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Updated: Feb 17, 2026
Author Spotlight: Studying the Epithelial Effects of Intestinal Inflammation In Vitro on Established Murine Colonoids
Published on: June 2, 2023
Gut Epithelial Vitamin D Receptor Regulates Microbiota-Dependent Mucosal Inflammation by Suppressing Intestinal
Lei He1, Tianjing Liu1,2, Yongyan Shi1,2
1Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, Illinois.
Abstract:
Recent studies show that colonic vitamin D receptor (VDR) signaling protects the mucosal epithelial barrier and suppresses colonic inflammation, but the underlying molecular mechanism remains to be fully understood. To investigate the implication of colonic VDR downregulation seen in patients with inflammatory bowel disease, we assessed the effect of gut epithelial VDR deletion on colonic inflammatory responses in an experimental colitis model. In a 2,4,6-trinitrobenzenesulfonic acid-induced colitis model, mice carrying VDR deletion in gut epithelial cells [VDRflox/flox (VDRf/f);Villin-Cre or VDRΔIEC] or in colonic epithelial cells (VDRf/f;CDX2-Cre or VDRΔCEC) developed more severe clinical colitis than VDRf/f control mice, characterized by more robust T-helper (TH)1 and TH17 responses, with greater increases in mucosal interferon (IFN)-γ+, interleukin (IL)-17+, and IFN-γ+IL-17+ T cells. Accompanying the severe mucosal inflammation was more profound colonic epithelial cell apoptosis in the mutant mice. Treatment with caspase inhibitor Q-VD-OPh dramatically reduced colitis severity and attenuated TH1 and TH17 responses in VDRΔCEC mice. The blockade of cell apoptosis also prevented the increase in mucosal CD11b+CD103+ dendritic cells (DCs), known to be critical for TH17-cell activation. Moreover, depletion of gut commensal bacteria with antibiotics eliminated the robust TH1 and TH17 responses and CD11b+CD103+ DC induction. Taken together, these observations demonstrate that gut epithelial VDR deletion aggravates epithelial cell apoptosis, resulting in increases in mucosal barrier permeability. Consequently, invading luminal bacteria activate CD11b+CD103+ DCs, which promote mucosal TH1 and TH17 responses. Therefore, gut epithelial VDR signaling controls mucosal inflammation by suppressing epithelial cell apoptosis.
Insights
Gut epithelial vitamin D receptor (VDR) signaling prevents colitis by suppressing epithelial cell apoptosis. Deleting VDR worsens inflammation, increasing T-helper cell responses and barrier permeability.
Area of Science:
- Gastroenterology
- Immunology
- Molecular Biology
Background:
- Colonic vitamin D receptor (VDR) signaling is known to protect the epithelial barrier and reduce inflammation.
- The precise molecular mechanisms underlying VDR's protective role in the colon are not fully understood.
- VDR downregulation is observed in patients with inflammatory bowel disease (IBD).
Purpose of the Study:
- To investigate the role of gut epithelial VDR in regulating colonic inflammatory responses.
- To elucidate the molecular mechanisms by which VDR deletion exacerbates experimental colitis.
- To assess the impact of VDR deletion on epithelial cell apoptosis and immune cell activation.
Main Methods:
- Utilized a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis model in mice with specific deletion of VDR in gut epithelial cells (VDRΔIEC) or colonic epithelial cells (VDRΔCEC).
- Assessed clinical colitis severity, T-helper (TH)1 and TH17 cell responses (IFN-γ+, IL-17+), and epithelial cell apoptosis.
- Investigated the effect of caspase inhibition and antibiotic-induced bacterial depletion on colitis parameters.
Main Results:
- VDR deletion in gut or colonic epithelial cells led to more severe colitis, characterized by heightened TH1 and TH17 responses and increased epithelial cell apoptosis.
- Caspase inhibition significantly reduced colitis severity and TH1/TH17 responses in VDRΔCEC mice.
- Blocking apoptosis prevented the increase in CD11b+CD103+ dendritic cells (DCs) and subsequent TH17 activation.
- Antibiotic treatment abrogated TH1/TH17 responses and DC induction, indicating a role for commensal bacteria.
Conclusions:
- Gut epithelial VDR signaling suppresses colonic inflammation by inhibiting epithelial cell apoptosis.
- VDR deletion promotes apoptosis, leading to increased mucosal barrier permeability.
- Luminal bacteria activate CD11b+CD103+ DCs, which drive TH1 and TH17 responses, exacerbating colitis.
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