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Alcohol shifts gut microbial networks and ameliorates a murine model of neuroinflammation in a sex-specific pattern

Significance While alcohol is widely known for its proinflammatory effects, there is also evidence that it may improve outcomes in several autoimmune conditions. Alcohol’s mechanism of potential beneficial effects is unclear, and there are no clinical guidelines on the acceptable level of patient consumption. Using a model of autoimmune neuroinflammation, experimental autoimmune encephalomyelitis, we present data that moderate alcohol consumption ameliorates disease symptoms, decreases central nervous system (CNS) microglia, and enriches protective gut microbial networks in a sex-specific pattern. Our results implicate the gut–CNS axis in alcohol’s effects in autoimmunity and raise important broader implications about sex-specific diet effects. Alcohol is a widely consumed dietary component by patients with autoimmune neuroinflammatory diseases, but current evidence on the effects of alcohol in these conditions is confounding. Epidemiological studies suggest moderate consumption of alcohol may be protective in some autoimmune diseases; however, this correlation has not been directly investigated. Here, we characterize the effects of moderate-dose alcohol in a model system of autoimmune neuroinflammation, experimental autoimmune encephalomyelitis (EAE). Male and female C57BL/6J mice were fed a 2.6% alcohol or isocaloric diet for 3 wk prior to MOG35–55 EAE induction. Surprisingly, alcohol-fed males experienced significantly greater disease remission compared to alcohol-fed females and control-fed counterparts. We observed a male-specific decrease in microglial density in alcohol-consuming animals in cervical and thoracic spinal cord in late-stage disease. In the gut, alcohol diet resulted in several sex-specific alterations in key microbiota known for their regulatory immune roles, including Turicibacter, Akkermansia, Prevotella, and Clostridium. Using a correlation network modeling approach, we identified unique bacterial modules that are significantly enriched in response to treatment and sex, composed of Clostridial taxa and several Firmicutes known to be protective in EAE. Together, these data demonstrate the potential of alcohol to significantly alter the course of autoimmunity differentially in males and females via effects on gut bacterial networks and support further need to evaluate dose and sex-specific alcohol effects in multiple sclerosis (MS) and other autoimmune neuroinflammatory conditions.