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

Abstract

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.

• Authors: Elisa Pose, Elsa Solà, Juan J Lozano, Adrià Juanola, Julia Sidorova, Giacomo Zaccherini, Koos de Wit, Frank Uschner, Marta Tonon, Konstantin Kazankov, Cesar Jiménez, Daniela Campion, Laura Napoleone, Ann T Ma, Marta Carol, Manuel Morales-Ruiz, Carlo Alessandria, Ulrich Beuers, Paolo Caraceni, Claire Francoz, François Durand, Rajeshwar P Mookerjee, Jonel Trebicka, Victor Vargas, Salvatore Piano, Hugh Watson, Juan G Abraldes, Patrick S Kamath, Mark M Davis, Pere Ginès, investigators of the LIVERHOPE Consortium
• Journal: Hepatology communications (Hepatol Commun) Vol. 6 Issue 5 Pg. 1100-1112 (05 2022) ISSN: 2471-254X [Electronic] United States
• PMID: 34964311 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.

Chemical References

• Kynurenine
• Tryptophan
• Simvastatin
• Rifaximin
• Carnitine

Topics

• 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)