Necrotizing enterocolitis: Pathophysiology from a historical context.

Necrotizing enterocolitis (NEC) continues to afflict approximately 7% of preterm infants born weighing less than 1500g, though recent investigations have provided novel insights into the pathogenesis of this complex disease. The disease has been a major cause of morbidity and mortality in neonatal intensive care units worldwide for many years, and our current understanding reflects exceptional observations made decades ago. In this review, we will describe NEC from a historical context and summarize seminal findings that underscore the importance of enteral feeding, the gut microbiota, and intestinal inflammation in this complex pathophysiology.

[1]  V. Reyes,et al.  Amniotic fluid-borne hepatocyte growth factor protects rat pups against experimental necrotizing enterocolitis. , 2014, American journal of physiology. Gastrointestinal and liver physiology.

[2]  M. V. Østergaard,et al.  Modulation of intestinal inflammation by minimal enteral nutrition with amniotic fluid in preterm pigs. , 2014, JPEN. Journal of parenteral and enteral nutrition.

[3]  B. Kramer,et al.  Endotoxin Induced Chorioamnionitis Prevents Intestinal Development during Gestation in Fetal Sheep , 2009, PloS one.

[4]  R. Siggers,et al.  Postnatal amniotic fluid intake reduces gut inflammatory responses and necrotizing enterocolitis in preterm neonates. , 2013, American journal of physiology. Gastrointestinal and liver physiology.

[5]  P. Wipf,et al.  Discovery and Validation of a New Class of Small Molecule Toll-Like Receptor 4 (TLR4) Inhibitors , 2013, PloS one.

[6]  W. Stenson Preventing necrotising enterocolitis with amniotic fluid stem cells , 2013, Gut.

[7]  Charlotte E. Egan,et al.  Toll-like receptor 4-mediated lymphocyte influx induces neonatal necrotizing enterocolitis. , 2016, The Journal of clinical investigation.

[8]  L. Duffy,et al.  Concordance of Bacterial Cultures with Endotoxin and Interleukin-6 in Necrotizing Enterocolitis , 1997, Digestive Diseases and Sciences.

[9]  M. Butel,et al.  Clostridial pathogenicity in experimental necrotising enterocolitis in gnotobiotic quails and protective role of bifidobacteria. , 1998, Journal of medical microbiology.

[10]  W. Berdon,et al.  NECROTIZING ENTEROCOLITIS IN PREMATURE INFANTS. , 1965, The Journal of pediatrics.

[11]  P. Panigrahi,et al.  Stool microflora in extremely low birthweight infants , 1999, Archives of disease in childhood. Fetal and neonatal edition.

[12]  M. Caplan,et al.  Bifidobacterial supplementation reduces the incidence of necrotizing enterocolitis in a neonatal rat model. , 1999, Gastroenterology.

[13]  J. Fruchart,et al.  Preformed PAF‐acether and lyso PAF‐acether are bound to blood lipoproteins , 1988, FEBS letters.

[14]  D. Hackam,et al.  A Critical Role for TLR4 in the Pathogenesis of Necrotizing Enterocolitis by Modulating Intestinal Injury and Repair1 , 2007, The Journal of Immunology.

[15]  D. Hackam,et al.  Evidence-based feeding strategies before and after the development of necrotizing enterocolitis , 2014, Expert review of clinical immunology.

[16]  C. Berseth,et al.  Prolonging small feeding volumes early in life decreases the incidence of necrotizing enterocolitis in very low birth weight infants. , 2003, Pediatrics.

[17]  Charlotte E. Egan,et al.  Breast milk protects against the development of necrotizing enterocolitis through inhibition of Toll Like Receptor 4 in the intestinal epithelium via activation of the epidermal growth factor receptor , 2015, Mucosal Immunology.

[18]  P. Wipf,et al.  Synthesis of anti-inflammatory α-and β-linked acetamidopyranosides as inhibitors of toll-like receptor 4 (TLR4). , 2015, Tetrahedron letters.

[19]  D. Hackam,et al.  Animal models of gastrointestinal and liver diseases. Animal models of necrotizing enterocolitis: pathophysiology, translational relevance, and challenges. , 2014, American journal of physiology. Gastrointestinal and liver physiology.

[20]  T. Cole,et al.  Breast milk and neonatal necrotising enterocolitis , 1990, The Lancet.

[21]  R. Ohls,et al.  Cytokines and growth factors in the developing intestine and during necrotizing enterocolitis. , 2017, Seminars in perinatology.

[22]  B. Barlow,et al.  Protection against Experimental Necrotizing Enterocolitis by Maternal Milk. I. Role of Milk Leukocytes , 1977, Pediatric Research.

[23]  D. Hackam,et al.  Necrotizing enterocolitis: new insights into pathogenesis and mechanisms , 2016, Nature Reviews Gastroenterology &Hepatology.

[24]  R. Uauy,et al.  The Mechanism of Excessive Intestinal Inflammation in Necrotizing Enterocolitis: An Immature Innate Immune Response , 2011, PloS one.

[25]  L. Duffy,et al.  Bacterial toxins and enteral feeding of premature infants at risk for necrotizing enterocolitis. , 2001 .

[26]  Charlotte E. Egan,et al.  Toll-like Receptor 4-mediated Endoplasmic Reticulum Stress in Intestinal Crypts Induces Necrotizing Enterocolitis* , 2014, The Journal of Biological Chemistry.

[27]  Charlotte E. Egan,et al.  Toll-like Receptor 4 Is Expressed on Intestinal Stem Cells and Regulates Their Proliferation and Apoptosis via the p53 Up-regulated Modulator of Apoptosis* , 2012, The Journal of Biological Chemistry.

[28]  C. Hunter,et al.  Variability in Antibiotic Regimens for Surgical Necrotizing Enterocolitis Highlights the Need for New Guidelines. , 2017, Surgical infections.

[29]  R. Medzhitov,et al.  Innate Sensors of Microbial Infection , 2005, Journal of Clinical Immunology.

[30]  R. Ehrenkranz,et al.  An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. , 2010, The Journal of pediatrics.

[31]  S. Gross,et al.  Effect of early low-volume enteral substrate on subsequent feeding tolerance in very low birth weight infants. , 1988, The Journal of pediatrics.

[32]  J. M. Rhoads,et al.  Oral Administration of Surfactant Protein-A Reduces Pathology in an Experimental Model of Necrotizing Enterocolitis , 2015, Journal of pediatric gastroenterology and nutrition.

[33]  W. Zhou,et al.  Glutamine downregulates TLR-2 and TLR-4 expression and protects intestinal tract in preterm neonatal rats with necrotizing enterocolitis. , 2014, Journal of pediatric surgery.

[34]  P. Brocklehurst,et al.  Donor breast milk versus infant formula for preterm infants: systematic review and meta-analysis , 2006, Archives of Disease in Childhood - Fetal and Neonatal Edition.

[35]  M. Morowitz,et al.  The intestinal microbiome and necrotizing enterocolitis , 2013, Current opinion in pediatrics.

[36]  K. Bibby,et al.  Lactobacillus rhamnosus HN001 decreases the severity of necrotizing enterocolitis in neonatal mice and preterm piglets: evidence in mice for a role of TLR9. , 2014, American journal of physiology. Gastrointestinal and liver physiology.

[37]  J. Ozolek,et al.  A Critical Role for TLR4 Induction of Autophagy in the Regulation of Enterocyte Migration and the Pathogenesis of Necrotizing Enterocolitis , 2013, The Journal of Immunology.

[38]  Charlotte E. Egan,et al.  Amniotic fluid inhibits Toll-like receptor 4 signaling in the fetal and neonatal intestinal epithelium , 2012, Proceedings of the National Academy of Sciences.

[39]  D. Hackam,et al.  The development of animal models for the study of necrotizing enterocolitis , 2008, Disease Models & Mechanisms.

[40]  D. Nielsen,et al.  Provision of Amniotic Fluid During Parenteral Nutrition Increases Weight Gain With Limited Effects on Gut Structure, Function, Immunity, and Microbiology in Newborn Preterm Pigs. , 2016, JPEN. Journal of parenteral and enteral nutrition.

[41]  M. Caplan,et al.  New Medical and Surgical Insights Into Neonatal Necrotizing Enterocolitis: A Review , 2017, JAMA pediatrics.

[42]  G. Weinstock,et al.  Gut bacteria dysbiosis and necrotising enterocolitis in very low birthweight infants: a prospective case-control study , 2016, The Lancet.

[43]  A. Y. Sweet,et al.  Preventing necrotizing enterocolitis in neonates. , 1978, JAMA.

[44]  R. Kliegman,et al.  Beneficial effects of early hypocaloric enteral feeding on neonatal gastrointestinal function: preliminary report of a randomized trial. , 1988, The Journal of pediatrics.

[45]  M. Caplan,et al.  The Role of Recombinant Platelet-Activating Factor Acetylhydrolase in a Neonatal Rat Model of Necrotizing Enterocolitis , 1997, Pediatric Research.

[46]  L. Morelli,et al.  Probiotics for prevention of necrotizing enterocolitis in preterm infants: systematic review and meta-analysis , 2015, Italian Journal of Pediatrics.

[47]  R. Thomson,,et al.  The Roles of Bacteria and TLR4 in Rat and Murine Models of Necrotizing Enterocolitis1 , 2006, The Journal of Immunology.

[48]  Intestinal dysbiosis in preterm infants preceding necrotizing enterocolitis: a systematic review and meta-analysis , 2017, Microbiome.

[49]  J. Ozolek,et al.  Reciprocal Expression and Signaling of TLR4 and TLR9 in the Pathogenesis and Treatment of Necrotizing Enterocolitis1 , 2009, The Journal of Immunology.

[50]  D. Relman,et al.  Microbiome Assembly across Multiple Body Sites in Low-Birthweight Infants , 2013, mBio.

[51]  P. Ng,et al.  Comparative MiRNA Expressional Profiles and Molecular Networks in Human Small Bowel Tissues of Necrotizing Enterocolitis and Spontaneous Intestinal Perforation , 2015, PloS one.

[52]  R. Turner ON THE PATHOLOGY AND TREATMENT OF LARYNGO-TRACHEAL INFLAMMATION , 1854 .

[53]  B. Firek,et al.  Mucosa-Associated Bacterial Diversity in Necrotizing Enterocolitis , 2014, PloS one.

[54]  S. Oddie,et al.  Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants. , 2017, The Cochrane database of systematic reviews.

[55]  O. Stiennon PNEUMATOSIS INTESTINALIS IN THE NEWBORN , 1951 .

[56]  M. Caplan,et al.  The platelet-activating factor receptor antagonist WEB 2170 prevents neonatal necrotizing enterocolitis in rats. , 1997, Journal of pediatric gastroenterology and nutrition.

[57]  D. Antonopoulos,et al.  16S rRNA gene-based analysis of fecal microbiota from preterm infants with and without necrotizing enterocolitis , 2009, The ISME Journal.

[58]  D. Hackam,et al.  Toll-like receptor-4 inhibits enterocyte proliferation via impaired beta-catenin signaling in necrotizing enterocolitis. , 2010, Gastroenterology.

[59]  Charlotte E. Egan,et al.  Endothelial TLR4 activation impairs intestinal microcirculatory perfusion in necrotizing enterocolitis via eNOS–NO–nitrite signaling , 2013, Proceedings of the National Academy of Sciences.

[60]  T. Billiar,et al.  Intestinal epithelial Toll-like receptor 4 regulates goblet cell development and is required for necrotizing enterocolitis in mice. , 2012, Gastroenterology.

[61]  M. Caplan,et al.  Necrotizing enterocolitis: pathophysiology, platelet-activating factor, and probiotics. , 2013, Seminars in pediatric surgery.

[62]  W. Walker,et al.  The Toll-like receptor-4 in human and mouse colonic epithelium is developmentally regulated: a possible role in Necrotizing Enterocolitis , 2014, Pediatric Research.

[63]  B. Barlow,et al.  Importance of multiple episodes of hypoxia or cold stress on the development of enterocolitis in an animal model. , 1975, Surgery.

[64]  M. Lythgoe,et al.  Amniotic Fluid Stem Cells Prevent Development of Ascites in a Neonatal Rat Model of Necrotizing Enterocolitis , 2013, European Journal of Pediatric Surgery.

[65]  W. Hsueh,et al.  Experimental model of ischemic bowel necrosis. The role of platelet-activating factor and endotoxin. , 1983, The American journal of pathology.

[66]  G. Besner,et al.  Evaluating the efficacy of different types of stem cells in preserving gut barrier function in necrotizing enterocolitis. , 2017, The Journal of surgical research.

[67]  S. Dasgupta,et al.  Protective effects of amniotic fluid in the setting of necrotizing enterocolitis , 2017, Pediatric Research.

[68]  H. Stein,et al.  Gastroenteritis with Necrotizing Enterocolitis in Premature Babies , 1972, British medical journal.

[69]  M. Caplan,et al.  Necrotizing enterocolitis: role of platelet activating factor, endotoxin, and tumor necrosis factor. , 1990, The Journal of pediatrics.