Central role of intestinal epithelial glucocorticoid receptor in alcohol‐ and corticosterone‐induced gut permeability and systemic response

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