Saclay, Lab Etud Metabol Medicaments, SPI, CEA,INRA,MetaboHUB, F-91191 Gif Sur Yvette, France
Caraceni, P:
Univ Bologna, Dept Med & Surg Sci, Bologna, Italy
Trebicka, J:
EASL CLIF Consortium & Grifols Chair, EF Clif, Barcelona, Spain
JW Goethe Univ Hosp, Frankfurt, Germany
Pavesi, M:
EASL CLIF Consortium & Grifols Chair, EF Clif, Barcelona, Spain
Alessandria, C:
San Giovanni Battista Hosp, Div Gastroenterol & Hepatol, Turin, Italy
Nevens, F:
Katholieke Univ Leuven, Univ Hosp Gasthuisberg, Leuven, Belgium
Saliba, F:
Univ Paris Sud, Hop Paul Brousse, Villejuif, France
Welzel, TM:
JW Goethe Univ Hosp, Frankfurt, Germany
Albillos, A:
Hosp Ramon & Cajal, Madrid, Spain
Univ Bonn, Dept Internal Med 1, Bonn, Germany
Gustot, T:
Univ Libre Bruxelles, CUB Hop Erasme, Brussels, Belgium
Fernandez, J:
EASL CLIF Consortium & Grifols Chair, EF Clif, Barcelona, Spain
Univ Barcelona, Hosp Clin IDIBAPS, Barcelona, Spain
CIBEREHD, Barcelona, Spain
Moreno, C:
Univ Libre Bruxelles, CUB Hop Erasme, Brussels, Belgium
Baldassarre, M:
Univ Bologna, Dept Med & Surg Sci, Bologna, Italy
Zaccherini, G:
Univ Bologna, Dept Med & Surg Sci, Bologna, Italy
Piano, S:
Univ Padua, Dept Med, Unit Internal Med & Hepatol, DIMED, Padua, Italy
Montagnese, S:
Univ Padua, Dept Med, Unit Internal Med & Hepatol, DIMED, Padua, Italy
Vargas, V:
Univ Autonoma Barcelona, VHIR, Hosp Univ Vall Hebron, Liver Unit, Barcelona, Spain
Genesca, J:
Univ Autonoma Barcelona, VHIR, Hosp Univ Vall Hebron, Liver Unit, Barcelona, Spain
Sola, E:
Univ Barcelona, Hosp Clin IDIBAPS, Barcelona, Spain
CIBEREHD, Barcelona, Spain
Bernal, W:
Kings Coll London, Div Inflammat Biol, Inst Liver Studies, Liver Intens Therapy Unit, London, England
Butin, N:
Univ Paris Saclay, Lab Etud Metabol Medicaments, SPI, CEA,INRA,MetaboHUB, F-91191 Gif Sur Yvette, France
Hautbergue, T:
Univ Paris Saclay, Lab Etud Metabol Medicaments, SPI, CEA,INRA,MetaboHUB, F-91191 Gif Sur Yvette, France
Cholet, S:
Univ Paris Saclay, Lab Etud Metabol Medicaments, SPI, CEA,INRA,MetaboHUB, F-91191 Gif Sur Yvette, France
Castelli, F:
Univ Paris Saclay, Lab Etud Metabol Medicaments, SPI, CEA,INRA,MetaboHUB, F-91191 Gif Sur Yvette, France
Jansen, C:
Univ Bonn, Dept Internal Med 1, Bonn, Germany
Steib, C:
Univ Hosp LMU Munich, Liver Ctr Munich, Dept Med 2, Munich, Germany
Campion, D:
San Giovanni Battista Hosp, Div Gastroenterol & Hepatol, Turin, Italy
Mookerjee, R:
UCL, Royal Free Hosp, Inst Liver Dis Hlth, Liver Failure Grp, London, England
Rodriguez-Gandia, M:
Hosp Ramon & Cajal, Madrid, Spain
Soriano, G:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Dept Gastroenterol, Barcelona, Spain
Durand, F:
Univ Paris, CRI, INSERM, U1149,UMRS1149, Clichy, France
Benten, D:
Univ Hosp Hamburg Eppendorf, Hamburg, Germany
Banares, R:
Hosp Gen Univ Gregorio Maranon, Digest Dis Dept, Madrid, Spain
Inst Invest Sanitaria Gregorio Maranon, Madrid, Spain
Univ Complutense, Fac Med, Madrid, Spain
CIBEREHD, Madrid, Spain
Stauber, RE:
Med Univ Graz, Graz, Austria
Coenraad, MJ:
Leiden Univ, Med Ctr, Dept Gastroenterol & Hepatol, Leiden, Netherlands
Gines, P:
Univ Barcelona, Hosp Clin IDIBAPS, Barcelona, Spain
CIBEREHD, Barcelona, Spain
Gerbes, A:
Hosp Ramon & Cajal, Madrid, Spain
Univ Hosp LMU Munich, Liver Ctr Munich, Dept Med 2, Munich, Germany
Jalan, R:
EASL CLIF Consortium & Grifols Chair, EF Clif, Barcelona, Spain
UCL, Royal Free Hosp, Inst Liver Dis Hlth, Liver Failure Grp, London, England
Bernardi, M:
Univ Bologna, Dept Med & Surg Sci, Bologna, Italy
Arroyo, V:
EASL CLIF Consortium & Grifols Chair, EF Clif, Barcelona, Spain
Angeli, P:
EASL CLIF Consortium & Grifols Chair, EF Clif, Barcelona, Spain
Univ Padua, Dept Med, Unit Internal Med & Hepatol, DIMED, Padua, Italy
Hop Beaujon, AP HP, Serv Hepatol, Clichy, France.
Aarhus Univ Hosp, Dept Gastroenterol & Hepatol, Aarhus, Denmark.
Green Published
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