FS3-Shukla etal-Intestinal GR in Alcohol effects

Corticosterone, the stress hormone, exacerbates alcohol-associated tissue injury, but the mechanism involved is unknown. We examined the role of the glucocorticoid receptor (GR) in corticosterone-mediated potentiation of alcohol-induced gut barrier dysfunction and systemic response. Hepatocyte-specific GR deficient (GRHC) and intestinal epithelial-specific GR deficient (GRIEC) mice were fed ethanol, combined with corticosterone treatment. Intestinal epithelial tight junction integrity, mucosal barrier function, microbiota dysbiosis, endotoxemia, systemic inflammation, liver damage, and neuroinflammation were assessed. Corticosterone potentiated ethanol-induced epithelial tight junction disruption, mucosal permeability, and inflammatory response in GRHC mouse colon; these effects of ethanol and corticosterone were absent in GRIEC mice. Gut microbiota compositions in ethanol-fed GRIEC and GRIEC mice were similar to each other. However, corticosterone treatment in ethanol-fed mice shifted the microbiota composition to distinctly different directions in GRHC and GRIEC mice. Ethanol and corticosterone synergistically elevated the abundance of Enterobacteriaceaeand E. coli and reduced the abundance of Lactobacillus in GRHCmice but not in GRIEC mice. In GRHC mice, corticosterone potentiated ethanol-induced endotoxemia and systemic inflammation, but these effects were absent in GRIEC mice. Interestingly, ethanol-induced liver damage and its potentiation by corticosterone were observed in GRHC mice but not in GRIEC mice. GRIECmice were also resistant to ethanol and corticosterone-induced inflammatory response in the hypothalamus. These data indicate that the intestinal epithelial GR plays a central role in alcohol and corticosterone-induced gut barrier dysfunction, microbiota dysbiosis, endotoxemia, systemic inflammation, liver damage, and neuroinflammation. This study identifies a novel target for potential therapeutic for alcohol-associated tissue injury.