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Updated: Jan 12, 2026
Mechanistic Insight into the Development of TNBS-Mediated Intestinal Fibrosis and Evaluating the Inhibitory Effects of Rapamycin
Published on: September 12, 2019
Rapamycin and parenteral administration attenuate the harmful effects of glucocorticoids on the intestinal barrier
Diego Ceacero-Heras1, Guillermo Ruiz-Henares2, Juan José Enguix-Huete2
1Department of Biochemistry and Molecular Biology (II), Faculty of Pharmacy, University of Granada, Granada, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain.
Abstract:
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.
Insights
Glucocorticoids weaken intestinal barrier function. Parenteral administration and rapamycin cotreatment mitigate these adverse effects, preserving therapeutic efficacy for inflammatory conditions.
Area of Science:
- Gastroenterology
- Pharmacology
- Immunology
Background:
- Glucocorticoids are vital anti-inflammatory and immunosuppressant drugs.
- However, they impair intestinal barrier function, limiting clinical utility.
- Strategies to counteract these effects are needed, especially in compromised gut conditions.
Purpose of the Study:
- To investigate methods for minimizing glucocorticoid-induced intestinal barrier weakening.
- To compare parenteral versus oral administration of glucocorticoids.
- To evaluate the impact of rapamycin cotreatment on glucocorticoid side effects.
Main Methods:
- A dextran sulfate sodium-induced colitis model in mice was employed.
- Prednisolone served as the prototypic glucocorticoid.
- RNA sequencing and intestinal epithelial cell cultures were utilized.
Main Results:
- Both oral and intraperitoneal prednisolone showed similar anti-inflammatory effects.
- Oral prednisolone led to greater bacterial translocation than intraperitoneal.
- Rapamycin cotreatment partially protected against barrier defects and modulated gene expression, preserving efficacy.
- Rapamycin counteracted prednisolone's wound healing inhibition in intestinal cells.
Conclusions:
- Parenteral administration and rapamycin cotreatment can limit glucocorticoid-induced intestinal barrier dysfunction.
- These strategies may enhance the clinical performance of glucocorticoids in inflammatory diseases.
- Rapamycin influences glucocorticoid transcriptome modulation without compromising anti-inflammatory efficacy.
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