From Auto-Brewery Syndrome to Metabolic Disease: A Microbiome-Driven Ethanol–Acetaldehyde Axis

Abstract Emerging evidence suggests that endogenous ethanol production by the gut microbiome contributes to metabolic disease. While traditionally considered negligible, microbiome-derived ethanol can reach clinically relevant levels in dysbiotic states and is efficiently metabolized to acetaldehyde, a highly reactive and toxic metabolite. Here, we propose an integrative conceptual framework: the Microbiome-Driven Ethanol–Acetaldehyde Axis. We argue that sustained local exposure to acetaldehyde, even in the absence of elevated blood alcohol concentrations, triggers metabolic dysfunction. This model provides a mechanistic explanation for the overlap between alcohol-related and nonalcoholic fatty liver disease (MASLD). By dissociating injury from circulating ethanol levels, this framework highlights the gut microbiome as a central driver of metabolic pathology. Keywords: Auto-Brewery Syndrome, Gut Microbiome, Acetaldehyde, MASLD (NAFLD), Endogenous Ethanol, Gut-Liver Axis, Longevity. Summary:This paper proposes an innovative conceptual framework: the Microbiome-Driven Ethanol–Acetaldehyde Axis. We argue that endogenous ethanol production, driven by gut dysbiosis (bacteria and fungi), represents a critical mechanistic link to metabolic diseases such as MASLD (formerly NAFLD).The model highlights the role of acetaldehyde as the primary mediator of tissue injury and explains the "paradox" of metabolic damage occurring even in the absence of elevated blood alcohol concentrations—a phenomenon we term "first-pass masking." By integrating microbial metabolism with host biochemical pathways, including the impact of insulin resistance on ethanol clearance, this work offers new perspectives for microbiome-targeted therapies and public health.