Vitamin D Receptor Protects against Radiation-Induced Intestinal Injury in Mice via Inhibition of Intestinal Crypt Stem/Progenitor Cell Apoptosis

Li, Wusun; Lin, Yingying; Luo, Yujia; Wang, Yuqi; Lu, Yao; Li, Yixuan; Guo, Huiyuan

doi:10.3390/nu13092910

Cited by 20 publications

(20 citation statements)

References 43 publications

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“…The results of our study are in accordance with current findings, as VD supplementation improved epithelial proliferation, enterocyte apoptosis rate and IEC turnover in the small intestine and colon in cholestasis rats [ 56 ]. In addition, crypt stem cells exhibited high VDR expression, which was absent in VDR-KO mice resulting in reduced stem cell proliferation and crypt depth [ 57 ]. Consistently, Yeung et al [ 52 ] showed that VDd led to crypt hyperplasia, loss of epithelial integrity as well as a decreased mucosa thickness in colon of mice.…”

Section: Discussionmentioning

confidence: 99%

Vitamin A- and D-Deficient Diets Disrupt Intestinal Antimicrobial Peptide Defense Involving Wnt and STAT5 Signaling Pathways in Mice

et al. 2023

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Vitamin A and D deficiencies are associated with immune modulatory effects and intestinal barrier impairment. However, the underlying mechanisms remain unclear. C57BL/6J mice were fed either a diet lacking in vitamin A (VAd), vitamin D (VDd) or a control diet (CD) for 12 weeks. Gut barrier function, antimicrobial peptide (AMP) defense and regulatory pathways were assessed. VAd mice compared to CD mice showed a reduced villus length in the ileum (p < 0.01) and decreased crypt depth in the colon (p < 0.05). In both VAd- and VDd-fed mice, ileal α-defensin 5 (p < 0.05/p < 0.0001 for VAd/VDd) and lysozyme protein levels (p < 0.001/p < 0.0001) were decreased. Moreover, mRNA expression of lysozyme (p < 0.05/p < 0.05) and total cryptdins (p < 0.001/p < 0.01) were reduced compared to controls. Furthermore, matrix metalloproteinase-7 (Mmp7) mRNA (p < 0.0001/p < 0.001) as well as components of the Wnt signaling pathway were decreased. VAd- and VDd-fed mice, compared to control mice, exhibited increased expression of pro-inflammatory markers and β-defensins in the colon. Organoid cell culture confirmed that vitamins A and D regulate AMP expression, likely through the Jak/STAT5 signaling pathway. In conclusion, our data show that vitamin A and D regulate intestinal antimicrobial peptide defense through Wnt and STAT5 signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Vitamin A- and D-Deficient Diets Disrupt Intestinal Antimicrobial Peptide Defense Involving Wnt and STAT5 Signaling Pathways in Mice

et al. 2023

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“…Actually, despite few reports about the relationship between ionizing radiation and VDR, it has been clarified that UV irradiation promotes skin vitamin D synthesis. 14 , 15 , 16 Ionizing radiation can directly induce increased VDR expression in MODE‐K cells, which is dose and time‐dependent. It should be illustrated that, clear as the direct effect has been, the potential indirect effect cannot be denied.…”

Section: Discussionmentioning

confidence: 99%

Protective effects of activated vitamin D receptor on radiation‐induced intestinal injury

Lin

Xia

Cao

et al. 2022

J Cellular Molecular Medi

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Radiation‐induced intestinal injury (RIII) is a common complication after radiation therapy in patients with pelvic, abdominal, or retroperitoneal tumours. Recently, in the model of DSS (Dextran Sulfate Sodium Salt) ‐induced intestinal inflammatory injury, it has been found in the study that transgenic mice expressing hVDR in IEC (Intestinal Epithelial Cell) manifest highly anti‐injury properties in colitis, suggesting that activated VDR in the epithelial cells of intestine may inhibit colitis by protecting the mucosal epithelial barrier. In this study, we investigated the effect of the expression and regulation of VDR on the protection of RIII, and the radiosensitivity in vitro experiments, and explored the initial mechanism of VDR in regulating radiosensitivity of IEC. As a result, we found that the expression of VDR in intestinal tissues and cells in mice can be induced by ionizing radiation. VDR agonists are able to prolong the average survival time of mice after radiation and reduce the radiation‐induced intestinal injury. For lack of vitamin D, the radiosensitivity of intestinal epithelial cells in mice increased, which can be reduced by VDR activation. Ensuing VDR activation, the radiation‐induced intestinal stem cells damage is decreased, and the regeneration and differentiation of intestinal stem cells is promoted as well. Finally, on the basis of sequencing analysis, we validated and found that VDR may target the HIF/PDK1 pathway to mitigate RIII. We concluded that agonism or upregulation of VDR expression attenuates radiation‐induced intestinal damage in mice and promotes the repair of epithelial damage in intestinal stem cells.

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“…It is known that the VDR is expressed by LGR5 + stem cell in patients’ intestine ( 34 ). In a murine model, VDR deficiency impaired intestinal stem cell proliferation and suppressed epithelial regeneration ( 35 ). In line, Vitamin D3 rich diet led to higher count of Lgr5 + stem cells ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of the vitamin D receptor expression during acute gastrointestinal graft versus host disease is associated with poor outcome after allogeneic stem cell transplantation

Matos

Mamilos²,

Shah³

et al. 2022

Front. Immunol.

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The vitamin D receptor (VDR) is critical in regulating intestinal homeostasis and emerging evidence demonstrates that VDR deficiency is a critical factor in inflammatory bowel disease pathology. However, no clinical data exist regarding the intestinal expression of VDR in patients after allogeneic haematopoietic stem cell transplantation (HSCT). Analyzing intestinal biopsies from 90 patients undergoing HSCT with mortality follow-up, we demonstrated that patients with severe acute gastrointestinal graft versus host disease (GI-GvHD) showed significant downregulation of VDR gene expression compared to mild or no acute GI-GvHD patients (p = 0.007). Reduced VDR expression was already detectable at acute GI-GvHD onset compared to GvHD-free patients (p = 0.01). These results were confirmed by immunohistochemistry (IHC) where patients with severe acute GI-GvHD showed fewer VDR+ cells (p = 0.03) and a reduced VDR staining score (p = 0.02) as compared to mild or no acute GI-GvHD patients. Accordingly, low VDR gene expression was associated with a higher cumulative incidence of treatment-related mortality (TRM) (p = 1.6x10-6) but not with relapse-related mortality (RRM). A multivariate Cox regression analysis identified low VDR as an independent risk factor for TRM (p = 0.001, hazard ratio 4.14, 95% CI 1.78-9.63). Furthermore, VDR gene expression significantly correlated with anti-microbial peptides (AMPs) gene expression (DEFA5: r = 0.637, p = 7x10-5, DEFA6: r 0 0.546, p = 0.001). In conclusion, our findings suggest an essential role of the VDR in the pathogenesis of gut GvHD and the prognosis of patients undergoing HSCT.

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Vitamin D Receptor Protects against Radiation-Induced Intestinal Injury in Mice via Inhibition of Intestinal Crypt Stem/Progenitor Cell Apoptosis

Cited by 20 publications

References 43 publications

Vitamin A- and D-Deficient Diets Disrupt Intestinal Antimicrobial Peptide Defense Involving Wnt and STAT5 Signaling Pathways in Mice

Vitamin A- and D-Deficient Diets Disrupt Intestinal Antimicrobial Peptide Defense Involving Wnt and STAT5 Signaling Pathways in Mice

Protective effects of activated vitamin D receptor on radiation‐induced intestinal injury

Downregulation of the vitamin D receptor expression during acute gastrointestinal graft versus host disease is associated with poor outcome after allogeneic stem cell transplantation

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