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Updated: Mar 18, 2026
Author Spotlight: Studying the Epithelial Effects of Intestinal Inflammation In Vitro on Established Murine Colonoids
Published on: June 2, 2023
Loss of prolyl hydroxylase-1 protects against colitis through reduced epithelial cell apoptosis and increased barrier
Murtaza M Tambuwala1, Eoin P Cummins, Colin R Lenihan
1The Conway Institute, University College Dublin, Ireland.
Background & Aims:
Hypoxia inducible factor (HIF) prolyl hydroxylase inhibitors are protective in mouse models of inflammatory bowel disease (IBD). Here, we investigated the therapeutic target(s) and mechanism(s) involved.
Methods:
The effect of genetic deletion of individual HIF-prolyl hydroxylase (PHD) enzymes on the development of dextran sulphate sodium (DSS)-induced colitis was examined in mice.
Results:
PHD1(-/-), but not PHD2(+/-) or PHD3(-/-), mice were less susceptible to the development of colitis than wild-type controls as determined by weight loss, disease activity, colon histology, neutrophil infiltration, and cytokine expression. Reduced susceptibility of PHD1(-/-) mice to colitis was associated with increased density of colonic epithelial cells relative to wild-type controls, which was because of decreased levels of apoptosis that resulted in enhanced epithelial barrier function. Furthermore, with the use of cultured epithelial cells it was confirmed that hydroxylase inhibition reversed DSS-induced apoptosis and barrier dysfunction. Finally, PHD1 levels were increased with disease severity in intestinal tissue from patients with IBD and in colonic tissues from DSS-treated mice.
Conclusions:
These results imply a role for PHD1 as a positive regulator of intestinal epithelial cell apoptosis in the inflamed colon. Genetic loss of PHD1 is protective against colitis through decreased epithelial cell apoptosis and consequent enhancement of intestinal epithelial barrier function. Thus, targeted PHD1 inhibition may represent a new therapeutic approach in IBD.
Insights
Targeting PHD1, an enzyme involved in inflammatory bowel disease (IBD), may offer a new therapeutic strategy. Loss of PHD1 reduces colon inflammation by decreasing cell death and improving gut barrier function.
Area of Science:
- Gastroenterology
- Immunology
- Molecular Biology
Background:
- Hypoxia-inducible factor (HIF) prolyl hydroxylase (PHD) inhibitors show promise in inflammatory bowel disease (IBD) mouse models.
- The specific PHD enzymes and mechanisms underlying this protective effect require elucidation.
Purpose of the Study:
- To investigate the therapeutic targets and mechanisms of PHD inhibitors in IBD.
- To determine the role of individual PHD enzymes in dextran sulphate sodium (DSS)-induced colitis.
Main Methods:
- Genetic deletion of individual HIF-prolyl hydroxylase (PHD) enzymes in mice.
- Assessment of DSS-induced colitis severity, colon histology, neutrophil infiltration, and cytokine expression.
- In vitro studies using cultured epithelial cells to confirm hydroxylase inhibition effects.
Main Results:
- PHD1 knockout mice exhibited reduced susceptibility to colitis compared to wild-type controls.
- PHD1 deficiency led to decreased epithelial cell apoptosis and enhanced intestinal barrier function.
- Increased PHD1 levels correlated with IBD disease severity in patients and DSS-treated mice.
Conclusions:
- PHD1 acts as a positive regulator of intestinal epithelial cell apoptosis in the inflamed colon.
- Genetic loss of PHD1 confers protection against colitis by improving epithelial barrier function.
- Targeted PHD1 inhibition presents a potential novel therapeutic strategy for IBD.
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