Mucins and Tight Junctions are Severely Altered in Necrotizing Enterocolitis Neonates

Liu, Dong; Xu, Yijuan; Feng, Jinxing; Yu, Jialin; Huang, Jian; Li, Chi Kong

doi:10.1055/s-0040-1710558

Cited by 23 publications

(20 citation statements)

References 22 publications

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“…The loss of tight junctions in NEC contributes to a leaky gut barrier (24,25) allowing bacterial translocation and increasing the risk of sepsis and death (18,26,27). Previous studies have found that ZO-1 mRNA expression is decreased in NEC tissue (24,25,28). We also demonstrated a decrease in the expression of the tight junction ZO-1 as well as its internalization by confocal microscopy and further demonstrated that the apparent paracellular permeability of the NEC-on-a-Chip system increases with time.…”

Section: Discussionsupporting

confidence: 66%

“…Similar to previous adult and pediatric Intestine-on-a-Chip models (16,17), the Neonatal-Intestine-on-a-Chip overcomes many limitations of traditional 2D and 3D intestinal cell culture techniques. The loss of tight junctions in NEC contributes to a leaky gut barrier (24,25) allowing bacterial translocation and increasing the risk of sepsis and death (18,26,27). Previous studies have found that ZO-1 mRNA expression is decreased in NEC tissue (24,25,28).…”

Section: Discussionmentioning

confidence: 99%

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Microfluidic Device Facilitates NovelIn VitroModeling of Human Neonatal Necrotizing Enterocolitis-on-a-Chip

Nolan

et al. 2020

Preprint

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Necrotizing enterocolitis (NEC) is a deadly gastrointestinal disease of premature infants characterized by an exaggerated inflammatory response, dysbiosis of the gut microbiome, decreased epithelial cell proliferation, and gut barrier disruption. Here, we describe a novel in vitro model of human neonatal small intestinal epithelium (Neonatal-Intestine-on-a-Chip) that mimics key features of intestinal physiology by utilizing a combination of premature infant intestinal enteroids co-cultured with human intestinal microvascular endothelial cells within a microfluidic device. We used our Neonatal-Intestine-on-a-Chip to recapitulate NEC pathophysiology in an in vitro model system of the premature gut inoculated with infant-derived microbiota. This model, also known as NEC-on-a-Chip, emulates the prominent features of NEC, demonstrating significant upregulation of pro-inflammatory cytokines, decreased intestinal epithelial cell markers, reduced epithelial proliferation and disrupted epithelial barrier integrity. NEC-on-a-Chip provides a novel preclinical model of NEC, which may be used as a personalized medicine approach to test new therapeutics for this devastating disease.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Microfluidic Device Facilitates NovelIn VitroModeling of Human Neonatal Necrotizing Enterocolitis-on-a-Chip

Nolan

et al. 2020

Preprint

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“…Muc2 deficient mice develop a more severe NEC pathology compared to those with normal mucin. [ 64 , 65 , 66 , 67 ]. Collectively, these data indicate a possible role for goblet cells in the development of NEC.…”

Section: Discussionmentioning

confidence: 99%

Early Antibiotic Exposure Alters Intestinal Development and Increases Susceptibility to Necrotizing Enterocolitis: A Mechanistic Study

et al. 2022

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Increasing evidence suggests that prolonged antibiotic therapy in preterm infants is associated with increased mortality and morbidities, such as necrotizing enterocolitis (NEC), a devastating gastrointestinal pathology characterized by intestinal inflammation and necrosis. While a clinical correlation exists between antibiotic use and the development of NEC, the potential causality of antibiotics in NEC development has not yet been demonstrated. Here, we tested the effects of systemic standard-of-care antibiotic therapy for ten days on intestinal development in neonatal mice. Systemic antibiotic treatment impaired the intestinal development by reducing intestinal cell proliferation, villi height, crypt depth, and goblet and Paneth cell numbers. Oral bacterial challenge in pups who received antibiotics resulted in NEC-like intestinal injury in more than half the pups, likely due to a reduction in mucous-producing cells affecting microbial–epithelial interactions. These data support a novel mechanism that could explain why preterm infants exposed to prolonged antibiotics after birth have a higher incidence of NEC and other gastrointestinal disorders.

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“…During the early stages of NEC development, abnormal cell death and epithelial barrier disruption are necessary conditions for further development ( 11 , 15 , 16 ). Numerous studies have demonstrated that the intestinal barrier dysfunction observed in human NEC is characterized by the downregulation of mucins and TJ proteins, such as zonula occludens-1, occludin and claudin-4 ( 54 – 56 ). In this study, we found that the leakage of FITC-D into the circulation increased and the expression of claudin-1 and occludin decreased in NEC samples, suggesting severe barrier dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Selective targeting of MD2 attenuates intestinal inflammation and prevents neonatal necrotizing enterocolitis by suppressing TLR4 signaling

et al. 2022

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Neonatal necrotizing enterocolitis (NEC) is an inflammatory disease that occurs in premature infants and has a high mortality rate; however, the mechanisms behind this disease remain unclear. The TLR4 signaling pathway in intestinal epithelial cells, mediated by TLR4, is important for the activation of the inflammatory storm in NEC infants. Myeloid differentiation protein 2 (MD2) is a key auxiliary component of the TLR4 signaling pathway. In this study, MD2 was found to be significantly increased in intestinal tissues of NEC patients at the acute stage. We further confirmed that MD2 was upregulated in NEC rats. MD2 inhibitor (MI) pretreatment reduced the occurrence and severity of NEC in neonatal rats, inhibited the activation of NF-κB and the release of inflammatory molecules (TNF-α and IL-6), and reduced the severity of intestinal injury. MI pretreatment significantly reduced enterocyte apoptosis while also maintaining tight junction proteins, including occludin and claudin-1, and protecting intestinal mucosal permeability in NEC rats. In addition, an NEC in vitro model was established by stimulating IEC-6 enterocytes with LPS. MD2 overexpression in IEC-6 enterocytes significantly activated NF-κB. Further, both MD2 silencing and MI pretreatment inhibited the inflammatory response. Overexpression of MD2 increased damage to the IEC-6 monolayer cell barrier, while both MD2 silencing and MI pretreatment played a protective role. In conclusion, MD2 triggers an inflammatory response through the TLR4 signaling pathway, leading to intestinal mucosal injury in NEC. In addition, MI alleviates inflammation and reduces intestinal mucosal injury caused by the inflammatory response by blocking the TLR4-MD2/NF-κB signaling axis. These results suggest that inhibiting MD2 may be an important way to prevent NEC.

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Mucins and Tight Junctions are Severely Altered in Necrotizing Enterocolitis Neonates

Cited by 23 publications

References 22 publications

Microfluidic Device Facilitates NovelIn VitroModeling of Human Neonatal Necrotizing Enterocolitis-on-a-Chip

Microfluidic Device Facilitates NovelIn VitroModeling of Human Neonatal Necrotizing Enterocolitis-on-a-Chip

Early Antibiotic Exposure Alters Intestinal Development and Increases Susceptibility to Necrotizing Enterocolitis: A Mechanistic Study

Selective targeting of MD2 attenuates intestinal inflammation and prevents neonatal necrotizing enterocolitis by suppressing TLR4 signaling

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