Vitamin D ameliorates neonatal necrotizing enterocolitis via suppressing TLR4 in a murine model

Abstract

BACKGROUND: The toll-like receptor 4 (TLR4) has been reported to play an important role in necrotizing enterocolitis (NEC). As an established regulator of TLR4, vitamin D has been demonstrated to be intestinal-protective. This study aims at finding out whether the vitamin D/vitamin D receptor (VDR) pathway ameliorates NEC by regulating TLR4. METHODS: Serum 25-hydrovitamin D (25(OH)D) was tested and compared in 15 preterm infants with NEC, 12 preterm infants without known complications and 20 healthy term infants. Neonatal Wistar rats were grouped and NEC was induced through formula feeding and cold/asphyxia stress. Vitamin D and the vehicle were administered to compare the microscopic structure, apoptotic protein expression, intestinal barrier function, inflammatory response, and TLR4 expression. RESULTS: Preterm infants with NEC had significantly lower 25 (OH)D levels than those without NEC and healthy subjects. VDR expression was suppressed, whereas TLR4 expression was elevated in the NEC intestine. Vitamin D may increase the survival rate, alleviate structure damage, and preserve intestinal barrier function. These were achieved partly through restoration of VDR and suppression of TLR4. CONCLUSION: NEC infants have lower levels of vitamin D. The vitamin D/VDR pathway protects against intestinal injury of NEC partly through suppressing the expression of TLR4.

Maltodextrin-induced intestinal injury in a neonatal mouse model

“…Previous studies in animal NEC models have shown changes in expression levels of claudin-3, occludin and ZO-1 (Clark et al, 2006;Khailova et al, 2009;Rentea et al, 2012;Shiou et al, 2011). Consistent with previous animal NEC studies (Clark et al, 2006;Rentea et al, 2012;Shi et al, 2018), we found a decrease in ZO-1 expression with an increase in claudin-3. Reduced expression of ZO-1 was evident in all groups, including DHK, where the mice did not show histological evidence of intestinal injury, suggesting that lower expression could be a predisposing factor and could partly explain changes in intestinal permeability in our intestinal injury model.…”

Impact of Toll-Like Receptor 4 Signaling in Necrotizing Enterocolitis

“…In addition, Vitamin D vitiates NF-Κb signaling, resulting in reduced epithelial cell death 83 . In the same way, a low level of maternal/neonatal 1,25-dihydroxyvitamin D was shown to be a risk for NEC development 85,86 . In accordance with the protective role of vitamin D in the context of adult IBD, Shi et al have found that vitamin D treatment significantly attenuates NEC severity in a rat model.…”

“…In accordance with the protective role of vitamin D in the context of adult IBD, Shi et al have found that vitamin D treatment significantly attenuates NEC severity in a rat model. Notably, they also and found that Vitamin D significantly repressed TLR4 expression, while promoting the expression of tight junction proteins and dampening epithelial cell apoptosis 86 .…”

Toll-Like Receptor–Mediated Intestinal Inflammatory Imbalance in the Pathogenesis of Necrotizing Enterocolitis

“… 56 Although TLR4 has a signature role in host defense through its expression on immune cells, we and others have shown that TLR4 also is expressed on the intestinal epithelium, where it regulates intestinal epithelial apoptosis and migration, and proliferation, and thus contributes to the pathogenesis of NEC. 19 , 22 , 25 , 57 , 58 , 59 , 60 , 61 , 62 , 63 Evidence for a role for TLR4 in human NEC from a variety of investigators includes the observations that levels of expression of TLR4 messenger RNA and protein are both significantly higher in the intestine of patients with NEC as compared with control patients, while activating mutations in the TLR4 signaling pathway are found in a greater proportion of premature infants with NEC as compared with those without this disease. These findings suggest but by no means prove the fact that TLR4 activation plays a role in NEC development.…”