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

Abstract

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.

Vitamin D is a potential treatment for the management of gastrointestinal mucositis

“…Furthermore, both studies showed that mice with activated VDR had an increased survival rate compared to wild-type or VDR KO mice 23,38▪▪ . Additionally, in-vitro results showed similar findings that upregulation of VDR could attenuate radiation-induced apoptosis in both IEC-6 and Mode-K cells 23,38▪▪ . Both Lin et al and Li et al .…”

“… 38▪▪ both demonstrated that VDR knockout (KO) mice and vitamin D-deficient mice significantly increased intestinal damage post-radiation exposure, which was associated with shortened villus height, increased intestinal basal shedding, as well as increased cell apoptosis leading to increased intestinal permeability. Furthermore, both studies showed that mice with activated VDR had an increased survival rate compared to wild-type or VDR KO mice 23,38▪▪ . Additionally, in-vitro results showed similar findings that upregulation of VDR could attenuate radiation-induced apoptosis in both IEC-6 and Mode-K cells 23,38▪▪ .…”

“…Therefore, this study is a good insight into the potential mechanism through which vitamin D deficiency causes mucositis. IL-1β and TNF-α are critical molecules in activating the NF-κB pathway as they work synergistically to promote apoptosis and inflammation, as well as interrupt epithelial tight junction activity 38▪▪,45 . While it is established that vitamin D, acting through the VDR, plays a functional role in the intestine, the exact mechanisms that vitamin D regulates in the epithelial barrier are poorly understood.…”

“…During exposure to radiation in mice, the activation of intestinal VDR is essential in protecting against induced intestinal injury 23,38▪▪ . Following the administration of ionizing radiation (IR), the intestine upregulated the expression of VDR in the intestinal crypt in a time- and dose-dependent manner 23,38▪▪ . Li et al .…”

Oral Administration of Probiotic Spore Ghosts for Efficient Attenuation of Radiation-Induced Intestinal Injury

“…It is well known that radiation-induced intestinal injury is always accompanied with in ammatory response. [41] Therefore, we evaluated the activity of myeloperoxidase (MPO) and the level of pro-in ammatory cytokines in intestinal tissue after different treatment. As depicted in Fig.…”