High-Dose Ethanol-Induced Immunosuppression Modulates Sex-Specific Disease Outcomes in a Murine Model of Multiple Sclerosis

Both epidemiological studies and prior work in animal models suggest that moderate-dose alcohol reduces disease severity across several autoimmune conditions, including multiple sclerosis (MS). However, the mechanisms underlying the potentially beneficial effects of alcohol and how these effects may change with alcohol dose in autoimmunity remain underexplored. In this study, we characterize the effects of chronic, high-dose ethanol consumption in experimental autoimmune encephalomyelitis (EAE), a murine model of MS, by examining EAE disease severity, gut microbial composition, and peripheral cell immunophenotypes. We found that high-dose ethanol-fed males exhibited a significant amelioration in peak EAE disease severity, in association with decreased T cell activation and B cell proportions. Concurrently, we observed proinflammatory shifts in gut microbiota and hepatic lipid accumulation. Our results suggest that high dose ethanol may benefit autoimmune neuroinflammation in EAE through immunosuppressive effects on adaptive immunity, however its toxic systemic effects preclude the use of alcohol as an immunomodulator in MS. Overall, our findings reveal a mechanistic basis for alcohol's beneficial properties in autoimmunity and could inform the development of more targeted disease modifying therapies that recapitulate these benefits without alcohol-associated toxicity.