Predicted functional alterations in colonic microbiota metabolism underlie ethanol consumption and preference behavior in mice.

BACKGROUND

Alcohol use disorder (AUD) is a complex condition affecting several body systems. Gut microbiota alterations, intestinal-barrier disruption, and the consequent translocation of metabolites foster chronic inflammation, lower short-chain fatty acid (SCFA) output, and depleted beneficial bacteria may contribute to transcriptional, epigenetic, and metabolic changes that influence ethanol preference.

METHODS

Two experimental phases were used. T1 (8 weeks): mice received either the American Institute of Nutrition standard diet (AING) or a high-sugar-butter (HSB) diet. T2 (4 weeks): HSB animals switched to AING (SWITCH), while AING mice maintained the same diet. Each diet arm was split into ethanol (EtOH; free access to 10% ethanol) or H2O, generating four groups (AING + H2O, AING + EtOH, SWITCH + H2O, and SWITCH + EtOH). Sample processing involved colonic-content collection, 16S rRNA sequencing, microbiome profiling, functional inference, metabolic-network analysis, and SCFA/amino acid quantification.

RESULTS

SWITCH + EtOH mice displayed high ethanol consumption and preference, whereas AING + EtOH mice showed ethanol aversion. Their colonic microbiota differed markedly; amino acid metabolism fell, secondary bile acid synthesis rose, and SCFA production dropped in SWITCH + EtOH animals. Direct measurements confirmed significant reductions in butyrate, acetate, propionate, and selected amino acids. Network analysis revealed enrichment of bacterial metabolism, oxidative stress, and dopamine pathway genes.

CONCLUSIONS

Diet-induced dysbiosis, reflected in shifts in microbiota-derived metabolites, was associated with excessive alcohol intake; the metabolites identified can represent potential therapeutic targets for AUD.