@misc{10481/108059,
year = {2025},
month = {12},
url = {https://hdl.handle.net/10481/108059},
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.},
organization = {MICIU/AEI/10.13039/501100011033 - ERDF - Unión Europea (PID2023–151294OB-I00)},
organization = {Fondo de Investigaciones Sanitarias - Instituto de Salud Carlos III (PI21/00952)},
organization = {Junta de Andalucía and FEDER (A-AGR-468-UGR20 and P20–00695)},
organization = {Junta de Andalucía (CTS235, 463 CTS164)},
publisher = {Elsevier},
keywords = {Glucocorticoid},
keywords = {Intestinal barrier function},
keywords = {mTOR},
title = {Rapamycin and parenteral administration attenuate the harmful effects of glucocorticoids on the intestinal barrier function},
doi = {10.1016/j.biopha.2025.118721},
author = {Ceacero Heras, Diego and Ruiz-Henares, Guillermo and Enguix-Huete, Juan José and Tena Garitaonaindia, Mireia and Jiménez-Ortas, Ángela and Seguí-Pérez, Alba and Martínez Augustin, Olga and Sánchez De Medina López-Huertas, Fermín},
}