Epithelial deletion of the glucocorticoid receptor (Nr3c1) protects the mouse intestine against experimental inflammation

Background and Purpose Glucocorticoids are the first line treatment for the flare-ups of inflammatory bowel disease, but they have significant limitations. The objective of this study is to investigate whether glucocorticoid epithelial actions contribute to such limitations. Experimental Approach Intestinal epithelium glucocorticoid receptor knockout mice (Nr3c1(Delta IEC)) received dextran sulfate sodium (DSS) to induce colitis. Inflammatory status was assessed by morphological and biochemical methods, and corticoid production was measured in colonic explants. Some mice were administered budesonide. Key Results After 7 days of DSS Nr3c1(Delta IEC), mice exhibited 23.1% lower disease activity index (DAI) and 37% lower diarrheal score than WT mice, with decreased weight loss in days 5-7 of colitis, attenuated tissue damage, reduced colonic expression of S100A9 and STAT3 phosphorylation, and a better overall state. Ki67 immunoreactivity was increased at the crypt base, indicating enhanced epithelial proliferation. Mice administered budesonide (6 mu g center dot day(-1) PO) showed modest antiinflammatory effects but increased weight loss, which was prevented in knockout mice. Epithelial deletion of the glucocorticoid receptor also protected mice in a protracted colitis protocol. Conversely, knockout mice presented a worse status compared to the control group at 1 day post DSS. In a separate experiment, colonic corticosterone production was shown to be significantly increased in knockout mice at 7 days of colitis but not at earlier stages. Conclusions and Implications The intestinal epithelial glucocorticoid receptor has deleterious effects in experimental colitis induced by DSS, probably related to inhibition of epithelial proliferative responses leading to impaired wound healing and reduced endogenous corticosterone production.

Automated summary

The study found that in a colitis model, intestinal epithelial glucocorticoid receptor knockout mice performed better in reducing disease activity, preventing weight loss, and limiting tissue damage compared to WT mice. Budesonide treatment had limited anti-inflammatory effects on mice, but resulted in weight loss. Knockout of the receptor also provided protection in a protracted colitis protocol.