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 (<em>GR</em>^<em>HC</em>) and intestinal epithelial-specific GR deficient (<em>GR</em>^<em>IEC</em>) 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 <em>GR</em>^<em>HC</em> mouse colon; these effects of ethanol and corticosterone were absent in <em>GR</em>^<em>IEC</em> mice. Gut microbiota compositions in ethanol-fed <em>GR</em>^<em>IEC</em> and <em>GR</em>^<em>IEC</em> mice were similar to each other. However, corticosterone treatment in ethanol-fed mice shifted the microbiota composition to distinctly different directions in <em>GR</em>^<em>HC</em> and <em>GR</em>^<em>IEC</em> mice. Ethanol and corticosterone synergistically elevated the abundance of <em>Enterobacteriaceae</em>and <em>E. coli</em> and reduced the abundance of <em>Lactobacillus</em> in <em>GR</em>^<em>HC</em>mice but not in <em>GR</em>^<em>IEC</em> mice. In <em>GR</em>^<em>HC</em> mice, corticosterone potentiated ethanol-induced endotoxemia and systemic inflammation, but these effects were absent in <em>GR</em>^<em>IEC</em> mice. Interestingly, ethanol-induced liver damage and its potentiation by corticosterone were observed in <em>GR</em>^<em>HC</em> mice but not in <em>GR</em>^<em>IEC</em> mice. <em>GR</em>^<em>IEC</em>mice 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.