Dual Role of Glucocorticoids on Intestinal Mucosa Integrity: Barrier Function Competence vs Inflammation

Glucocorticoids are widely used as anti-inflammatory drugs in inflammatory bowel disease. In the DSS induced model of colitis budesonide improves colonic inflammation, but it causes body weight loss and increased mortality. We hypothesized that glucocorticoids, and budesonide in particular, alter the mucosal barrier leading to these deleterious systemic effects. To test this hypothesis, C57BL6/J mice received budesonide (1-60 micrograms/day) by gavage and dextran sulfate sodium (DSS) in the drinking water for 7 days. A dose-dependent negative effect of budesonide, as shown by increased body weight loss, rectal bleeding and disease activity index, was observed. This effect correlated with higher bacterial translocation to mesenteric lymph nodes and liver, and higher concentration of LPS in the liver. Besides, animals receiving budesonide showed hallmark signs of sepsis: hypothermia, increased lung expression of iNOS and p-eNOS/eNOS ratio and myeloperoxidase activity, and higher levels of IL-18 and nitrates in plasma. Conversely, budesonide treated mice showed improved colonic inflammatory condition, studied by RT-PCR of colonic tissue. In line with this, budesonide inhibited the Th17-Th23 protective response axis within the mucosal compartment and additional data point to inhibition of epithelial cell proliferation (BrdU incorporation) and beta-catenin signalling.

We conclude that budesonide exerts a dual effect in DSS-induced colitis, dampening intestinal inflammation but at the same time weakening mucosal barrier function.