Potential Therapeutic Options for Ethanol-Producing Ethanol-Resistant Gut Microbes associated with Liver Diseases

BackgroundEndogenous ethanol (EtOH) production is an emerging pathophysiological mechanism involved in metabolic dysfunction-associated steatohepatitis (MASH). Therefore, characterizing EtOH-producing species enriched in patients with liver disease could help identify putative pathobionts and potential therapeutic treatments. MethodsWe investigated EtOH production and tolerance, antimicrobial susceptibility and antimicrobial resistance gene(s) in 33 strains enriched in MASH, alcoholic hepatitis (AH) and HBV patients. An antimicrobial was considered a potential therapeutic option when the ratio of the fecal concentration/minimum inhibitory concentration (FC/MIC) was > 10 (1 log10). Results92% of species enriched in patients with liver diseases produced detectable amounts of ethanol with a strong association between EtOH tolerance and production (p < 0.05). Candida albicans, Nakaseomyces glabratus and Pichia kudriavzevii produced the highest concentrations of EtOH (1.8 to 3.3 g/L). Enterocloster, a strictly anaerobic bacterial genus, was the bacterial genus with the highest EtOH production (0.8 to 1.6 g/L) in 5 g/L of glucose. Poorly absorbed drugs, amphotericin B, rifaximin and vancomycin, together constituted potential therapeutic options for all tested strains. ConclusionsIn addition to yeasts, Lactobacillaceae and Klebsiella, strains of Enterocloster genus isolated from patients with liver diseases produced significant amount of EtOH. Most gut microbial species associated with liver diseases produce and tolerate ethanol, suggesting a possible vicious microbial-ethanol cycle in such context. Finally, non-absorbed antimicrobials (rifaximin, vancomycin and amphotericin B) already used for gut microbiota-targeted therapies may open new avenues in the design of precision medicine.