Ragab, Mohab and Schlichting, Heidi and Hicken, Maren and Mester, Patricia and Hirose, Misa and Almeida, Larissa N. and Christiansen, Lea and Ibrahim, Saleh and Tews, Hauke Christian and Divanovic, Senad and Sina, Christian and Derer, Stefanie (2024) Azathioprine promotes intestinal epithelial cell differentiation into Paneth cells and alleviates ileal Crohn's disease severity. SCIENTIFIC REPORTS, 14 (1): 12879. ISSN 2045-2322,
Full text not available from this repository. (Request a copy)Abstract
Paneth cells (PCs), a subset of intestinal epithelial cells (IECs) found at the base of small intestinal crypts, play an essential role in maintaining intestinal homeostasis. Altered PCs function is associated with diverse intestinal pathologies, including ileal Crohn's disease (CD). CD patients with ileal involvement have been previously demonstrated to display impairment in PCs and decreased levels of anti-microbial peptides. Although the immunosuppressive drug Azathioprine (AZA) is widely used in CD therapy, the impact of AZA on IEC differentiation remains largely elusive. In the present study, we hypothesized that the orally administered drug AZA also exerts its effect through modulation of the intestinal epithelium and specifically via modulation of PC function. AZA-treated CD patients exhibited an ileal upregulation of AMPs on both mRNA and protein levels compared to non-AZA treated patients. Upon in vitro AZA stimulation, intestinal epithelial cell line MODE-K exhibited heightened expression levels of PC marker in concert with diminished cell proliferation but boosted mitochondrial OXPHOS activity. Moreover, differentiation of IECs, including PCs differentiation, was boosted in AZA-treated murine small intestinal organoids and was associated with decreased D-glucose consumption and decreased growth rates. Of note, AZA treatment strongly decreased Lgr5 mRNA expression as well as Ki67 positive cells. Further, AZA restored dysregulated PCs associated with mitochondrial dysfunction. AZA-dependent inhibition of IEC proliferation is accompanied by boosted mitochondria function and IEC differentiation into PC.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | MITOCHONDRIAL GENE POLYMORPHISMS; T-CELLS; DEFENSIN EXPRESSION; DNA MUTATIONS; 6-MERCAPTOPURINE; PHARMACOLOGY; METABOLISM; MICE; HEPATOCYTES; ACTIVATION; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin I |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 18 Aug 2025 09:34 |
| Last Modified: | 18 Aug 2025 09:34 |
| URI: | https://pred.uni-regensburg.de/id/eprint/65612 |
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