Table 1.
Summary of claudin isoform changes seen in animal and human models of NEC.
| Study | Model | Claudin findings |
|---|---|---|
| Prematurity | ||
| Bein et al. (2018) | Human | ↓ Claudin-4 gene expression appreciated in human preterm neonates with NEC. |
| Ferretti et al. (2017) | Human | ↓ Claudin-1, ↑ claudin-2, and ↓ claudin-7 seen in human preterm neonatal interstitial explants treated with indomethacin (INDO) was associated with barrier disruption, mediated through the highly expressed nitric oxide synthase (NOS2) enzyme, whereas EGF was shown to have a protective effect through a similar pathway. |
| Ares et al. (2019) | Rat | ↓ Claudin-1, ↑ claudin-2, ↓ claudin-3, and ↓ claudin-4 expression seen in a rat model which was consistent with increased barrier permeability |
| Bergmann et al. (2013) | MouseHuman | ↑ Claudin-2 and internalization of claudin-4 shown to precede intestinal permeability in a time-dependent manner in a mouse model, prior to evidence of histological injury. Human tissue samples showed ↑claudin-2 expression in crypts of colonic epithelium and small intestines in NEC. |
| Gut microbiota | ||
| Bergmann et al. (2013) | Mouse | Claudin-4 expression levels were preserved after administration of B. infantis, which correlated with reduced incidence of NEC in the mouse model and a preservation of intestinal permeability. |
| Ling et al. (2016) | Rat | ↑ Claudin-3 expression normalized after administration of Bifidobacterium and was associated with decreased incidence and severity of NEC by reducing gut permeability in a rat model. |
| Patel et al. (2012) | Mouse | ↑ Claudin-3 expression associated with colonization of commensal bacterial and enteral administration of Lactobacillus in the mouse model, suggesting role for claudin-3 in the stability of the intestinal barrier through maturation of tight junctions. |
| Jakaitis and Denning (2017) | Mouse | ↑ Claudin-3 expression in the first 2–3 weeks of life in a mouse model which correlated with intestinal maturity and was potentially upregulated by the presence of both live- and heat-killed LGG through modification of tight junctions. |
| Intestinal inflammation | ||
| Formula | ||
| Siggers et al. (2011) | Pig | ↑ Claudin-1 in response to enteral feeding of formula following 2 days of TPN, in contrast to colostrum feeding which reflected no change from the baseline. |
| Ravisankar et al. (2018) | Mouse | ↑ Claudin-2, ↓ claudin-3, ↓ claudin-4, and ↓ claudin-7 expression in mouse model of NEC induced by formula feeding, cold stress, and hypoxia and is associated with elevated apoptosis (PARP), inflammatory markers (NF-κB and TGF-β), and intestinal permeability. |
| Roy et al. (2018) | Pig | ↓ Claudin-2 expression associated with elevated intestinal permeability and inflammation in a newborn pig model fed fermented formula. |
| Nutrition | ||
| Xu et al. (2018) | Pig | ↑ Claudin-1 expression with supplementation of medium-chain TAG (MCT) in diets of piglets compared to maise oil diet. Suggests a protective role for MCT in improving intestinal barrier digestive function following LPS challenge, mediated through changes in claudin proteins |
| Xiao, Cao, et al. (2016) | Pig | ↑ Claudin-1 expression in the jejunum following supplementation with dietary anemonin with alleviation of LPS-induced intestinal injury and inflammation |
| Zhu et al. (2018) | Pig | ↑ Claudin-1 expression in intestines when supplemented with flaxseed oil, associated with intact epithelial barrier and reduced inflammation in pig model exposed to LPS. |
| Xiao et al. (2018) | Mouse | ↑ Claudin-1 expression and lower inflammatory markers in response to vitamin A treatment in the mouse model. Low vitamin A levels are associated with human NEC. |
| Xiao, Jiao, et al. (2016) | Pig | Prevention of LPS-induced claudin-1 downregulation following administration of whey protein concentrate (WPC) and inflammation in jejunal mucosa. Suggests that WPC may help attenuate LPS-induced intestinal damage and stabilize the mucosal barrier. |
| Li et al. (2013) | Pig | ↑ Claudin-4 expression in a pig model fed conventional formula, correlated with intestinal permeability and increases in response to epithelial damage in the preterm pig model. Normalization of claudin-4 expression with supplementation of whey protein concentrate |
| Enzymes and peptides | ||
| Seo et al. (2019) | Mouse | ↓ Claudin-3 gene expression in NEC mouse model, with administration of vasoactive intestinal peptide (VIP) leading to ↑ claudin-3 gene expression in the crypts of NEC animals. |
| Rentea et al. (2012) | Rat | ↓ Claudin-1 and ↑ claudin-3 expression correlated with decreased intestinal permeability and severity of NEC with supplementation of intestinal alkaline phosphatase in the rat model |
| Ares et al. (2019) | Rat | Rho kinase inhibition may have a protective role by normalizing claudin-2 expression in a rat model. |
| Ischemia | ||
| Jensen et al. (2017) | Mouse | Preservation of claudin-1 levels and intestinal stability in a mouse model given human adipose–derived stromal stem cell (hASC) therapy, likely due to improved mesenteric perfusion and intestinal mucosal integrity. |
| Hogberg et al. (2013) | Rat | ↓ Claudin-1, -14, and -15, and ↑ claudin-8 following exposure to hypoxic-reoxygenation therapy to mimic early pathogenesis of NEC. |
| Breast milk | ||
| Gunasekaran et al. (2019) | Mouse | ↑ Claudin-2, ↑ claudin-3, and ↑ claudin-4 ileal expression associated with increased survival and lower intestinal injury in NEC+HA35- and HA35-treated mouse models compared to untreated NEC mouse model. The effect of hyaluronan (HA), a human milk glycosaminoglycan, was shown to reduce intestinal permeability, bacterial translocation, and pro-inflammatory cytokine release. |
| Shen et al. (2019) | Rat | ↑ Claudin-3 expression in the ileum of rat model. Supplementation with lactadherin associated with reduced claudin-3, histological damage, intestinal permeability, and incidence of NEC |
| Systemic associations | ||
| Garg et al. (2015) | Mouse | ↑claudin-1, ↑claudin-2, ↑claudin-3 and ↑claudin-4, ↑claudin-7, and ↑claudin-8 has been appreciated in tight junctions of site-specific regions of the nephron in mouse model induced by formula feeding, hypoxia and cold stress. |
| Blackwood et al. (2015) | Human | ↓ Claudin-2 expression in intestinal epithelium and ↑ claudin-2 expression in urine found to correlate with severity of NEC independent of other conditions in human neonates. |
| Thuijls et al. (2010) | Human | ↑ Claudin-3 in urine of human neonates with suspected NEC that later on developed NEC. |