Microbiome-derived ethanol in nonalcoholic fatty liver disease
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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.
Originalsprog | Engelsk |
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Tidsskrift | Nature Medicine |
Vol/bind | 28 |
Sider (fra-til) | 2100-2106 |
ISSN | 1078-8956 |
DOI | |
Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
M.N. is supported by a ZONMW VICI grant 2020 (number 09150182010020). H.H. is supported by a Senior Fellowship of the Dutch Diabetes Research Foundation (2019.82.004). A.S.M. is supported by a Lilly/EFSD grant for Young Investigators. O.A. and V.T. are appointed on a NNF GUTMMM grant 2016 NNF15OC0016798 (to M.N., T.W.S. and F.B.). The study reported here was additionally supported by Le Ducq consortium grant 17CVD01 to F.B. and M.N. M.N, H.H. and A.K.G. are supported by a Dutch Heart Foundation CVON IN CONTROL-2 consortium grant. S.F. has a senior clinical research mandate from the Fund for Scientific Research (FWO) Flanders (1802154N). A.G.H. is supported by the Amsterdam UMC Fellowship, two TKI-PPP grants from Health~Holland and the Gilead Research Scholar grant.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
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