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  • Review Article
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Endogenous ethanol production in health and disease

Abstract

The gut microbiome exerts metabolic actions on distal tissues and organs outside the intestine, partly through microbial metabolites that diffuse into the circulation. The disruption of gut homeostasis results in changes to microbial metabolites, and more than half of the variance in the plasma metabolome can be explained by the gut microbiome. Ethanol is a major microbial metabolite that is produced in the intestine of nearly all individuals; however, elevated ethanol production is associated with pathological conditions such as metabolic dysfunction-associated steatotic liver disease and auto-brewery syndrome, in which the liver’s capacity to metabolize ethanol is surpassed. In this Review, we describe the mechanisms underlying excessive ethanol production in the gut and the role of ethanol catabolism in mediating pathogenic effects of ethanol on the liver and host metabolism. We conclude by discussing approaches to target excessive ethanol production by gut bacteria.

Key points

  • Ethanol production occurs in the intestines of nearly all individuals, with a stepwise increase from healthy subjects to those with metabolic dysfunction-associated steatotic liver disease, and further to auto-brewery syndrome, in which the liver’s capacity to metabolize ethanol is surpassed.

  • The onset of excessive ethanol production in the gut is linked to a disruption in gut homeostasis. This disturbance often arises from the use of medications, notably proton pump inhibitors and antibiotics. When combined with a Western diet rich in fat and simple sugars, these factors significantly contribute to altering the gut environment and subsequently, ethanol production.

  • Various microbial species have the potential for ethanol production. However, many of these species are commonly found in the human gut and do not typically cause harm. Therefore, it is an oversimplification to ascribe excessive ethanol production to just a single strain.

  • Endogenous and exogenous ethanol both exhibit similar detrimental effects on the host, impacting vital organs such as the liver, intestine and brain.

  • Currently, there are no standardized treatments for excessive endogenous ethanol production, as most knowledge has been derived from case reports. There is a critical need for large-scale studies to better understand this condition, to identify ethanol-producing bacteria and to explore potential therapeutic targets in clinical trials.

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Fig. 1: Different mechanisms by which bacteria produce ethanol.
Fig. 2: Ethanol catabolism in the host and effects on the host.
Fig. 3: Ways of targeting ethanol-producing bacteria.

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Acknowledgements

A.S.M. is supported by a personal Niels Stensen Fellowship. M.N. is supported by a personal ZONMW-VICI grant 2020 (09150182010020) and a personal ERC advanced FATGAP number 101141346 grant. This study was supported in part by NIH grants R01 AA24726, R37 AA020703, U01 AA026939, U01 AA026939-04S1, by Award Number BX004594 from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development, and a Harrington Discovery Institute Foundation Grant (to B.S.) and services provided by NIH centers P30 DK120515 and P50 AA011999.

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A.S.M. wrote the review. M.N. and B.S. edited the manuscript.

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Correspondence to Bernd Schnabl.

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M.N. is co-founder and member of the Scientific Advisory Board of Caelus Pharmaceuticals and Advanced Microbial Interventions, Netherlands. None of these is directly relevant to the current paper. B.S. has been consulting for Ambys Medicines, Ferring Research Institute, Gelesis, HOST Therabiomics, Intercept Pharmaceuticals, Mabwell Therapeutics, Patara Pharmaceuticals, Surrozen and Takeda. B.S. is founder of Nterica Bio. UC San Diego has filed several patents with B.S. as inventor related to this work. B.S.’s institution UC San Diego has received research support from Axial Biotherapeutics, BiomX, ChromoLogic, CymaBay Therapeutics, Intercept Pharmaceuticals, NGM Biopharmaceuticals, Prodigy Biotech and Synlogic Operating Company. A.S.M. declares no competing interests.

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Nature Reviews Gastroenterology & Hepatology thanks Qixiao Zhai and Dennis Nielsen for their contribution to the peer review of this work.

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Glossary

Culturomics

A microbiological technique that uses diverse culture conditions, including varied growth media, atmospheric conditions and incubation times, to mimic the natural environments of microorganisms closely and enhances the capacity to culture and identify a wide array of microorganisms from various environments, particularly those previously deemed uncultivatable or difficult to grow under laboratory conditions.

Hypochlorhydria

A condition marked by reduced levels of stomach acid (hydrochloric acid), which occurs when the gastric parietal cells in the stomach lining produce insufficient amounts of hydrochloric acid.

Mallory bodies

Also known as Mallory–Denk bodies; cytoplasmic inclusions found in the hepatocytes composed of aggregated intermediate filaments, mainly cytokeratin, along with other proteins such as ubiquitin, that are typically associated with cellular stress or injury and are commonly observed in various liver diseases, including alcohol-associated liver disease and metabolic dysfunction-associated steatotic liver disease.

Postprandial

The physiological phase subsequent to the ingestion of a meal; this term is frequently used within clinical and nutritional sciences to characterize various metabolic and digestive processes that are initiated or altered in response to food intake.

Pseudo-obstruction

Manifests as bowel dilation devoid of any anatomical blockage; this condition mimics the clinical presentation of an actual bowel obstruction, marked by symptoms such as nausea, vomiting, abdominal swelling and inability to pass stools, with imaging studies such as plain radiography and CT scans revealing dilation of the bowel.

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Meijnikman, A.S., Nieuwdorp, M. & Schnabl, B. Endogenous ethanol production in health and disease. Nat Rev Gastroenterol Hepatol (2024). https://doi.org/10.1038/s41575-024-00937-w

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