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  • Review Article
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Necrotizing enterocolitis: new insights into pathogenesis and mechanisms

Key Points

  • Necrotizing enterocolitis (NEC) is the most common and devastating gastrointestinal disease affecting premature infants; overall NEC mortality has remained unchanged over the past 30 years owing to a lack of treatment options

  • The main risk factors for the development of NEC are prematurity, bacterial colonization and administration of formula feeds

  • The premature intestinal epithelium is predisposed to mounting an exaggerated inflammatory response to colonizing bacteria, leading to mucosal destruction and impaired mesenteric perfusion in the pathogenesis of NEC

  • The exaggerated inflammatory response is partially due to the increased expression of Toll-like receptor 4 (TLR4), which is expressed at high levels on the premature newborn intestinal epithelium

  • Increased expression of TLR4 in the intestinal epithelium of the premature gut reflects the surprising function that TLR4 plays in the regulation of normal gut development through effects on Notch signalling

  • Although no specific treatment for NEC exists, several potential biological targets have been identified, including growth factors, modifiers of perfusion and novel TLR4 inhibitors with potential translational importance

Abstract

Necrotizing enterocolitis (NEC) is the most frequent and lethal disease of the gastrointestinal tract of preterm infants. At present, NEC is thought to develop in the premature host in the setting of bacterial colonization, often after administration of non-breast milk feeds, and disease onset is thought to be due in part to a baseline increased reactivity of the premature intestinal mucosa to microbial ligands as compared with the full-term intestinal mucosa. The increased reactivity leads to mucosal destruction and impaired mesenteric perfusion and partly reflects an increased expression of the bacterial receptor Toll-like receptor 4 (TLR4) in the premature gut, as well as other factors that predispose the intestine to a hyper-reactive state in response to colonizing microorganisms. The increased expression of TLR4 in the premature gut reflects a surprising role for this molecule in the regulation of normal intestinal development through its effects on the Notch signalling pathway. This Review will examine the current approach to the diagnosis and treatment of NEC, provide an overview of our current knowledge regarding its molecular underpinnings and highlight advances made within the past decade towards the development of specific preventive and treatment strategies for this devastating disease.

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Figure 1: Factors that attenuate or prevent the development of NEC in experimental models.

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Acknowledgements

DJH is supported by R01GM078238 and R01DK083752 from the NIH.

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Niño, D., Sodhi, C. & Hackam, D. Necrotizing enterocolitis: new insights into pathogenesis and mechanisms. Nat Rev Gastroenterol Hepatol 13, 590–600 (2016). https://doi.org/10.1038/nrgastro.2016.119

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