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Bench to bedside — new insights into the pathogenesis of necrotizing enterocolitis

Abstract

Necrotizing enterocolitis (NEC) is the leading cause of death and disability from gastrointestinal disease in premature infants. Recent discoveries have shed light on a unifying theorem to explain the pathogenesis of NEC, suggesting that specific treatments might finally be forthcoming. A variety of experiments have highlighted how the interaction between bacterial signalling receptors on the premature intestine and an abnormal gut microbiota incites a pro-inflammatory response in the intestinal mucosa and its underlying endothelium that leads to NEC. Central amongst the bacterial signalling receptors implicated in NEC development is the lipopolysaccharide receptor Toll-like receptor 4 (TLR4), which is expressed at higher levels in the premature gut than in the full-term gut. The high prenatal intestinal expression of TLR4 reflects the role of TLR4 in the regulation of normal gut development, and supports additional studies indicating that NEC develops in response to signalling events that occur in utero. This Review provides new evidence explaining the pathogenesis of NEC, explores new findings indicating that NEC development has origins before birth, and discusses future questions and opportunities for discovery in this field.

Key points

  • Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in premature infants and is characterized by the acute onset of patchy necrosis throughout the intestine, leading to systemic sepsis.

  • NEC induction requires the activation of Toll-like receptor 4 (TLR4) on the intestinal epithelium by the intestinal microbiota of the premature host, leading to enterocyte death, mucosal injury and translocation of bacteria into the circulation.

  • TLR4 is expressed at higher levels in the premature than in the full-term intestine due to its role in the regulation of normal gut development, and is inhibited by breast milk and amniotic fluid in vitro and in vivo.

  • Studies in animals and human NEC tissue have shown that activation of the aryl hydrocarbon receptor in utero can modulate the risk of NEC through effects on TLR4, potentially offering an opportunity during pregnancy for NEC prevention.

  • Additional studies have identified causative roles for epigenetic modulation of key signalling molecules and the inflammasome in NEC pathogenesis, and have shed light on the effects of NEC on the developing brain and lung.

  • New prevention and therapeutic approaches for NEC are designed to interfere with the abnormal host–microorganism signalling that occurs during the prenatal and early postnatal periods that lead to NEC.

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Fig. 1: A model for the pathogenesis of NEC based on bacterial signalling through TLR4 on the intestinal epithelium of the premature intestinal epithelium.
Fig. 2: Necrotizing enterocolitis beyond the gut.
Fig. 3: Key areas of research focus in the field of NEC.

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Acknowledgements

The authors thank all the investigators in the field who have contributed in so many ways to the research described in this Review, and apologize to those authors whose work was omitted owing to space considerations. The authors also thank T. H. Phelps from Johns Hopkins University Department of Art as Applied to Medicine for assistance with the original illustrations. D.J.H. is supported by R01GM078238 and R01DK117186 and R35GM141956 from the National Institutes of Health.

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D.J.H. is principal investigator on a sponsored research grant from Abbott Nutrition, and a sponsored research grant from Noveome; neither Noveome nor Abbott had any role in the current manuscript. C.P.S. declares no competing interests.

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Hackam, D.J., Sodhi, C.P. Bench to bedside — new insights into the pathogenesis of necrotizing enterocolitis. Nat Rev Gastroenterol Hepatol 19, 468–479 (2022). https://doi.org/10.1038/s41575-022-00594-x

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