Intestinal Glucocorticoid Receptor Mediates Alcohol and Corticosterone-Induced Synergistic Tissue Injury at the Gut-Liver-Brain Axis
Alcohol use disorders are associated with altered stress responses, but the influence of stress or stress hormones on alcoholic tissue injury remains uninvestigated. We evaluated the effects of chronic stress and corticosterone on alcohol-induced gut barrier dysfunction and inflammatory responses at the Gut-Liver-Brain (GLB) axis.Adult wildtype and tissue-specific glucocorticoid receptor (GR)-deficient mice were fed ethanol combined with either chronic restraint stress or corticosterone administration. Intestinal epithelial tight junction integrity, mucosal barrier function, endotoxemia, systemic inflammation, liver damage, and neuroinflammation were assessed. For in vitro studies, Caco-2 cell monolayers, treated with corticosterone, were exposed to ethanol and acetaldehyde, and the barrier function assessed by measuring transepithelial electrical resistance and inulin permeability.In Caco-2 cell monolayers, corticosterone dose-dependently potentiated ethanol and acetaldehyde-induced tight junction disruption and barrier dysfunction. In mice, chronic restraint stress or corticosterone administration exacerbated alcohol-induced colonic epithelial tight junction disruption, gut permeability, and liver damage. Corticosterone potentiated alcohol-induced dysbiosis, endotoxemia, systemic inflammation, and inflammatory responses in the colon, liver, and hypothalamus. These effects of alcohol and corticosterone were absent in Vilcre-GRfl mice but intact in Albcre-GRfl mice. Alcohol and corticosterone down-regulated intestinal alpha-defensin expression and altered gut microbiota in Albcre-GRfl mice, but not in Vilcre-GRfl mice.These data demonstrate that an intestinal GR-dependent mechanism mediates alcohol-induced epithelial tight junction disruption, mucosal barrier dysfunction, dysbiosis, endotoxemia, systemic inflammation, liver damage, and neuroinflammation. Chronic stress and corticosterone exacerbate alcohol-induced tissue injury at the GLB axis. These novel findings present mechanistic insights into the interactions between alcohol and stress or glucocorticoids.