Microbiome-derived ethanol in nonalcoholic fatty liver disease
Journal article, 2022
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.
Author
A. S. Meijnikman
Spaarne Hospital
University of Amsterdam
Mark Davids
University of Amsterdam
H. Herrema
University of Amsterdam
O. Aydin
University of Amsterdam
Spaarne Hospital
Valentina Tremaroli
Wallenberg Lab.
Melany Rios-Morales
University of Amsterdam
Han Levels
University of Amsterdam
S. C. Bruin
Spaarne Hospital
Maurits de Brauw
Spaarne Hospital
J. Verheij
University of Amsterdam
Marleen Kemper
University of Amsterdam
Adriaan G. Holleboom
University of Amsterdam
Maarten E. Tushuizen
Leiden University
Thue W. Schwartz
University of Copenhagen
Jens B Nielsen
Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology
Dees Brandjes
University of Amsterdam
Eveline Dirinck
UZA (Antwerp University Hospital)
Jonas Weyler
UZA (Antwerp University Hospital)
An Verrijken
UZA (Antwerp University Hospital)
Christophe E.M. De Block
UZA (Antwerp University Hospital)
Luisa Vonghia
UZA (Antwerp University Hospital)
Sven Francque
UZA (Antwerp University Hospital)
Ulrich Beuers
University of Amsterdam
V. E.A. Gerdes
University of Amsterdam
Spaarne Hospital
Fredrik Bäckhed
Wallenberg Lab.
University of Copenhagen
A. K. Groen
University of Amsterdam
M. Nieuwdorp
Spaarne Hospital
University of Amsterdam
Nature Medicine
1078-8956 (ISSN) 1546170x (eISSN)
Vol. 28 10 2100-2106Subject Categories
Other Clinical Medicine
Gastroenterology and Hepatology
Nutrition and Dietetics
DOI
10.1038/s41591-022-02016-6
PubMed
36216942