A1 Refereed original research article in a scientific journal
Lactic acid bacteria and endogenous ethanol mediate proton pump inhibitor-associated MASLD: a multicohort cross-sectional mediation analysis
Authors: Davids, Mark; Herrema, Hilde; K. Groen, Albert; Galenkamp, Henrike; Zwinderman, Aeilko; Palmu, Joonatan; Havulinna, Aki; Niiranen, Teemu; Knight, Rob; Acherman, Yaïr; Franken, Rutger; Verheij, Joanne; Dukas, Michael; Dutch Liver Pathology Panel; Bajaj, Jasmohan; Llorente, Cristina; Schnabl, Bernd; Nieuwdorp, Max; Meijnikman, Abraham
Publisher: Informa UK Limited
Publication year: 2026
Journal: Gut Microbes
Article number: 2664712
Volume: 18
Issue: 1
ISSN: 1949-0976
eISSN: 1949-0984
DOI: https://doi.org/10.1080/19490976.2026.2664712
Publication's open availability at the time of reporting: Open Access
Publication channel's open availability : Open Access publication channel
Web address : https://doi.org/10.1080/19490976.2026.2664712
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/523176820
Self-archived copy's licence: CC BY
Self-archived copy's version: Publisher`s PDF
Background & aims: Proton pump inhibitor (PPI) use has been associated with metabolic dysfunction associated with steatotic liver disease (MASLD) in multiple studies. While the association is confounded by various risk factors, such as BMI and age, a potential mediating factor of the microbiome has been suggested. In this study, we aimed to identify bacterial clades with the highest mediating potential and evaluate the serially mediated path through microbially derived endogenous ethanol.
Methods: Microbiome mediation analysis of PPI use and MASLD was conducted in two cohorts. In a bariatric surgery cohort (n = 122), liver biopsy-proven steatosis grade and postprandial ethanol concentrations were used as outcomes. In the HELIUS cohort (n = 2440), a general population cohort study, mediation was performed using the Fatty Liver Index (FLI) score. The strongest associations were validated in the FINRISK cohort (n = 7066).
Results: Several bacterial taxa, which are predominantly found in the small intestine, showed a potential role in mediating the effects of PPIs on MASLD, postprandial ethanol levels, and FLI score. The Lactobacillales order showed the strongest mediating potential across the outcomes tested in both discovery cohorts. A notable serial mediation pathway was identified, linking PPI use to MASLD via Lactobacillales abundance and postprandial plasma ethanol concentrations. The mediating role of Lactobacillales in the association between PPI use and FLI scores was confirmed in the final study cohort.
Conclusions: Data from multiple cross-sectional cohort studies support a mediating potential of the microbiome in the association between PPI use and hepatic steatosis, independent of alcohol consumption. The effect of PPIs on MASLD appears to be mediated mainly by increased lactic acid bacteria abundance, and is potentially, in part, serially mediated by endogenous ethanol production.
Keywords: MASLD; ethanol; fermentation; gastrointestinal microbiome; lactobacillales; mediation analysis; obesity; proton pump inhibitors; small intestine.
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Funding information in the publication:
This study was supported in part by services provided by the National Institutes of Health (NIH) Center P30 DK120515 (B.S.). MN is supported by a personal NWO VICI grant 2020 (09150182010020) and an European Research Council (ERC) Advanced grant (101141346). A.S.M. is supported by a Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO) VENI grant (09150162310148). The HELIUS study is conducted by the Amsterdam University Medical Center, AMC location, and the Public Health Service of Amsterdam. Both organisations provide core support for HELIUS. The HELIUS baseline measurement was additionally funded by the Dutch Heart Foundation, the Netherlands Organization for Health Research and Development (ZonMw), the European Union (FP-7), and the European Fund for the Integration of non-EU immigrants (EIF). The funders of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the manuscript. The HELIUS follow-up measurement was additionally supported by the Netherlands Organization for Health Research and Development (ZonMw; 10430022010002), Novo Nordisk (18157/80927), the Swiss National Foundation (189235), the University of Amsterdam (Research Priority Area 25-08-2020 “Personal Microbiome Health”) and the Dutch Kidney Foundation (Collaboration Grant 19OS004).
