Nec-Mini-Symposium
New insights into necrotizing enterocolitis: From laboratory observation to personalized prevention and treatment☆,☆☆

https://doi.org/10.1016/j.jpedsurg.2018.06.012Get rights and content

Abstract

Background/purpose

Necrotizing enterocolitis (NEC) is a devastating disease of prematurity that develops after feeding, often without warning, and results in diffuse intestinal necrosis leading to sepsis and death in many cases. The lack of improvement in overall survival is influenced by nonspecific diagnostic modalities as well as inexact and nonpersonalized treatment strategies.

Methods/Results

Recently, we and others have shown that NEC develops in response to exaggerated bacterial signaling in the premature intestine, as a consequence of elevated expression and activity of the bacterial receptor toll-like receptor 4 (TLR4), which is important for normal gut development. Breast milk is a powerful TLR4 inhibitor, while mutations in TLR4 genes lead to increased NEC risk in humans, providing proof-of-concept for its role in NEC. Recently, a drug discovery approach has revealed a novel class of TLR4 inhibitors which are being developed for personalized approaches to NEC treatment.

Conclusion

This review will highlight the current understanding of the role of bacterial signaling in NEC pathogenesis, and will describe advances in diagnosis, prevention and treatment of NEC that may hopefully improve survival for these most fragile patients.

Systematic Review

Level of Evidence: Level II.

Section snippets

Introduction: Challenges and opportunities in the care of the child with necrotizing enterocolitis

Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in premature infants and affects up to 10% of all premature infants [1]. Despite significant advances in the care of premature infants in general, the overall survival of infants with NEC remains unchanged since the disease was first described over 30 years ago [2]. The presentation of NEC – at least in the most severe form – is well known to pediatric surgeons and neonatologists, i.e. a premature

The role of bacterial signaling in the newborn intestine in the pathogenesis of NEC

Work from the Hackam laboratory and others has advanced a unifying hypothesis to explain the pathogenesis of NEC, while also building on the work of many others in this complex field [recently reviewed by Nino et al. [5] and summarized in Fig. 1]. It should be mentioned that the studies described were performed using a variety of animal models of NEC, in mice, rats and piglets, and while each model has important limitations, each also shares critical similarities with the human disease, and we

Proof-of-concept studies for a role for TLR4 activation in the pathogenesis of human NEC

Several observations provide proof-of-concept for the role of TLR4 in the pathogenesis of human NEC. First, breast milk – which has long been known to be protective against NEC – significantly reduces TLR4 signaling in neonatal mice, in part through its constituent epidermal growth factor content, as we recently showed [19]. Further, probiotic bacteria – which have been shown in several clinical trials to limit the incidence of NEC – can activate Toll-Like receptor 9 (TLR9), a molecular cousin

Can the TLR4-mediated pathogenesis of NEC explain clinical risk factors for this disease?

The above description of the pathogenesis of NEC provides a framework for understanding the clinical presentation of this disease, while also opening up the possibility of more sensitive diagnostic measures. For instance, the timing of NEC onset is inversely related to the number of weeks of life at birth, i.e. a premature infant who is born at 24 weeks’ gestation will typically develop NEC at 6–8 weeks of life, while an infant who is born at 30 weeks’ gestation typically will develop NEC much

New diagnostic approaches for NEC and the bacterial-enterocyte signaling hypothesis of NEC development

One of the most important challenges in the NEC field is the ability to render an appropriate diagnosis. Unlike other diseases in modern medicine, the diagnosis of NEC remains largely a clinical one, based upon readily available data obtained from the history, physical examination and laboratory findings [43]. It is frustrating that a disease with such an impressively high mortality cannot be diagnosed more accurately, yet it is this very reality that likely contributes to the stubbornly high

A rational approach to the treatment of NEC in the current era

The treatment of infants who have NEC is guided by a set of accepted principles that include attention to normalizing hemodynamic derangements, minimizing progression of sepsis, and removal of dead intestine in cases in which the infant is clearly not responding to lesser measures. Each of these principles is driven by a goal of reducing the exaggerated bacterial enterocyte signaling that plays a critical role in NEC pathogenesis. For instance, in the early stages of disease, treatment is

Towards zero cases of NEC: strategies for prevention

Since treatment of NEC is so often ineffective in improving outcomes [1], [2], and since the overall survival of infants with NEC has not improved since the disease was first described 40 years ago [44], there has been a focus in the field of NEC towards an understanding of prevention strategies [83], and indeed several neonatal intensive care units have experienced zero cases of NEC within the time period in which the preventative measures have been undertaken [84]. These measures are listed

Unanswered questions and the future of NEC research and practice

This review has provided insights into how the molecular underpinnings of bacterial enterocyte signaling in the premature intestine through TLR4 may lead to the development of NEC. We have also shared how these insights into the molecular biology of NEC can guide our understanding of the major signs and symptoms of NEC and provide a rationale for novel diagnostic and therapeutic approaches to this disease. It should be mentioned that several investigators have made great strides in recent years

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    ☆

    Funding Sources: DJH is supported by R01GM078238, R01DK083752 and T32DK007713 from the National Institutes of Health. MG is supported by grants K08DK101608 and R03DK111473 from the National Institutes of Health, March of Dimes Foundation Grant No. 5-FY17-79, the Children's Discovery Institute of Washington University and St. Louis Children's Hospital.

    ☆☆

    Disclosures: The authors have nothing to disclose and no conflicts of interest.

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