Microbiome-derived ethanol in nonalcoholic fatty liver disease

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; Thue W. Schwartz; 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

doi:10.1038/s41591-022-02016-6

Microbiome-derived ethanol in nonalcoholic fatty liver disease

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, Thue W. Schwartz, Jens Nielsen, Dees Brandjes, Eveline Dirinck, Jonas Weyler, An Verrijken, Christophe E.M. De BlockLuisa Vonghia, Sven Francque, Ulrich Beuers, Victor E.A. Gerdes, Fredrik Bäckhed, Albert K. Groen, Max Nieuwdorp^*

^*Corresponding author af dette arbejde

Schwartz Group

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

114 Citationer (Scopus)

Abstract

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
Tidsskrift	Nature Medicine
Vol/bind	28
Sider (fra-til)	2100-2106
ISSN	1078-8956
DOI	https://doi.org/10.1038/s41591-022-02016-6
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.

Adgang til dokumentet

10.1038/s41591-022-02016-6

Citationsformater

Meijnikman, A. S., Davids, M., Herrema, H., Aydin, O., Tremaroli, V., Rios-Morales, M., Levels, H., Bruin, S., de Brauw, M., Verheij, J., Kemper, M., Holleboom, A. G., Tushuizen, M. E., Schwartz, T. W., Nielsen, J., Brandjes, D., Dirinck, E., Weyler, J., Verrijken, A., ... Nieuwdorp, M. (2022). Microbiome-derived ethanol in nonalcoholic fatty liver disease. Nature Medicine, 28, 2100-2106. https://doi.org/10.1038/s41591-022-02016-6

Meijnikman, AS, Davids, M, Herrema, H, Aydin, O, Tremaroli, V, Rios-Morales, M, Levels, H, Bruin, S, de Brauw, M, Verheij, J, Kemper, M, Holleboom, AG, Tushuizen, ME, Schwartz, TW, Nielsen, J, Brandjes, D, Dirinck, E, Weyler, J, Verrijken, A, De Block, CEM, Vonghia, L, Francque, S, Beuers, U, Gerdes, VEA, Bäckhed, F, Groen, AK & Nieuwdorp, M 2022, 'Microbiome-derived ethanol in nonalcoholic fatty liver disease', Nature Medicine, bind 28, s. 2100-2106. https://doi.org/10.1038/s41591-022-02016-6

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title = "Microbiome-derived ethanol in nonalcoholic fatty liver disease",

abstract = "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{\textquoteright}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.",

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AU - Meijnikman, Abraham S.

AU - Davids, Mark

AU - Herrema, Hilde

AU - Aydin, Omrum

AU - Tremaroli, Valentina

AU - Rios-Morales, Melany

AU - Levels, Han

AU - Bruin, Sjoerd

AU - de Brauw, Maurits

AU - Verheij, Joanne

AU - Kemper, Marleen

AU - Holleboom, Adriaan G.

AU - Tushuizen, Maarten E.

AU - Schwartz, Thue W.

AU - Nielsen, Jens

AU - Brandjes, Dees

AU - Dirinck, Eveline

AU - Weyler, Jonas

AU - Verrijken, An

AU - De Block, Christophe E.M.

AU - Vonghia, Luisa

AU - Francque, Sven

AU - Beuers, Ulrich

AU - Gerdes, Victor E.A.

AU - Bäckhed, Fredrik

AU - Groen, Albert K.

AU - Nieuwdorp, Max

PY - 2022

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N2 - 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.

AB - 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.

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DO - 10.1038/s41591-022-02016-6

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