Microbiome-derived ethanol in nonalcoholic fatty liver disease

Research output: Contribution to journalJournal articleResearchpeer-review

  • Abraham S. Meijnikman
  • Mark Davids
  • Hilde Herrema
  • Omrum Aydin
  • Valentina Tremaroli
  • Melany Rios-Morales
  • Han Levels
  • Sjoerd Bruin
  • Maurits de Brauw
  • Joanne Verheij
  • Marleen Kemper
  • Adriaan G. Holleboom
  • Maarten E. Tushuizen
  • Jens Nielsen
  • Dees Brandjes
  • Eveline Dirinck
  • Jonas Weyler
  • An Verrijken
  • Christophe E.M. De Block
  • Luisa Vonghia
  • Sven Francque
  • Ulrich Beuers
  • Victor E.A. Gerdes
  • Fredrik Bäckhed
  • Albert K. Groen
  • Max Nieuwdorp

To test the hypothesis that the gut microbiota of individuals with nonalcoholic fatty liver disease (NAFLD) produce enough ethanol to be a driving force in the development and progression of this complex disease, we performed one prospective clinical study and one intervention study. Ethanol was measured while fasting and 120 min after a mixed meal test (MMT) in 146 individuals. In a subset of 37 individuals and in an external validation cohort, ethanol was measured in portal vein blood. In an intervention study, ten individuals with NAFLD and ten overweight but otherwise healthy controls were infused with a selective alcohol dehydrogenase (ADH) inhibitor before an MMT. When compared to fasted peripheral blood, median portal vein ethanol concentrations were 187 (interquartile range (IQR), 17–516) times higher and increased with disease progression from 2.1 mM in individuals without steatosis to 8.0 mM in NAFL 21.0 mM in nonalcoholic steatohepatitis. Inhibition of ADH induced a 15-fold (IQR,1.6- to 20-fold) increase in peripheral blood ethanol concentrations in individuals with NAFLD, although this effect was abolished after antibiotic treatment. Specifically, Lactobacillaceae correlated with postprandial peripheral ethanol concentrations (Spearman’s rho, 0.42; P < 10−5) in the prospective study. Our data show that the first-pass effect obscures the levels of endogenous ethanol production, suggesting that microbial ethanol could be considered in the pathogenesis of this highly prevalent liver disease.

Original languageEnglish
JournalNature Medicine
Pages (from-to)2100-2106
Publication statusPublished - 2022

Bibliographical note

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

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