Azathioprine promotes intestinal epithelial cell differentiation into Paneth cells and alleviates ileal Crohn’s disease severity

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 wit...

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Bibliographic Details
Published in:Scientific reports Vol. 14; no. 1; pp. 12879 - 18
Main Authors: Ragab, Mohab, Schlichting, Heidi, Hicken, Maren, Mester, Patricia, Hirose, Misa, Almeida, Larissa N., Christiansen, Lea, Ibrahim, Saleh, Tews, Hauke Christian, Divanovic, Senad, Sina, Christian, Derer, Stefanie
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 05.06.2024
Nature Publishing Group
Nature Portfolio
Subjects:
631/80/304
692/699/1503/257/1402
Adult
Animals
Antimicrobial peptides
Azathioprine
Azathioprine - pharmacology
Cell differentiation
Cell Differentiation - drug effects
Cell Line
Cell proliferation
Cell Proliferation - drug effects
Crohn Disease - drug therapy
Crohn Disease - metabolism
Crohn Disease - pathology
Crohn's disease
Epithelial cells
Epithelial Cells - drug effects
Epithelial Cells - metabolism
Epithelial Cells - pathology
Epithelium
Female
Gene expression
Glucose
Homeostasis
Humanities and Social Sciences
Humans
Ileum - drug effects
Ileum - metabolism
Ileum - pathology
Immunosuppressive agents
Intestinal Mucosa - drug effects
Intestinal Mucosa - metabolism
Intestinal Mucosa - pathology
Male
Mice
Middle Aged
Mitochondria
multidisciplinary
Oral administration
Organoids
Organoids - drug effects
Organoids - metabolism
Paneth cells
Paneth Cells - drug effects
Paneth Cells - metabolism
Paneth Cells - pathology
Peptides
Science
Science (multidisciplinary)
Severity of Illness Index
Small intestine
ISSN:2045-2322, 2045-2322
Online Access:Get full text
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Summary: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.
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ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-024-63730-4