| First Author | Shukla PK | Year | 2022 |
| Journal | FASEB J | Volume | 36 |
| Issue | 1 | Pages | e22061 |
| PubMed ID | 34861075 | Mgi Jnum | J:332345 |
| Mgi Id | MGI:7355085 | Doi | 10.1096/fj.202101424R |
| Citation | Shukla PK, et al. (2022) Central role of intestinal epithelial glucocorticoid receptor in alcohol- and corticosterone-induced gut permeability and systemic response. FASEB J 36(1):e22061 |
| abstractText | 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(DeltaHC) ) and intestinal epithelial-specific GR-deficient (GR(DeltaIEC) ) 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(DeltaHC) mouse colon; these effects of ethanol and corticosterone were absent in GR(DeltaIEC) mice. Gut microbiota compositions in ethanol-fed GR(DeltaHC) and GR(DeltaIEC) mice were similar to each other. However, corticosterone treatment in ethanol-fed mice shifted the microbiota composition to distinctly different directions in GR(DeltaHC) and GR(DeltaIEC) mice. Ethanol and corticosterone synergistically elevated the abundance of Enterobacteriaceae and Escherichia coli and reduced the abundance of Lactobacillus in GR(DeltaHC) mice but not in GR(DeltaIEC) mice. In GR(DeltaHC) mice, corticosterone potentiated ethanol-induced endotoxemia and systemic inflammation, but these effects were absent in GR(DeltaIEC) mice. Interestingly, ethanol-induced liver damage and its potentiation by corticosterone were observed in GR(DeltaHC) mice but not in GR(DeltaIEC) mice. GR(DeltaIEC) 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. |
