Elsevier

Early Human Development

Volume 97, June 2016, Pages 33-39
Early Human Development

Current research in necrotizing enterocolitis

https://doi.org/10.1016/j.earlhumdev.2016.01.013Get rights and content

Abstract

Despite decades of research on necrotizing enterocolitis, we still do not fully understand the pathogenesis of the disease, how to prevent or how to treat the disease. However, as a result of recent significant advances in the microbiology, molecular biology, and cell biology of the intestine of premature infants and infants with necrotizing enterocolitis, there is some hope that research into this devastating disease will yield some important translation into improved outcomes.

Introduction

Although necrotizing enterocolitis (NEC) is one of the most common life-threatening surgical diseases affecting neonates, we still do not completely understand the pathogenesis or how to prevent or treat the disease [1]. The high mortality (around 30% for surgical NEC [2], [3] and long-term morbidity [4, 5] of survivors mandates urgent research into the pathogenesis, diagnosis, prevention and treatment of this devastating disease. There are several animal models of NEC, however, it is not completely clear how accurately these models recapitulate the human disease. This is particularly difficult as clinical NEC itself is quite variable, with some authors arguing for sub-classification into different forms reflecting the differences in disease onset and progression between a ‘typical’ NEC presentation in an extremely premature infant who has been fed enterally for a few weeks, and other presentations such as NEC in a term infant who has a cardiac defect or who has had gastroschisis [6]. As a consequence of the limitations of the animal models, it is vital to undertake clinical research studies in parallel with basic science/animal model studies, and in this brief review article, our aim is to describe some areas of current research interest; an exhaustive review of all current NEC research is unfeasible.

Section snippets

Pathogenesis

The main factors thought to be involved in the pathogenesis of NEC are: intestinal immaturity, enteral feeds, the intestinal microbiome, inflammation and local ischaemia and/or reperfusion injury. We will briefly discuss recent research in each of these areas below.

Diagnosis

Diagnosis of NEC currently relies on a combination of clinical symptoms and signs, and radiological features such as pneumatosis intestinalis and pneumoperitoneum, which are encapsulated in the Bell's stages of disease, which although frequently criticized, are still widely used to describe populations of infants with NEC. For many years, researchers have sought biomarkers that would be diagnostic for NEC in plasma, urine or stool samples (reviewed [57], [58]). One of the most widely researched

Dietary/pharmacological approaches

There are several suggested dietary and/or pharmacological approaches to the prevention of NEC. Many of these agents are found in human breast milk, for example lactoferrin is a glycoprotein that forms part of the innate immune response. It is found in high concentration in colostrum and lower concentration in breast milk and has antibacterial and antiviral properties. It has been speculated that it would be a potential preventative measure for NEC, but few animal or human studies have yet been

Conclusions

Despite understanding the cardinal features involved in the pathogenesis of NEC, and decades of research, we still do not fully understand this devastating disease, how to prevent it or treat it. Nevertheless, the broad range and depth of research on the topic does lead to a degree of optimism that clinicians and scientists will hopefully be able to deliver novel preventative, diagnostic and therapeutic strategies that will translate into improved outcomes.

Research directions

  • Testing of research-based biomarkers in large clinical cohorts to determine whether they improve decision-making

  • Improve understanding of the interplay between microbiota and intestinal inflammation

  • Elucidation of the molecular basis of the protective effect of probiotics, in order to optimise probiotic strains to be used in prevention of NEC

Conflict of interest statement

Simon Eaton has received consultancy fees from Fresenius Kabi and a speaker's honorarium from Danone. The authors have no other relevant financial interests or affiliations.

Acknowledgements

SE gratefully acknowledges support from Great Ormond Street Hospital Children's Charity and NJH is supported by the NIHR Southampton Biomedical Research Centre in Nutrition.

References (116)

  • S.K. Walker et al.

    Intraperitoneal 1.5% delflex improves intestinal blood flow in necrotizing enterocolitis

    J Surg Res

    (2013)
  • H.J. Amin et al.

    Arginine supplementation prevents necrotizing enterocolitis in the premature infant

    J Pediatr

    (2002)
  • R.M. Becker et al.

    Reduced serum amino acid concentrations in infants with necrotizing enterocolitis

    J Pediatr

    (2000)
  • S.A. Zamora et al.

    Plasma L-arginine concentrations in premature infants with necrotizing enterocolitis

    J Pediatr

    (1997)
  • N.J. Evennett et al.

    A systematic review of serologic tests in the diagnosis of necrotizing enterocolitis

    J Pediatr Surg

    (2009)
  • N. Evennett et al.

    Urinary intestinal fatty acid-binding protein concentration predicts extent of disease in necrotizing enterocolitis

    J Pediatr. Surg

    (2010)
  • F.H. Heida et al.

    Intestinal fatty acid-binding protein levels in necrotizing enterocolitis correlate with extent of necrotic bowel: results from a multicenter study

    J Pediatr Surg

    (2015)
  • B.A. Sullivan et al.

    Predictive monitoring for sepsis and necrotizing enterocolitis to prevent shock

    Semin Fetal Neonatal Med

    (2015)
  • P. Manzoni et al.

    Bovine lactoferrin supplementation for prevention of necrotizing enterocolitis in very-low-birth-weight neonates: a randomized clinical trial

    Early Hum Dev

    (2014)
  • P. Wipf et al.

    Synthesis of -inflammatory alpha-and beta-linked acetamidopyranosides as inhibitors of toll-like receptor 4 (TLR4)

    Tetrahedron Lett

    (2015)
  • C.D. Downard et al.

    Treatment of necrotizing enterocolitis: an American Pediatric Surgical Association outcomes and clinical trials committee systematic review

    J Pediatr Surg

    (2012)
  • C.O. Abernathy et al.

    Immaturity of the biliary excretory system predisposes neonates to intrahepatic cholestasis

    Med Hypotheses

    (1979)
  • R.H. Siggers et al.

    Early administration of probiotics alters bacterial colonization and limits diet-induced gut dysfunction and severity of necrotizing enterocolitis in preterm pigs

    J Nutr

    (2008)
  • M.S. Cilieborg et al.

    The incidence of necrotizing enterocolitis Is Increased Following Probiotic Administration to preterm pigs

    J Nutr

    (2011)
  • R.M. Patel et al.

    Probiotic bacteria induce maturation of intestinal claudin 3 expression and barrier function

    Am J Pathol

    (2012)
  • S.C. Fitzgibbons et al.

    Mortality of necrotizing enterocolitis expressed by birth weight categories

    J Pediatr Surg

    (2009)
  • M. Thyoka et al.

    Advanced necrotizing enterocolitis part 1: mortality

    Eur J Pediatr Surg

    (2012)
  • C.M. Rees et al.

    Neurodevelopmental outcomes of neonates with medically and surgically treated necrotizing enterocolitis

    ArchDisChild Fetal Neonatal Ed

    (2007)
  • N.N. Nanthakumar et al.

    Inflammation in the developing human intestine: A possible pathophysiologic contribution to necrotizing enterocolitis

    Proc Natl Acad Sci U. S. A.

    (2000)
  • Y. Yu et al.

    Increased inflammatory reaction to intestinal ischemia–reperfusion in neonatal versus adult mice

    Eur J Pediatr Surg

    (2015)
  • T. Thymann et al.

    Carbohydrate maldigestion induces necrotizing enterocolitis in preterm pigs

    Am J Physiol Gastrointest Liver Physiol

    (2009)
  • N. Bekkali et al.

    Duration of meconium passage in preterm and term infants

    Arch Dis Child Fetal Neonatal Ed

    (2008)
  • K.E. Gregory et al.

    Stooling pattern and early nutritional exposures associated with necrotizing enterocolitis in premature infants

    J Perinat Neonatal Nurs

    (2015)
  • B. Li et al.

    Early maternal separation induces alterations of colonic epithelial permeability and morphology

    Pediatr Surg Int

    (2014)
  • J. Meinzen-Derr et al.

    Role of human milk in extremely low birth weight infants' risk of necrotizing enterocolitis or death

    J Perinatol

    (2009)
  • M.S. Caplan

    Neonatal necrotizing enterocolitis: clinical observations, pathophysiology, and prevention

  • E. Verduci et al.

    Epigenetic effects of human breast milk

    Nutrients

    (2014)
  • F. Gao et al.

    Marked methylation changes in intestinal genes during the perinatal period of preterm neonates

    BMC Genomics

    (2014)
  • R. Willems et al.

    Introducing enteral feeding induces intestinal subclinical inflammation and respective chromatin changes in preterm pigs

    Epigenomics

    (2015)
  • V.A. Schroeder et al.

    Effects of lactose-containing vs lactose-free infant formula on postprandial Superior mesenteric artery flow in term infants

    JPEN J Parenter Enteral Nutr

    (2014)
  • J. van Acker et al.

    Outbreak of necrotizing enterocolitis associated with Enterobacter sakazakii in powdered milk formula

    J Clin Microbiol

    (2001)
  • H.A. Rotbart et al.

    How contagious is necrotizing enterocolitis?

    Pediatr Infect Dis

    (1983)
  • D.W. Scheifele

    Role of bacterial toxins in neonatal necrotizing enterocolitis

    J Pediatr

    (1990)
  • D.W. Scheifele et al.

    Endotoxinemia and thrombocytopenia during neonatal necrotizing enterocolitis

    Am J Clin Pathol

    (1985)
  • H.W. Cheu et al.

    Breath hydrogen excretion as a screening test for the early diagnosis of necrotizing enterocolitis

    Am J Dis Child

    (1989)
  • T.V. Santulli et al.

    Acute necrotizing enterocolitis in infancy: a review of 64 cases

    Pediatrics

    (1975)
  • H.J. Niemarkt et al.

    Necrotizing enterocolitis: a clinical review on diagnostic biomarkers and the role of the intestinal microbiota

    Inflamm Bowel Dis

    (2015)
  • C.J. Stewart et al.

    Development of the preterm gut microbiome in twins at risk of necrotising enterocolitis and sepsis

    PLoS One

    (2013)
  • R. Brower-Sinning et al.

    Mucosa-associated bacterial diversity in necrotizing enterocolitis

    PLoS One

    (2014)
  • J.V. Been et al.

    Chorioamnionitis as a risk factor for necrotizing enterocolitis: a systematic review and meta-analysis

    J Pediatr

    (2013)
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