Endogenous ethanol production in health and disease

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. Ethanol is produced in the gut by several different species of fermentative bacteria. This Review discusses the sources and consequences of endogenously produced ethanol, explores its relationship with liver diseases such as metabolic dysfunction-associated steatotic liver disease and covers approaches to target excessive ethanol production in the gut. 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