Glucocorticoids are important anti-inflammatory and immunosuppressant agents. They have weakening actions on intestinal barrier function, including epithelial antiproliferative and mucus antisecretory effects, which may limit their clinical benefit. Thus, reducing such deleterious glucocorticoid actions may enhance their clinical performance, particularly in conditions where the intestinal barrier function is compromised. Here we explore two different strategies to minimize glucocorticoid barrier weakening, namely the use of the parenteral vs. the oral route of administration, and cotreatment with the mTOR inhibitor rapamycin. The dextran sulfate sodium model of colitis in mice was used and prednisolone as prototypic glucocorticoid. Oral and intraperitoneal prednisolone exerted comparable anti-inflammatory effects and early rectal blood loss, body weight loss and bacterial translocation to the liver (oral > intraperitoneal). On the other hand, mice receiving oral prednisolone and rapamycin were partially protected against barrier-related adverse effects, suggesting intestinal barrier reinforcement. RNAseq analysis indicated that rapamycin had a profound impact on glucocorticoid transcriptome modulation, without limiting efficacy. In addition, several candidate genes for barrier enhancement were identified. Importantly, proliferation related genes downregulated by prednisolone ceased to be affected with rapamycin cotreatment, such as Myc , Ccnd1 , Pcna and Ki67 . In IEC4.1 intestinal epithelial cells rapamycin was found to counteract the wound healing depressing effects of prednisolone, associated with downregulation of Ddit4 expression, which may modulate the transcriptomic impact of the glucocorticoid receptor towards a less prominent epithelial antiproliferative action. Glucocorticoid induced weakening of intestinal barrier function is limited by the used of the parenteral pathway and by cotreatment with rapamycin.