Data from multiple cross-sectional cohort studies support a mediating potential of the microbiome in the association between PPI use and hepatic steatosis, with the effect of PPIs on MASLD appearing to be mediated mainly by increased lactic acid bacteria abundance, and potentially, in part, serially mediated by endogenous ethanol production.
Key Findings
Background
Proton pump inhibitor use was associated with metabolic dysfunction associated with steatotic liver disease (MASLD) across multiple cohorts, with the microbiome identified as a potential mediating factor.
The study used three cohorts: a bariatric surgery cohort (n=122), the HELIUS general population cohort (n=2440), and the FINRISK validation cohort (n=7066).
Outcomes included liver biopsy-proven steatosis grade, postprandial ethanol concentrations, and Fatty Liver Index (FLI) score.
The association between PPI use and MASLD is confounded by various risk factors such as BMI and age.
The mediation analysis was conducted cross-sectionally across all cohorts.
Results
The Lactobacillales order showed the strongest mediating potential between PPI use and MASLD outcomes across both discovery cohorts.
Lactobacillales are predominantly found in the small intestine.
The mediating role of Lactobacillales was observed across multiple outcomes: liver biopsy-proven steatosis grade, postprandial ethanol levels, and FLI score.
The association was observed in both the bariatric surgery cohort and the HELIUS cohort.
The mediating role of Lactobacillales in the association between PPI use and FLI scores was confirmed in the FINRISK validation cohort (n=7066).
Results
A serial mediation pathway was identified linking PPI use to MASLD via Lactobacillales abundance and postprandial plasma ethanol concentrations.
The serial mediation pathway proceeds: PPI use → increased Lactobacillales abundance → elevated postprandial plasma ethanol → MASLD.
Postprandial ethanol concentrations were measured as an outcome in the bariatric surgery cohort (n=122).
This pathway suggests endogenous ethanol production as a mechanistic link between gut microbiome changes and hepatic steatosis.
The mediation was identified as independent of alcohol consumption.
Results
Several bacterial taxa predominantly found in the small intestine showed a potential mediating role in the effects of PPIs on MASLD, postprandial ethanol levels, and FLI score.
Beyond Lactobacillales, multiple bacterial taxa were implicated in the mediation analysis.
The small intestinal localization of these taxa is consistent with the known effect of PPIs on upper gastrointestinal pH and microbiome composition.
Findings were identified in the two discovery cohorts (bariatric surgery cohort n=122; HELIUS cohort n=2440) and the strongest associations were validated in FINRISK (n=7066).
The analysis was cross-sectional in design across all cohorts.
Results
The mediating effect of the microbiome on PPI-associated hepatic steatosis was independent of alcohol consumption.
The study specifically controlled for alcohol consumption to distinguish endogenous ethanol production from exogenous alcohol intake as a driver of MASLD.
This finding supports endogenous microbial ethanol production as a distinct and independent pathway to hepatic steatosis in PPI users.
The independence from alcohol consumption was noted across the multiple cohort analyses.
Methods
The study design employed multicohort cross-sectional mediation analysis using three cohorts of varying clinical context and size.
The bariatric surgery cohort (n=122) used liver biopsy-proven steatosis grade as a gold-standard outcome.
The HELIUS cohort (n=2440) is described as a general population cohort study using FLI score as an outcome.
The FINRISK cohort (n=7066) served as a validation cohort for the strongest associations identified in discovery cohorts.
Total participants across all cohorts exceeded 9,600 individuals.
What This Means
This research suggests that proton pump inhibitors (PPIs) — common medications used to reduce stomach acid for conditions like heartburn and ulcers — may contribute to fatty liver disease (MASLD) partly through changes in gut bacteria. The study analyzed data from over 9,600 people across three separate groups: patients undergoing bariatric surgery, a large general population study, and a Finnish population health survey. Using statistical methods called mediation analysis, the researchers found that a group of bacteria called Lactobacillales (lactic acid bacteria, which thrive when stomach acid is reduced) appear to play a key role in connecting PPI use to liver fat accumulation.
A particularly notable finding was a chain of events the researchers identified: PPI use appears to increase lactic acid bacteria in the gut, which in turn produce more ethanol internally (endogenous ethanol), and this elevated ethanol in the bloodstream after eating may then contribute to fatty liver disease. This is significant because it suggests that the liver damage associated with PPI use may not require a person to drink alcohol — the gut bacteria themselves may be producing enough alcohol-like compounds to affect the liver. This internal ethanol production was found to be independent of the participants' own alcohol consumption.
This research matters because PPIs are among the most widely used medications in the world, and fatty liver disease is a growing global health concern. These findings suggest a possible biological mechanism — changes in gut bacteria and endogenous ethanol — that could explain why PPI users may be at higher risk for liver problems. However, because the study was cross-sectional (meaning it looked at people at a single point in time rather than following them over time), it cannot definitively prove that PPIs cause fatty liver disease, only that the associations are consistent with this pathway.
Davids M, Herrema H, K Groen A, Galenkamp H, Zwinderman A, Palmu J, et al.. (2026). Lactic acid bacteria and endogenous ethanol mediate proton pump inhibitor-associated MASLD: a multicohort cross-sectional mediation analysis.. Gut microbes. https://doi.org/10.1080/19490976.2026.2664712