Prevention and mitigation of alcohol-induced neuroinflammation by by an EGF receptor-dependent mechanism.

Neuroinflammation is implicated in the pathogenesis of alcohol use disorders. We investigated the role of Gut-Brain interactions in alcohol-induced neuroinflammation by probiotic-mediated manipulation of intestinal dysbiosis in mice. Chronic ethanol feeding induced dysbiosis, as evidenced by an increase in Firmicutes/Bacteroidetes ratio and depletion of species in the colon. Ethanol increased the levels of IL-1β, IL-6, and TNFα in plasma and the mRNA for , , , and genes in the cerebral cortex and hippocampus. Ethanol feeding increased inulin flux from the circulation into different brain regions, accompanied by the increase in TLR4 mRNA levels in the cerebral cortex and hippocampus. The immunofluorescence confocal microscopy showed that ethanol elevates the expression of microglial activation marker TMEM119 in the cerebral cortex. Feeding suppressed the ethanol-induced dysbiosis to some extent, as evidenced by attenuation of ethanol effects on Firmicutes/Bacteroidetes ratio and abundance of . blocked ethanol-induced elevation of plasma cytokines, inulin permeability to the brain, mRNA for , , , , and in brain regions, and the expression of TMEM119 in the cerebral cortex. The effect was absent in mice that express a dominant-negative EGFR, suggesting that the EGFR receptor plays an essential role in the protective effect of against ethanol-induced neuroinflammation. , when administered after chronic ethanol-induced injury, rescued the ethanol-induced systemic inflammation and neuroinflammation. This study demonstrates that in the gut prevents and mitigates ethanol-induced neuroinflammation by an EGFR-dependent mechanism.