Microbial ethanol production in patients with auto-brewery syndrome

Researchers confirm endogenous ethanol in clinical study: LINK to full article

Cynthia L. Hsu, Shikha Shukla, Linton Freund, Annie C. Chou, Yongqiang Yang, Ryan Bruellman, Fernanda Raya Tonetti, Noemí Cabré, Susan Mayo, Hyun Gyu Lim, Valeria Magallan, Barbara J. Cordell, Sonja Lang, Münevver Demir, Peter Stärkel, Cristina Llorente, Bernhard O. Palsson, Chitra Mandyam, Brigid S. Boland, Elizabeth Hohmann & Bernd Schnabl 

The question

Auto‑brewery syndrome (ABS) is a rare condition characterised by intoxication that occurs because gut microbiota produce high levels of ethanol, which enters the bloodstream1. Diagnosis of ABS is challenging, as the current gold standard approach requires monitoring a patient in a clinical setting for up to 24 hours to confirm a rise in blood alcohol levels after an oral glucose challenge. Moreover, no consensus treatment exists, in part because the microorganism(s) responsible for ABS remains poorly understood. Case reports have shown an association between ABS and yeast overgrowth or gastrointestinal diseases such as short gut syndrome and Crohn’s disease2, whereas more recent cases have identified ethanol‑producing strains of Klebsiella3. Understanding the microbial culprits of ABS and their ethanol‑producing mechanisms are essential for developing accurate diagnostics and effective treatments for patients with ABS.

The observation

We prospectively enrolled 22 patients with ABS and 21 unaffected household partners. Serial stool samples were collected to characterize microbial and physiological changes over time. To determine whether patient microbiota could directly generate ethanol, we first measured microbial ethanol production in fecal samples using an anaerobic in vitro culturing system. We then applied metagenomic sequencing to identify taxonomic differences and functional metabolic pathways that distinguished patients with ABS from their household partners and biologically matched healthy controls. Fecal metabolomic profiling was used to validate pathway‑level differences suggested by sequencing data. Finally, to test the biological relevance of these findings, we treated one patient with fecal microbiota transplantation and performed longitudinal analyses to link shifts in gut microbial composition with physiological measures and symptom improvement.

We found that fecal microbiota from patients with ABS produced substantially more ethanol in vitro than microbiota from asymptomatic partners, providing direct evidence for a microbial source of endogenous alcohol. Contrary to previous assumptions that fungi drive ABS, our data show that Proteobacteria such as E. coli are the predominant ethanol producing pathobionts in most patients (Fig. 1). Metagenomic profiling revealed that fermentation pathways capable of generating ethanol were consistently overrepresented in ABS microbiomes, offering a mechanistic explanation for symptomatic flares. Finally, in a patient treated with fecal microbiota transplantation, improvements in symptoms correlated with reductions in ethanol-producing microbes and fermentation pathways, confirming the clinical relevance of microbial alterations and providing preliminary evidence for a potential therapeutic approach.

The implications

Our findings have several important implications for improving the diagnosis and management of ABS. A major barrier to diagnosis is the need for supervised, serial ethanol measurements during symptomatic flares. By showing that cultured fecal microbiota from patients with ABS produce substantially more ethanol than those from asymptomatic household partners, we highlight a possible path toward developing more accessible diagnostic tools based on ex vivo microbial activity. Beyond ABS, our results suggest that gut‑derived ethanol production might be relevant to conditions such as diabetes and steatotic liver disease, in which low‑level endogenous ethanol production has been detected4,5. This finding raises important questions about how common microbial ethanol production is in the general population and its potential to contribute to broader metabolic or hepatic disease.

Our findings highlight potential therapeutic avenues. We demonstrate successful remission in a patient following fecal microbiota transplantation (FMT), accompanied by decreases in Proteobacteria and fermentation pathway enrichment. Given that many microbial species can activate ethanol‑producing pathways, our data further suggest that additional therapeutic strategies targeting key enzymes or metabolic steps, rather than individual taxa, might offer a more scalable and broadly effective therapeutic approach.

Further studies are needed to understand the episodic nature of ABS, with alternating remission and flares, and the effect of diet, stress, and other environmental factors. Exploring these dynamics could identify new therapeutic targets. The prevalence and clinical impact of gut‑derived ethanol production should be assessed in more diverse populations, with the goal of developing accessible diagnostics and mechanism‑based treatments for ABS.

Cynthia L. Hsu & Bernd Schnabl
University of California San Diego, La Jolla, CA, USA.