Abstract
NEC is a devastating disease that, once present, is very difficult to treat. In the absence of an etiologic treatment, preventive measures are required. Advances in decoding the pathophysiology of NEC are being made but a more comprehensive understanding is needed for the targeting of preventative strategies. A better definition of the disease as well as diagnostic criteria are needed to be able to specifically label a disease as NEC. Multiple environmental factors combined with host susceptibility appear to contribute to enhanced risks for developing this disease. Several different proximal pathways are involved, all leading to a common undesired outcome: Intestinal necrosis. The most common form of this disease appears to involve inflammatory pathways that are closely meshed with the intestinal microbiota, where a dysbiosis may result in dysregulated inflammation. The organisms present in the intestinal tract prior to the onset of NEC along with their diversity and functional capabilities are just beginning to be understood. Fulfillment of postulates that support causality for particular microorganisms is needed if bacteriotherapies are to be intelligently applied for the prevention of NEC. Identification of molecular effector pathways that propagate inflammation, understanding of, even incipient role of genetic predisposition and of miRNAs may help solve the puzzle of this disease and may bring the researchers closer to finding a treatment. Despite recent progress, multiple limitations of the current animal models, difficulties related to studies in humans, along with the lack of a “clear” definition will continue to make it a very challenging disease to decipher.
Keywords: Necrotizing enterocolitis, spontaneous intestinal perforations, prematurity, intestinal inflammation, pathophysiology, morbidity.
[1]
Bell MJ, Shackelford P, Feigin RD, Ternberg JL, Brotherton T. Epidemiologic and bacteriologic evaluation of neonatal necrotizing enterocolitis. J Pediatr Surg 1979; 14(1): 1-4.
[2]
Coursey CA, Hollingsworth CL, Gaca AM, Maxfield C, DeLong D, Bisset G. Radiologists’ agreement when using a 10-point scale to report abdominal radiographic findings of necrotizing enterocolitis in neonates and infants. Am J Roentgenol 2008; 191(1): 190-7.
[3]
Markiet K, Szymanska-Dubowik A, Janczewska I, Domazalska-Popadiuk I, Zawadzka-Kepczynska A, Bianek-Bodzak A. Agreement and reproducibility of radiological signs in NEC using The Duke Abdominal Assessment Scale (DAAS). Pediatr Surg Int 2017; 33(3): 335-40.
[4]
Battersby C, Longford N, Costeloe K, Modi N. Development of a Gestational Age–Specific Case Definition for Neonatal Necrotizing Enterocolitis. JAMA Pediatr 2017; 171(3): 256.
[5]
Yee WH, Soraisham AS, Shah VS, Aziz K, Yoon W, Lee SK. Incidence and Timing of Presentation of Necrotizing Enterocolitis in Preterm Infants. Pediatrics 2012; 129(2): e298-304.
[6]
Chen AC, Chung MY, Chang JH, Lin HC. Pathogenesis implication for necrotizing enterocolitis prevention in preterm very-low-birth-weight infants. J Pediatr Gastroenterol Nutr 2014; 58(1): 7-11.
[7]
Hull MA, Fisher JG, Gutierrez IM, et al. Mortality and management of surgical necrotizing enterocolitis in very low birth weight neonates: a prospective cohort study. J Am Coll Surg 2014 Jun; 218(6): 1148-55.
[8]
Patel RM, Kandefer S, Walsh MC, et al. Causes and Timing of Death in Extremely Premature Infants from 2000 through 2011. N Engl J Med 2015; 372(4): 331-40.
[9]
Fisher JG, Bairdain S, Sparks EA, et al. Serious congenital heart disease and necrotizing enterocolitis in very low birth weight neonates. J Am Coll Surg 2015; 220(6): 1018-26.e14.
[10]
González-Rivera R, Culverhouse RC, Hamvas A, Tarr PI, Warner BB. The age of necrotizing enterocolitis onset: An application of Sartwell’s incubation period model. J Perinatol 2011; 27;31(8): 519-23.
[11]
Gordon PV, Clark R, Swanson JR, Spitzer A. Can a national dataset generate a nomogram for necrotizing enterocolitis onset? J Perinatol 2014; 34(10): 732-5.
[12]
Nair J, Gugino SF, Nielsen LC, Caty MG, Lakshminrusimha S. Fetal and postnatal ovine mesenteric vascular reactivity. Pediatr Res 2016; 79(4): 575-82.
[13]
Pitt J, Barlow B, Heird WC. Protection against Experimental Necrotizing Enterocolitis by Maternal Milk. I. Role of Milk Leukocytes. Pediatr Res 1977; 11(8): 906-9.
[14]
Young CM, Kingma SDK, Neu J. Ischemia-reperfusion and neonatal intestinal injury. J Pediatr 2011; 158(2)(Suppl.): e25-8.
[15]
Adolph TE, Tomczak MF, Niederreiter L, Ko H-J, Böck J, Martinez-Naves E, et al. Paneth cells as a site of origin for intestinal inflammation. Nature 2013; 503(7475): 272-6.
[16]
Zhang C, Sherman MP, Prince LS, Bader D, Weitkamp J-H, Slaughter JC, et al. Paneth cell ablation in the presence of Klebsiella pneumoniae induces necrotizing enterocolitis (NEC)-like injury in the small intestine of immature mice. Dis Model Mech 2012; 5(4): 522-32.
[17]
McElroy SJ, Underwood MA, Sherman MP. Paneth Cells and Necrotizing Enterocolitis: A Novel Hypothesis for Disease Pathogenesis. Neonatology 2013; 103(1): 10-20.
[18]
Sanderson IR. WWA. Establishment of a human fetal small intestinal epithelial cell line. Int Arch Allergy Immunol 1995; 107: 396-7.
[19]
Fatehullah A, Tan SH, Barker N. Organoids as an in vitro model of human development and disease. Nat Cell Biol 2016; 18(3): 246-54.
[20]
Claud EC, Walker WA. Hypothesis: inappropriate colonization of the premature intestine can cause neonatal necrotizing enterocolitis. FASEB J 2001; 15(8): 1398-403.
[21]
Alexander VN, Northrup V, Bizzarro MJ. Antibiotic Exposure in the Newborn Intensive Care Unit and the Risk of Necrotizing Enterocolitis. J Pediatr 2011; 159(3): 392-7.
[22]
Cotten CM, Taylor S, Stoll B, Goldberg RN, Hansen NI, Sanchez PJ, et al. Prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants. Pediatrics 2009; 123(1): 58-66.
[23]
Abdel Ghany EA, Ali AA. Empirical antibiotic treatment and the risk of necrotizing enterocolitis and death in very low birth weight neonates. Ann Saudi Med 2012; 32(5): 521-6.
[24]
Greenwood C, Morrow AL, Lagomarcino AJ, Altaye M, Taft DH, Yu Z, et al. Early empiric antibiotic use in preterm infants is associated with lower bacterial diversity and higher relative abundance of enterobacter. J Pediatr 2014; 165(1): 23-9.
[25]
La Rosa PS, Warner BB, Zhou Y, et al. Patterned progression of bacterial populations in the premature infant gut. Proc Natl Acad Sci 2014; 111(34): 12522-7.
[26]
Mshvildadze M, Neu J, Shuster J, Theriaque D, Li N, Mai V. Intestinal Microbial Ecology in Premature Infants Assessed with Non-Culture-Based Techniques. J Pediatr 2010; 156(1): 20-5.
[27]
Aagaard K, Ma J, Antony KM, Ganu R, Petrosino J, Versalovic J. The Placenta Harbors a Unique Microbiome. Sci Transl Med 2014; 6(237): 237ra65-5.
[28]
Ardissone AN, de la Cruz DM, Davis-Richardson AG, et al. Meconium microbiome analysis identifies bacteria correlated with premature birth. Weitkamp J-H, editor. PLoS One. 2014; 9: p. (3)e90784.
[29]
Lim ES, Zhou Y, Zhao G, et al. Early life dynamics of the human gut virome and bacterial microbiome in infants. Nat Med 2015; 21(10): 1228-34.
[30]
DiGiulio DB. Diversity of microbes in amniotic fluid. Semin Fetal Neonatal Med 2012; 17(1): 2-11.
[31]
Neu J. The microbiome during pregnancy and early postnatal life. Semin Fetal Neonatal Med 2016; 21(6): 373-9.
[32]
Warner BB, Tarr PI. Necrotizing enterocolitis and preterm infant gut bacteria. Semin Fetal Neonatal Med 2016; 21(6): 394-9.
[33]
Stewart CJ, Marrs ECL, Nelson A, et al. Development of the Preterm Gut Microbiome in Twins at Risk of Necrotising Enterocolitis and Sepsis.Sanz Y, editor.PLoS One. 2013; 8: p. (8)e73465.
[34]
Torrazza RM, Ukhanova M, Wang X, et al. Intestinal microbial ecology and environmental factors affecting necrotizing enterocolitis.Chakravortty D, editor.PLoS One. 2013; 30;8: p. (12)e83304.
[35]
Mai V, Young CM, Ukhanova M, et al. Fecal Microbiota in Premature Infants Prior to Necrotizing Enterocolitis. Chakravortty D, editor.PLoS One. 2011; 6: p. (6)e20647.
[36]
Sim K, Shaw AG, Randell P, et al. Dysbiosis Anticipating Necrotizing Enterocolitis in Very Premature Infants. Clin Infect Dis 2015; 60(3): 389-97.
[37]
Cassir N, Benamar S, Khalil JB, et al. Clostridium butyricum Strains and Dysbiosis Linked to Necrotizing Enterocolitis in Preterm Neonates. Clin Infect Dis 2015; 61(7): 1107-15.
[38]
Zhou Y, Shan G, Sodergren E, Weinstock G, Walker WA, Gregory KE. Longitudinal Analysis of the Premature Infant Intestinal Microbiome Prior to Necrotizing Enterocolitis: A Case-Control Study.Lightfoot DA, editor.PLoS One. 2015; 10: p. (3)e0118632.
[39]
Warner BB, Deych E, Zhou Y, et al. Gut bacteria dysbiosis and necrotising enterocolitis in very low birthweight infants: a prospective case-control study. Lancet 2016; 387(10031): 1928-36.
[40]
McMurtry VE, Gupta RW, Tran L, et al. Bacterial diversity and Clostridia abundance decrease with increasing severity of necrotizing enterocolitis. Microbiome 2015; 3(1): 11.
[41]
Yang J, Wang Z, Feng J, et al. Application of Laser Capture Microdissection and 16S rRNA Gene Polymerase Chain Reaction in the Analysis of Bacteria Colonizing the Intestinal Tissue of Neonates With Necrotizing Enterocolitis. Pediatr Infect Dis J 2015; 34(10): e279-89.
[42]
Raveh-Sadka T, Thomas BC, Singh A, et al. Gut bacteria are rarely shared by co-hospitalized premature infants, regardless of necrotizing enterocolitis development. Elife 2015; 3: 4.
[43]
Pammi M, Cope J, Tarr PI, et al. Intestinal dysbiosis in preterm infants preceding necrotizing enterocolitis: A systematic review and meta-analysis. Microbiome 2017; 5(1): 31.
[44]
Coggins SA, Wynn JL, Weitkamp J-H. Infectious causes of Necrotizing Enterocolitis. Clin Perinatol 2015; 42(1): 133-54.
[45]
Skeath T, Stewart C, Waugh S, Embleton N, Cummings S, Berrington J. Cytomegalovirus and other common enteric viruses are not commonly associated with NEC. Acta Paediatr 2016; 105(1): 50-2.
[46]
Ginzel M, Yu Y, Klemann C, et al. The viral dsRNA analogue poly (I:C) induces necrotizing enterocolitis in neonatal mice. Pediatr Res 2016; 79(4): 596-602.
[47]
Dworkin LD, Levine GM, Farber NJ, Spector MH. Small intestinal mass of the rat is partially determined by indirect effects of intraluminal nutrition. Gastroenterology 1976; 71(4): 626-30.
[48]
Morgan J, Young L, McGuire W. Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants. In: McGuire W, Ed. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd 2014.
[49]
Konnikova Y, Zaman MM, Makda M, D’Onofrio D, Freedman SD, Martin CR. Late Enteral Feedings Are Associated with Intestinal Inflammation and Adverse Neonatal Outcomes.Neu J, editor.PLoS One. 2015; 10: p. (7)e0132924.
[50]
Kirtsman M, Yoon E, Ojah C, Cieslak Z, Lee S, Shah P. Nil-Per-Os Days and Necrotizing Enterocolitis in Extremely Preterm Infants. Am J Perinatol 2014; 32(08): 785-94.
[51]
Lucas A, Cole TJ. Breast milk and neonatal necrotising enterocolitis. Lancet (London, England) 1990; 336(8730): 1519-23.
[52]
Schanler RJ, Shulman RJ, Lau C. Feeding strategies for premature infants: beneficial outcomes of feeding fortified human milk versus preterm formula. Pediatrics 1999; 103(6 Pt 1): 1150-7.
[53]
Corpeleijn WE, Kouwenhoven SMP, Paap MC, et al. Intake of own mother’s milk during the first days of life is associated with decreased morbidity and mortality in very low birth weight infants during the first 60 days of life. Neonatology 2012; 102(4): 276-81.
[54]
Kimak KS, de Castro Antunes MM, Braga TD, Brandt KG, de Carvalho Lima M. Influence of Enteral Nutrition on Occurrences of Necrotizing Enterocolitis in Very-Low-Birth-Weight Infants. J Pediatr Gastroenterol Nutr 2015; 61(4): 445-50.
[55]
Chowning R, Radmacher P, Lewis S, Serke L, Pettit N, Adamkin DH. A retrospective analysis of the effect of human milk on prevention of necrotizing enterocolitis and postnatal growth. J 2016; 36(3): 221-4.
[56]
Sisk PM, Lovelady CA, Dillard RG, Gruber KJ, O’Shea TM. Early human milk feeding is associated with a lower risk of necrotizing enterocolitis in very low birth weight infants. J Perinatol 2007; 27(7): 428-33.
[57]
Meinzen-Derr J, Poindexter B, Wrage L, Morrow AL, Stoll B, Donovan EF. Role of human milk in extremely low birth weight infants’ risk of necrotizing enterocolitis or death. J Perinatol 2009; 29(1): 57-62.
[58]
Herrmann K, Carroll K. An Exclusively Human Milk Diet Reduces Necrotizing Enterocolitis. Breastfeed Med 2014; 9(4): 184-90.
[59]
Schanler RJ, Lau C, Hurst NM, Smith EO. Randomized trial of donor human milk versus preterm formula as substitutes for mothers’ own milk in the feeding of extremely premature infants. Pediatrics 2005; 116(2): 400-6.
[60]
Kantorowska A, Wei JC, Cohen RS, Lawrence RA, Gould JB, Lee HC. Impact of donor milk availability on breast milk use and necrotizing enterocolitis rates. Pediatrics 2016; 137(3)e20153123
[61]
Sullivan S, Schanler RJ, Kim JH, 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. J Pediatr 2010; 156(4): 562-7.e1.
[62]
Cristofalo EA, Schanler RJ, Blanco CL, et al. Randomized trial of exclusive human milk versus preterm formula diets in extremely premature infants. J Pediatr 2013; 163(6): 1592-5.e1.
[63]
Abrams SA, Schanler RJ, Lee ML, Rechtman DJ. Greater mortality and morbidity in extremely preterm infants fed a diet containing cow milk protein products. Breastfeed Med 2014; 9(6): 281-5.
[64]
Quigley M, McGuire W. Formula versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database Syst Rev 2014; (4): CD002971
[65]
Hair AB, Peluso AM, Hawthorne KM, et al. Beyond Necrotizing Enterocolitis Prevention: Improving Outcomes with an Exclusive Human Milk-Based Diet. Breastfeed Med 2016; 11(2): 70-4.
[66]
Assad M, Elliott MJ, Abraham JH. Decreased cost and improved feeding tolerance in VLBW infants fed an exclusive human milk diet. J Perinatol 2016; 36(3): 216-20.
[67]
Corpeleijn WE, de Waard M, Christmann V, et al. Effect of Donor Milk on Severe Infections and Mortality in Very Low-Birth-Weight Infants. JAMA Pediatr 2016; 170(7): 654.
[68]
Friel JK, Diehl-Jones B, Cockell KA, et al. Evidence of Oxidative Stress in Relation to Feeding Type During Early Life in Premature Infants. Pediatr Res 2011; 69(2): 160-4.
[69]
Diehl-Jones W, Archibald A, Gordon JW, Mughal W, Hossain Z, Friel JK. Human Milk Fortification Increases Bnip3 Expression Associated With Intestinal Cell Death In vitro. J Pediatr Gastroenterol Nutr 2015; 61(5): 583-90.
[70]
Koenig A, de Albuquerque Diniz EM, Barbosa SFC, Vaz FAC. Immunologic factors in human milk: the effects of gestational age and pasteurization. J Hum Lact 2005; 21(4): 439-43.
[71]
Silvestre D, Miranda M, Muriach M, Almansa I, Jareo E, Romero FJ. Antioxidant capacity of human milk: effect of thermal conditions for the pasteurization. Acta Pdiatrica 2008; 97(8): 1070-4.
[72]
Tully DB, Jones F, Tully MR. Donor milk: What’s in it and what’s not. J Hum Lact 2001; 17(2): 152-5.
[73]
Van Zoeren-Grobben D, Schrijver J, Van den Berg H, Berger HM. Human milk vitamin content after pasteurisation, storage, or tube feeding. Arch Dis Child 1987; 62(2): 161-5.
[74]
Bertino E, Coppa GV, Giuliani F, Coscia A, Gabrielli O, Sabatino G, et al. Effects of Holder pasteurization on human milk oligosaccharides. Int J Immunopathol Pharmacol 2008; 21(2): 381-5.
[75]
Peila C, Coscia A, Bertino E, et al. Effects of Holder pasteurization on the protein profile of human milk. Ital J Pediatr 2016; 42(1): 36.
[76]
Gottrand F. Long-chain polyunsaturated fatty acids influence the immune system of infants. J Nutr 2008; 138(9): 1807S-12S.
[77]
Arslanoglu S, Ziegler EE, Moro GE. World Association of Perinatal Medicine Working Group On Nutrition. Donor human milk in preterm infant feeding: evidence and recommendations. J Perinat Med 2010; 38(4): 347-51.
[78]
Shah SD, Dereddy N, Jones TL, Dhanireddy R, Talati AJ. Early versus Delayed Human Milk Fortification in Very Low Birth Weight Infants-A Randomized Controlled Trial. J Pediatr 2016; 174: 126-31.e1.
[79]
Li Y, Jensen ML, Chatterton DEW, Jensen BB, Thymann T, Kvistgaard AS, et al. Raw bovine milk improves gut responses to feeding relative to infant formula in preterm piglets. AJP Gastrointest Liver Physiol 2014; 306(1): G81-90.
[80]
Shen RL, Thymann T, Østergaard MV, et al. Early gradual feeding with bovine colostrum improves gut function and NEC resistance relative to infant formula in preterm pigs. Am J Physiol Gastrointest Liver Physiol 2015; 309(5): G310-23.
[81]
Rasmussen SO, Martin L, Østergaard MV, et al. Bovine colostrum improves neonatal growth, digestive function, and gut immunity relative to donor human milk and infant formula in preterm pigs. Am J Physiol Gastrointest Liver Physiol 2016; 311(3): G480-91.
[82]
Vegge A, Thymann T, Lund P, et al. Glucagon-like peptide-2 induces rapid digestive adaptation following intestinal resection in preterm neonates. AJP Gastrointest Liver Physiol 2013; 305(4): G277-85.
[83]
Støy ACF, Heegaard PMH, Thymann T, et al. Bovine colostrum improves intestinal function following formula-induced gut inflammation in preterm pigs. Clin Nutr 2014; 33(2): 322-9.
[84]
Seigel JK, Smith PB, Ashley PL, et al. Early Administration of Oropharyngeal Colostrum to Extremely Low Birth Weight Infants. Breastfeed Med 2013; 8(6): 491-5.
[85]
Lee J, Kim H-S, Jung YH, et al. Oropharyngeal Colostrum Administration in Extremely Premature Infants: An RCT. Pediatrics 2015; 135(2): e357-66.
[86]
Rodriguez NA, Vento M, Claud EC, Wang CE, Caplan MS. Oropharyngeal administration of mother’s colostrum, health outcomes of premature infants: study protocol for a randomized controlled trial. Trials 2015; 16(1): 453.
[87]
Balachandran B, Dutta S, Singh R, Prasad R, Kumar P. Bovine Colostrum in Prevention of Necrotizing Enterocolitis and Sepsis in Very Low Birth Weight Neonates: A Randomized, Double-blind, Placebo-controlled Pilot Trial. J Trop Pediatr 2017; 63(1): 10-7.
[88]
Good M, Sodhi CP, Egan CE, 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. Mucosal Immunol 2015; 8(5): 1166-79.
[89]
Actor JK, Hwang S-A, Kruzel ML. Lactoferrin as a natural immune modulator. Curr Pharm Des 2009; 15(17): 1956-73.
[90]
Mulligan P, White NRJ, Monteleone G, et al. Breast Milk Lactoferrin Regulates Gene Expression by Binding Bacterial DNA CpG Motifs But Not Genomic DNA Promoters in Model Intestinal Cells. Pediatr Res 2006; 59(5): 656-61.
[91]
Nguyen DN, Jiang P, Stensballe A, Bendixen E, Sangild PT, Chatterton DEW. Bovine lactoferrin regulates cell survival, apoptosis and inflammation in intestinal epithelial cells and preterm pig intestine. J Proteomics 2016; 139: 95-102.
[92]
Mirpuri J, Raetz M, Sturge CR, et al. Proteobacteria-specific IgA regulates maturation of the intestinal microbiota. Gut Microbes 2014; 5(1): 28-39.
[93]
Carlisle EM, Poroyko V, Caplan MS, Alverdy J, Morowitz MJ, Liu D. Murine Gut Microbiota and Transcriptome Are Diet Dependent. Ann Surg 2013; 257(2): 287-94.
[94]
Liu T, Hougen H, Vollmer AC, Hiebert SM. Gut bacteria profiles of Mus musculus at the phylum and family levels are influenced by saturation of dietary fatty acids. Anaerobe 2012; 18(3): 331-7.
[95]
Turnbaugh PJ, Bäckhed F, Fulton L, Gordon JI. Diet-Induced Obesity Is Linked to Marked but Reversible Alterations in the Mouse Distal Gut Microbiome. Cell Host Microbe 2008; 3(4): 213-23.
[96]
Turnbaugh PJ, Ridaura VK, Faith JJ, Rey FE, Knight R, Gordon JI. The Effect of Diet on the Human Gut Microbiome: A Metagenomic Analysis in Humanized Gnotobiotic Mice. Sci Transl Med 2009; 1(6): 6ra14-4.
[97]
Lu J, Jilling T, Li D, Caplan MS. Polyunsaturated fatty acid supplementation alters proinflammatory gene expression and reduces the incidence of necrotizing enterocolitis in a neonatal rat model. Pediatr Res 2007; 61(4): 427-32.
[98]
Jantscher-Krenn E, Zherebtsov M, Nissan C, et al. The human milk oligosaccharide disialyllacto-N-tetraose prevents necrotising enterocolitis in neonatal rats. Gut 2012; 61(10): 1417-25.
[99]
Autran CA, Schoterman MHC, Jantscher-Krenn E, Kamerling JP, Bode L. Sialylated galacto-oligosaccharides and 2′-fucosyllactose reduce necrotising enterocolitis in neonatal rats. Br J Nutr 2016; 116(02): 294-9.
[100]
Willems R, Krych L, Rybicki V, et al. Introducing enteral feeding induces intestinal subclinical inflammation and respective chromatin changes in preterm pigs. Epigenomics 2015; 7(4): 553-65.
[101]
Wahab Mohamed WA, Aseeri AM. Cord blood epidermal growth factor as a possible predictor of necrotizing enterocolitis in very low birth weight infants. J Neonatal Perinatal Med 2013; 6(3): 257-62.
[102]
Ferretti E, Tremblay E, Thibault M-P, Grynspan D, Burghardt KM, Bettolli M, et al. The nitric oxide synthase 2 pathway is targeted by both pro- and anti-inflammatory treatments in the immature human intestine. Nitric Oxide 2017; 66: 53-61.
[103]
Manzoni P, Meyer M, Stolfi I, et al. Bovine lactoferrin supplementation for prevention of necrotizing enterocolitis in very-low-birth-weight neonates: A randomized clinical trial. Early Hum Dev 2014; 90: S60-5.
[104]
Barrington KJ, Assaad M-A, Janvier A. The Lacuna Trial: a double-blind randomized controlled pilot trial of lactoferrin supplementation in the very preterm infant. J Perinatol 2016; 36(8): 666-9.
[105]
Sherman MP, Adamkin DH, Niklas V, et al. Randomized Controlled Trial of Talactoferrin Oral Solution in Preterm Infants. J Pediatr 2016; 175: 68-73.e3.
[106]
Akin IM, Atasay B, Dogu F, et al. Oral lactoferrin to prevent nosocomial sepsis and necrotizing enterocolitis of premature neonates and effect on T-regulatory cells. Am J Perinatol 2014; 31(12): 1111-20.
[107]
Bauer J, Gerss J. Longitudinal analysis of macronutrients and minerals in human milk produced by mothers of preterm infants. Clin Nutr 2011; 30(2): 215-20.
[108]
Lindquist S, Hernell O. Lipid digestion and absorption in early life: an update. Curr Opin Clin Nutr Metab Care 2010; 13(3): 314-20.
[109]
Andersson Y, Sävman K, Bläckberg L, Hernell O. Pasteurization of mother’s own milk reduces fat absorption and growth in preterm infants. Acta Paediatr 2007; 96(10): 1445-9.
[110]
Sjögren YM, Tomicic S, Lundberg A, et al. Influence of early gut microbiota on the maturation of childhood mucosal and systemic immune responses. Clin Exp Allergy 2009; 39(12): 1842-51.
[111]
Coppa GV, Facinelli B, Magi G, et al. Human milk glycosaminoglycans inhibit in vitro the adhesion of Escherichia coli and Salmonella fyris to human intestinal cells. Pediatr Res 2016; 79(4): 603-7.
[112]
Morrow AL, Meinzen-Derr J, Huang P, et al. Fucosyltransferase 2 Non-Secretor and Low Secretor Status Predicts Severe Outcomes in Premature Infants. J Pediatr 2011; 158(5): 745-51.
[113]
Blau J, Calo JM, Dozor D, Sutton M, Alpan G, La Gamma EF. Transfusion-related acute gut injury: Necrotizing Enterocolitis in very low birth weight neonates after packed red blood cell transfusion. J Pediatr 2011; 158(3): 403-9.
[114]
Stritzke AI, Smyth J, Synnes A, Lee SK, Shah PS. Transfusion-associated necrotising enterocolitis in neonates. Arch Dis Child Fetal Neonatal Ed 2013; 98(1): F10-4.
[115]
Doty M, Wade C, Farr J, Gomezcoello VC, Martin G, Nasr T. Feeding during Blood Transfusions and the Association with Necrotizing Enterocolitis. Am J Perinatol 2016; 33(9): 882-6.
[116]
Mohamed A, Shah PS. Transfusion associated necrotizing enterocolitis: a meta-analysis of observational data. Pediatrics 2012; 129(3): 529-40.
[117]
Sharma R, Kraemer DF, Torrazza RM, et al. Packed red blood cell transfusion is not associated with increased risk of necrotizing enterocolitis in premature infants. J Perinatol 2014; 34(11): 858-62.
[118]
Wallenstein MB, Arain YH, et al. Red blood cell transfusion is not associated with necrotizing enterocolitis: A review of consecutive transfusions in a tertiary neonatal intensive care unit. J Pediatr 2014; 165(4): 678-82.
[119]
Sood BG, Rambhatla A, Thomas R, Chen X. Decreased hazard of necrotizing enterocolitis in preterm neonates receiving red cell transfusions. J Matern Fetal Neonatal Med 2016; 29(5): 737-44.
[120]
AlFaleh K, Al-Jebreen A, Baqays A, et al. Association of packed red blood cell transfusion and necrotizing enterocolitis in very low birth weight infants. J Neonatal Perinatal Med 2014; 7(3): 193-8.
[121]
Derienzo C, Smith PB, Tanaka D, et al. Feeding practices and other risk factors for developing transfusion-associated necrotizing enterocolitis. Early Hum Dev 2014; 90(5): 237-40.
[122]
Kirpalani H, Zupancic JAF. Do transfusions cause necrotizing enterocolitis? The complementary role of randomized trials and observational studies. Semin Perinatol 2012; 36(4): 269-76.
[123]
Patel RM, Knezevic A, Shenvi N, et al. Association of Red Blood Cell Transfusion, Anemia, and Necrotizing Enterocolitis in Very Low-Birth-Weight Infants. JAMA 2016; 315(9): 889.
[124]
Hyung N, Campwala I, Boskovic DS, et al. The relationship of red blood cell transfusion to intestinal mucosal injury in premature infants. J Pediatr Surg 2016; 52(7): 1152-5.
[125]
Dani C, Poggi C, Gozzini E, et al. Red blood cell transfusions can induce proinflammatory cytokines in preterm infants. Transfusion 2017; 57(5): 1304-10.
[126]
Hay S, Zupancic JAF, Flannery DD, Kirpalani H, Dukhovny D. Should we believe in transfusion-associated enterocolitis? Applying a GRADE to the literature. Semin Perinatol 2017; 41(1): 80-91.
[127]
Nair J, Gugino SF, Nielsen LC, et al. Packed red cell transfusions alter mesenteric arterial reactivity and nitric oxide pathway in preterm lambs. Pediatr Res 2013; 74(6): 652-7.
[128]
Bernard A, Kasten M, Meier C, et al. Red blood cell arginase suppresses Jurkat (T cell) proliferation by depleting arginine. Surgery 2008; 143(2): 286-91.
[129]
Yazji I, Sodhi CP, Lee EK, et al. Endothelial TLR4 activation impairs intestinal microcirculatory perfusion in necrotizing enterocolitis via eNOS-NO-nitrite signaling. Proc Natl Acad Sci USA 2013; 110(23): 9451-6.
[130]
Chen Y, Chang KTE, Lian DWQ, et al. The role of ischemia in necrotizing enterocolitis. J Pediatr Surg 2016; 51(8): 1255-61.
[131]
Giuliani S, Tan Y-W, Zheng D, et al. Coagulation Gene Expression Profiling in Infants With Necrotizing Enterocolitis. J Pediatr Gastroenterol Nutr 2016; 63(6): e169-75.
[132]
Schat TE, Heida FH, Schurink M, van der Laan ME, Hulzebos CV, Bos AF, et al. The relation between splanchnic ischaemia and intestinal damage in necrotising enterocolitis. Arch Dis Child Fetal Neonatal Ed 2016; 101(6): F533-9.
[133]
Wu G, Morris SM. Arginine metabolism: nitric oxide and beyond. Biochem J 1998; 336(Pt 1): 1-17.
[134]
Wu G, Jaeger LA, Bazer FW, Rhoads JM. Arginine deficiency in preterm infants: Biochemical mechanisms and nutritional implications. J Nutr Biochem 2004; 15(8): 442-51.
[135]
Premkumar MH, Sule G, Nagamani SC, et al. Argininosuccinate lyase in enterocytes protects from development of necrotizing enterocolitis. AJP Gastrointest Liver Physiol 2014; 307(3): G347-54.
[136]
Erez A, Nagamani SCS, Shchelochkov OA, et al. Requirement of argininosuccinate lyase for systemic nitric oxide production. Nat Med 2011; 17(12): 1619-26.
[137]
Munder M. Arginase: an emerging key player in the mammalian immune system. Br J Pharmacol 2009; 158(3): 638-51.
[138]
Zamora SA, Amin HJ, McMillan DD, et al. Plasma L-arginine concentrations in premature infants with necrotizing enterocolitis. J Pediatr 1997; 131(2): 226-32.
[139]
Becker RM, Wu G, Galanko JA, et al. Reduced serum amino acid concentrations in infants with necrotizing enterocolitis. J Pediatr 2000; 137(6): 785-93.
[140]
Bauchart-Thevret C, Cui L, Wu G, Burrin DG. Arginine-induced stimulation of protein synthesis and survival in IPEC-J2 cells is mediated by mTOR but not nitric oxide. Am J Physiol Endocrinol Metab 2010; 299(6): E899-909.
[141]
Chapman JC, Liu Y, Zhu L, Rhoads JM. Arginine and citrulline protect intestinal cell monolayer tight junctions from hypoxia-induced injury in piglets. Pediatr Res 2012; 72(6): 576-82.
[142]
Pekarova M, Kubala L, Martiskova H, et al. The unique role of dietary L-arginine in the acceleration of peritoneal macrophage sensitivity to bacterial endotoxin. Immunol Res 2013; 56(1): 73-84.
[143]
Mieulet V, Yan L, Choisy C, et al. TPL-2-mediated activation of MAPK downstream of TLR4 signaling is coupled to arginine availability. Sci Signal 2010; 3(135): ra61.
[144]
Leung KT, Chan KYY, Ma TPY, et al. Dysregulated expression of arginine metabolic enzymes in human intestinal tissues of necrotizing enterocolitis and response of CaCO2 cells to bacterial components. J Nutr Biochem 2016; 29: 64-72.
[145]
Lamas B, Vergnaud-Gauduchon J, Goncalves-Mendes N, et al. Altered functions of natural killer cells in response to L-Arginine availability. Cell Immunol 2012; 280(2): 182-90.
[146]
Yu H-R, Kuo H-C, Huang L-T, Chen C-C, et al. L-Arginine modulates neonatal lymphocyte proliferation through an interleukin-2 independent pathway. Immunology 2014; 143(2): 184-92.
[147]
Celik IH, Demirel G, Canpolat FE, Dilmen U. Reduced plasma citrulline levels in low birth weight infants with necrotizing enterocolitis. J Clin Lab Anal 2013; 27(4): 328-32.
[148]
Badurdeen S, Mulongo M, Berkley JA. Arginine depletion increases susceptibility to serious infections in preterm newborns. Pediatr Res 2014; 77(2): 290-7.
[149]
Polycarpou E, Zachaki S, Tsolia M, et al. Enteral L-arginine supplementation for prevention of necrotizing enterocolitis in very low birth weight neonates: a double-blind randomized pilot study of efficacy and safety. JPEN J Parenter Enteral Nutr 2013; 37(5): 617-22.
[150]
Mitchell K, Lyttle A, Amin H. Arginine supplementation in prevention of necrotizing enterocolitis in the premature infant: an updated systematic review. BMC Pediatr 2014; 14: 226.
[151]
Nadler EP, Dickinson E, Knisely A, et al. Expression of inducible nitric oxide synthase and interleukin-12 in experimental necrotizing enterocolitis. J Surg Res 2000; 92(1): 71-7.
[152]
Tiso M, Schechter AN. Nitrate reduction to nitrite, nitric oxide and ammonia by gut bacteria under physiological conditions. PLoS One 2015; 10(3)e0119712
[153]
Jones JA, Hopper AO, Power GG, Blood AB. Dietary intake and bio-activation of nitrite and nitrate in newborn infants. Pediatr Res 2015; 77(1-2): 173-81.
[154]
Sorrells DL, Friend C, Koltuksuz U, et al. Inhibition of nitric oxide with aminoguanidine reduces bacterial translocation after endotoxin challenge in vivo. Arch Surg 1996; 131(11): 1155-63.
[155]
Kandasamy J. H uda S, Ambalavanan N, Jilling T. Inflammatory signals that regulate intestinal epithelial renewal, differentiation, migration and cell death: Implications for necrotizing enterocolitis. Pathophysiology 2014; 21(1): 67-80.
[156]
Grishin A, Bowling J, Bell B, Wang J, Ford HR. Roles of nitric oxide and intestinal microbiota in the pathogenesis of necrotizing enterocolitis. J Pediatr Surg 2016; 51(1): 13-7.
[157]
Talavera MM, Nuthakki S, Cui H, Jin Y, Liu Y, Nelin LD. Immunostimulated Arginase II Expression in Intestinal Epithelial Cells Reduces Nitric Oxide Production and Apoptosis. Front Cell Dev Biol 2017; 5: 15.
[158]
Pun P, Jones J, Wolfe C, Deming DD, Power GG, Blood AB. Changes in plasma and urinary nitrite after birth in premature infants at risk for necrotizing enterocolitis. Pediatr Res 2016; 79(3): 432-7.
[159]
Cho SX, Berger PJ, Nold-Petry CA, Nold MF. The immunological landscape in necrotising enterocolitis. Expert Rev Mol Med 2016; 18e12
[160]
Halac E, Halac J, Bégué EF, et al. Prenatal and postnatal corticosteroid therapy to prevent neonatal necrotizing enterocolitis: A controlled trial. J Pediatr 1990; 117(1 Pt 1): 132-8.
[161]
Rautava S, Walker WA, Lu L. Hydrocortisone-induced anti-inflammatory effects in immature human enterocytes depend on the timing of exposure. Am J Physiol Gastrointest Liver Physiol 2016; 310(11): G920-9.
[162]
Weng M, Walker WA. The role of gut microbiota in programming the immune phenotype. J Dev Orig Health Dis 2013; 4(03): 203-14.
[163]
Foster JP, Seth R, Cole MJ. Oral immunoglobulin for preventing necrotizing enterocolitis in preterm and low birth weight neonates. Cochrane database Syst Rev 2016; 4CD001816
[164]
McElroy SJ, Weitkamp J-H. Innate Immunity in the Small Intestine of the Preterm Infant. Neoreviews 2011; 12(9): e517-26.
[165]
Abreu MT. Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat Rev Immunol 2010; 10(2): 131-44.
[166]
He Y, Lawlor NT, Newburg DS. Human Milk Components Modulate Toll-Like Receptor-Mediated Inflammation. Adv Nutr 2016; 7(1): 102-11.
[167]
Gribar SC, Sodhi CP, Richardson WM, et al. Reciprocal expression and signaling of TLR4 and TLR9 in the pathogenesis and treatment of necrotizing enterocolitis. J Immunol 2009; 82(1): 636-46.
[168]
Nanthakumar N, Meng D, Goldstein AM, et al. The mechanism of excessive intestinal inflammation in necrotizing enterocolitis: an immature innate immune response. PLoS One 2011; 6(3)e17776
[169]
Chan KYY, Leung KT, Tam YH, et al. Genome-wide expression profiles of necrotizing enterocolitis versus spontaneous intestinal perforation in human intestinal tissues: dysregulation of functional pathways. Ann Surg 2014; 260(6): 1128-37.
[170]
Neal MD, Sodhi CP, Jia H, 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. J Biol Chem 2012; 287(44): 37296-308.
[171]
Afrazi A, Branca MF, Sodhi CP, et al. Toll-like receptor 4-mediated endoplasmic reticulum stress in intestinal crypts induces necrotizing enterocolitis. J Biol Chem 2014; 289(14): 9584-99.
[172]
Sampath V, Menden H, Helbling D, et al. SIGIRR genetic variants in premature infants with necrotizing enterocolitis. Pediatrics 2015; 135(6): e1530-4.
[173]
Yin Y, Liu F, Li Y, Tang R, Wang J. mRNA expression of TLR4, TLR9 and NF-κB in a neonatal murine model of necrotizing enterocolitis. Mol Med Rep 14(3): 1953-6.
[174]
Good M, Sodhi CP, Ozolek JA, 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. Am J Physiol Gastrointest Liver Physiol 2014; 306(11): G1021-32.
[175]
Voss E, Wehkamp J, Wehkamp K, Stange EF, Schröder JM, Harder J. NOD2/CARD15 mediates induction of the antimicrobial peptide human beta-defensin-2. J Biol Chem 2006; 281(4): 2005-11.
[176]
Härtel C, Hartz A, Pagel J, et al. NOD2 Loss-of-Function Mutations and Risks of Necrotizing Enterocolitis or Focal Intestinal Perforation in Very Low-birth-weight Infants. Inflamm Bowel Dis 2016; 22(2): 249-56.
[178]
De Plaen IG, Liu SXL, Tian R, et al. Inhibition of nuclear factor-kappaB ameliorates bowel injury and prolongs survival in a neonatal rat model of necrotizing enterocolitis. Pediatr Res 2007; 61(6): 716-21.
[179]
Minekawa R, Takeda T, Sakata M, et al. Human breast milk suppresses the transcriptional regulation of IL-1beta-induced NF-kappaB signaling in human intestinal cells. Am J Physiol Cell Physiol 2004; 287(5): C1404-11.
[180]
Claud EC, Lu L, Anton PM, Savidge T, Walker WA, Cherayil BJ. Developmentally regulated IkappaB expression in intestinal epithelium and susceptibility to flagellin-induced inflammation. Proc Natl Acad Sci USA 2004; 101(19): 7404-8.
[181]
Lotz M, Gütle D, Walther S, Ménard S, Bogdan C, Hornef MW. Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells. J Exp Med 2006; 203(4): 973-84.
[182]
Chae S, Eckmann L, Miyamoto Y, Pothoulakis C, Karin M, Kagnoff MF. Epithelial cell I kappa B-kinase beta has an important protective role in Clostridium difficile toxin A-induced mucosal injury. J Immunol 2006; 177(2): 1214-20.
[183]
Sampath V, Le M, Lane L, et al. The NFKB1 (g.-24519delATTG) variant is associated with necrotizing enterocolitis (NEC) in premature infants. J Surg Res 2011; 169(1): e51-7.
[184]
Adamzik M, Schäfer S, Frey UH, et al. The NFKB1 promoter polymorphism (-94ins/delATTG) alters nuclear translocation of NF-κB1 in monocytes after lipopolysaccharide stimulation and is associated with increased mortality in sepsis. Anesthesiology 2013; 118(1): 123-33.
[185]
O’Neill LAJ, Bowie AG. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol 2007; 7(5): 353-64.
[186]
Yang G, Bao P, Zhang L, et al. Critical role of myeloid differentiation factor 88 in necrotizing enterocolitis. Pediatr Res 2014; 75(6): 707-15.
[187]
Sodhi CP, Neal MD, Siggers R, et al. Intestinal epithelial Toll-like receptor 4 regulates goblet cell development and is required for necrotizing enterocolitis in mice. Gastroenterology 2012; 143(3): 708-18-e1-5.
[188]
Maheshwari A, Schelonka RL, Dimmitt RA, et al. Cytokines associated with necrotizing enterocolitis in extremely-low-birth-weight infants. Pediatr Res 2014; 76(1): 100-8.
[189]
Edelson MB, Bagwell CE, Rozycki HJ. Circulating pro- and counterinflammatory cytokine levels and severity in necrotizing enterocolitis. Pediatrics 1999; 103(4 Pt 1): 766-71.
[190]
Weitkamp J-H, Koyama T, Rock MT, Correa H, Goettel JA, Matta P, et al. Necrotising enterocolitis is characterised by disrupted immune regulation and diminished mucosal regulatory (FOXP3)/effector (CD4, CD8) T cell ratios. Gut 2013; 62(1): 73-82.
[191]
Dinarello CA, Simon A, van der Meer JWM. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov 2012; 11(8): 633-52.
[192]
Murgas Torrazza R, Li N, Young C, et al. Pilot study using proteomics to identify predictive biomarkers of necrotizing enterocolitis from buccal swabs in very low birth weight infants. Neonatology 2013; 104(3): 234-42.
[193]
Hunter CJ, Singamsetty VK, Chokshi NK, et al. Enterobacter sakazakii enhances epithelial cell injury by inducing apoptosis in a rat model of necrotizing enterocolitis. J Infect Dis 2008; 198(4): 586-93.
[194]
Tanaka T, Kishimoto T. The biology and medical implications of interleukin-6. Cancer Immunol Res 2014; 2(4): 288-94.
[195]
Shimizu H, Yamamoto K. NF-kappa B and C/EBP transcription factor families synergistically function in mouse serum amyloid A gene expression induced by inflammatory cytokines. Gene 1994; 149(2): 305-10.
[196]
Cahill CM, Zhu W, Oziolor E, et al. Differential Expression of the Activator Protein 1 Transcription Factor Regulates Interleukin-1ß Induction of Interleukin 6 in the Developing Enterocyte. Price BD, editor. PLoS One. 2016; 11: p. (1)e0145184.
[197]
Kilpinen S, Hulkkonen J, Wang XY, Hurme M. The promoter polymorphism of the interleukin-6 gene regulates interleukin-6 production in neonates but not in adults. Eur Cytokine Netw 2001; 12(1): 62-8.
[198]
Harris MC, Costarino AT, Sullivan JS, et al. Cytokine elevations in critically ill infants with sepsis and necrotizing enterocolitis. J Pediatr 1994; 124(1): 105-11.
[199]
Duffy LC, Zielezny MA, Carrion V, et al. Concordance of bacterial cultures with endotoxin and interleukin-6 in necrotizing enterocolitis. Dig Dis Sci 1997; 42(2): 359-65.
[200]
Martin CR, Bellomy M, Allred EN, Fichorova RN, Leviton A. Systemic inflammation associated with severe intestinal injury in extremely low gestational age newborns. Fetal Pediatr Pathol 2013; 32(3): 222-34.
[201]
Franklin AL, Said M, Cappiello CD, Gordish-Dressman H, Tatari-Calderone Z, Vukmanovic S, et al. Are Immune Modulating Single Nucleotide Polymorphisms Associated with Necrotizing Enterocolitis? Sci Rep 2015; 5: 18369.
[202]
Benkoe T, Reck C, Gleiss A, et al. Interleukin 8 correlates with intestinal involvement in surgically treated infants with necrotizing enterocolitis. J Pediatr Surg 2012; 47(8): 1548-54.
[203]
Maheshwari A, Lu W, Lacson A, et al. Effects of interleukin-8 on the developing human intestine. Cytokine 2002; 20(6): 256-67.
[204]
Nanthakumar NN, Fusunyan RD, Sanderson I, Walker WA. Inflammation in the developing human intestine: A possible pathophysiologic contribution to necrotizing enterocolitis. Proc Natl Acad Sci USA 2000; 97(11): 6043-8.
[205]
Paul G, Khare V, Gasche C. Inflamed gut mucosa: downstream of interleukin-10. Eur J Clin Invest 2012; 42(1): 95-109.
[206]
Emami CN, Chokshi N, Wang J, et al. Role of interleukin-10 in the pathogenesis of necrotizing enterocolitis. Am J Surg 2012; 203(4): 428-35.
[207]
Zigmond E, Bernshtein B, Friedlander G, et al. Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis. Immunity 2014; 40(5): 720-33.
[208]
Benkoe T, Baumann S, Weninger M, et al. Comprehensive evaluation of 11 cytokines in premature infants with surgical necrotizing enterocolitis. PLoS One 2013; 8(3)e58720
[209]
Garofalo R, Chheda S, Mei F, Palkowetz KH, Rudloff HE, Schmalstieg FC, et al. Interleukin-10 in human milk. Pediatr Res 1995; 37(4 Pt 1): 444-9.
[210]
Fituch CC, Palkowetz KH, Goldman AS, Schanler RJ. Concentrations of IL-10 in preterm human milk and in milk from mothers of infants with necrotizing enterocolitis. Acta Paediatr 2004; 93(11): 1496-500.
[211]
Chheda S, Palkowetz KH, Garofalo R, Rassin DK, Goldman AS. Decreased interleukin-10 production by neonatal monocytes and T cells: relationship to decreased production and expression of tumor necrosis factor-alpha and its receptors. Pediatr Res 1996; 40(3): 475-83.
[212]
Egan CE, Sodhi CP, Good M, Lin J, Jia H, Yamaguchi Y, et al. Toll-like receptor 4-mediated lymphocyte influx induces neonatal necrotizing enterocolitis. J Clin Invest 2016; 126(2): 495-508.
[213]
Niño DF, Sodhi CP, Egan CE, Zhou Q, Lin J, Lu P, et al. Retinoic Acid Improves Incidence and Severity of Necrotizing Enterocolitis by Lymphocyte Balance Restitution and Repopulation of LGR5+ Intestinal Stem Cells. Shock 2017; 47(1): 22-32.
[214]
Tian J, Liu Y, Jiang Y, Zhou H, Zhu T, Zhao X, et al. Association of single nucleotide polymorphisms of IL23R and IL17 with necrotizing enterocolitis in premature infants. Mol Cell Biochem 2017; 430(1-2): 201-9.
[215]
Hunter CJ, De Plaen IG. Inflammatory signaling in NEC: Role of NF-κB, cytokines and other inflammatory mediators. Pathophysiol Off J Int Soc Pathophysiol 2014; 21(1): 55-65.
[216]
Lu J, Caplan MS, Li D, Jilling T. Polyunsaturated fatty acids block platelet-activating factor-induced phosphatidylinositol 3 kinase/Akt-mediated apoptosis in intestinal epithelial cells. AJP Gastrointest Liver Physiol 2008; 294(5): G1181-90.
[217]
Izumi T, Shimizu T. Platelet-activating factor receptor: gene expression and signal transduction. Biochim Biophys Acta 1995; 1259(3): 317-33.
[218]
De Plaen IG, Tan XD, Chang H, Wang L, Remick DG, Hsueh W. Lipopolysaccharide activates nuclear factor kappaB in rat intestine: role of endogenous platelet-activating factor and tumour necrosis factor. Br J Pharmacol 2000; 129(2): 307-14.
[219]
Hsueh W, Caplan MS, Qu X-W, Tan X-D, De Plaen IG, Gonzalez-Crussi F. Neonatal necrotizing enterocolitis: clinical considerations and pathogenetic concepts. Pediatr Dev Pathol 6(1): 6-23.
[220]
Amer MD, Hedlund E, Rochester J, Caplan MS. Platelet-activating factor concentration in the stool of human newborns: effects of enteral feeding and neonatal necrotizing enterocolitis. Biol Neonate 2004; 85(3): 159-66.
[221]
Caplan M, Hsueh W, Kelly A, Donovan M. Serum PAF acetylhydrolase increases during neonatal maturation. Prostaglandins 1990; 39(6): 705-14.
[222]
Caplan MS, Sun XM, Hseuh W, Hageman JR. Role of platelet activating factor and tumor necrosis factor-alpha in neonatal necrotizing enterocolitis. J Pediatr 1990; 116(6): 960-4.
[223]
Baregamian N, Song J, Bailey CE, Papaconstantinou J, Evers BM, Chung DH. Tumor necrosis factor-alpha and apoptosis signal-regulating kinase 1 control reactive oxygen species release, mitochondrial autophagy, and c-Jun N-terminal kinase/p38 phosphorylation during necrotizing enterocolitis. Oxid Med Cell Longev 2009; 2(5): 297-306.
[224]
Yurttutan S, Ozdemir R, Canpolat FE, Oncel MY, Unverdi HG, Uysal B, et al. Beneficial effects of Etanercept on experimental necrotizing enterocolitis. Pediatr Surg Int 2014; 30(1): 71-7.
[225]
Tayman C, Aydemir S, Yakut I, Serkant U, Ciftci A, Arslan E, et al. TNF-α Blockade Efficiently Reduced Severe Intestinal Damage in Necrotizing Enterocolitis. J Invest Surg 2016; 29(4): 209-17.
[226]
Travis MA, Sheppard D. TGF-β activation and function in immunity. Annu Rev Immunol 2014; 32: 51-82.
[227]
Maheshwari A, Kelly DR, Nicola T, Ambalavanan N, Jain SK, Murphy-Ullrich J, et al. TGF-β2 suppresses macrophage cytokine production and mucosal inflammatory responses in the developing intestine. Gastroenterology 2011; 140(1): 242-53.
[228]
Shiou S-R, Yu Y, Guo Y, Westerhoff M, Lu L, Petrof EO, et al. Oral administration of transforming growth factor-β1 (TGF-β1) protects the immature gut from injury via Smad protein-dependent suppression of epithelial nuclear factor κB (NF-κB) signaling and proinflammatory cytokine production. J Biol Chem 2013; 288(48): 34757-66.
[229]
Nguyen DN, Sangild PT, Ostergaard MV, Bering SB, Chatterton DEW. Transforming growth factor-β2 and endotoxin interact to regulate homeostasis via interleukin-8 levels in the immature intestine. Am J Physiol Gastrointest Liver Physiol 2014; 307(7): G689-99.
[230]
Sangild PT, Mei J, Fowden AL, Xu RJ. The prenatal porcine intestine has low transforming growth factor-beta ligand and receptor density and shows reduced trophic response to enteral diets. Am J Physiol Regul Integr Comp Physiol 2009; 296(4): R1053-62.
[231]
Nguyen DN, Jiang P, Jacobsen S, Sangild PT, Bendixen E, Chatterton DEW. Protective Effects of Transforming Growth Factor β2 in Intestinal Epithelial Cells by Regulation of Proteins Associated with Stress and Endotoxin Responses. Weitkamp J-H, editor.PLoS One . 2015; 10: p. (2)e0117608.
[232]
Rautava S, Lu L, Nanthakumar NN, Dubert-Ferrandon A, Walker WA. TGF-β2 Induces Maturation of Immature Human Intestinal Epithelial Cells and Inhibits Inflammatory Cytokine Responses Induced via the NF-κB Pathway. J Pediatr Gastroenterol Nutr 2012; 54(5): 630-8.
[233]
Chatterton DEW, Nguyen DN, Bering SB, Sangild PT. Anti-inflammatory mechanisms of bioactive milk proteins in the intestine of newborns. Int J Biochem Cell Biol 2013; 45(8): 1730-47.
[234]
Frost BL, Jilling T, Lapin B, Maheshwari A, Caplan MS. Maternal breast milk transforming growth factor-beta and feeding intolerance in preterm infants. Pediatr Res 2014; 76(4): 386-93.
[235]
Namachivayam K, Coffing HP, Sankaranarayanan NV, et al. Transforming growth factor-β 2 is sequestered in preterm human milk by chondroitin sulfate proteoglycans. Am J Physiol Gastrointest Liver Physiol 2015; 309(3): G171-80.
[236]
Namachivayam K, Blanco CL, Frost BL, et al. Preterm human milk contains a large pool of latent TGF-, which can be activated by exogenous neuraminidase. AJP Gastrointest Liver Physiol 2013; 304(12): G1055-65.
[237]
Lee W-J. Bacterial-modulated signaling pathways in gut homeostasis. Sci Signal[Internet] 2008; 1(21): pe24.
[238]
Parks DA, Bulkley GB, Granger DN, Hamilton SR, McCord JM. Ischemic injury in the cat small intestine: role of superoxide radicals. Gastroenterology 1982; 82(1): 9-15.
[239]
Baregamian N, Song J, Papaconstantinou J, Hawkins HK, Evers BM, Chung DH. Intestinal mitochondrial apoptotic signaling is activated during oxidative stress. Pediatr Surg Int 2011; 27(8): 871-7.
[240]
Shang Q, Bao L, Guo H, et al. Contribution of glutaredoxin-1 to S-glutathionylation of endothelial nitric oxide synthase for mesenteric nitric oxide generation in experimental necrotizing enterocolitis. Transl Res 2016; 188: 92-105.
[241]
Li X, Li X, Shang Q, Gao Z, et al. Fecal microbiota transplantation (FMT) could reverse the severity of experimental necrotizing enterocolitis (NEC) via oxidative stress modulation. Free Radic Biol Med 2017; 108: 32-43.
[243]
Finkbeiner SR, Hill DR, Altheim CH, et al. Transcriptome-wide Analysis Reveals Hallmarks of Human Intestine Development and Maturation In vitro and In vivo. Stem cell reports 2015; S2213-6711(15): 00122-8.
[244]
Mallow EB, Harris A, Salzman N, et al. Human enteric defensins. Gene structure and developmental expression. J Biol Chem 1996; 23;271(8): 4038-5.
[245]
McElroy SJ, Castle SL, Bernard JK, et al. The ErbB4 ligand neuregulin-4 protects against experimental necrotizing enterocolitis. Am J Pathol 2014; 184(10): 2768-78.
[246]
Almohazey D, Lo Y-H, Vossler CV, Simmons AJ, Hsieh JJ, Bucar EB, et al. The ErbB3 receptor tyrosine kinase negatively regulates Paneth cells by PI3K-dependent suppression of Atoh1. Cell Death Differ 2017; 24(5): 855-65.
[247]
Takahashi N, Vanlaere I, de Rycke R, et al. IL-17 produced by Paneth cells drives TNF-induced shock. J Exp Med 2008; 205(8): 1755-61.
[248]
McElroy SJ, Prince LS, Weitkamp J-H, Reese J, Slaughter JC, Polk DB. Tumor necrosis factor receptor 1-dependent depletion of mucus in immature small intestine: a potential role in neonatal necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 2011; 301(4): G656-66.
[249]
Schaart MW, de Bruijn ACJM, Bouwman DM, de Krijger RR, van Goudoever JB, Tibboel D, et al. Epithelial functions of the residual bowel after surgery for necrotising enterocolitis in human infants. J Pediatr Gastroenterol Nutr 2009; 49(1): 31-41.
[250]
Remon JI, Amin SC, Mehendale SR, Rao R, Luciano AA, Garzon SA, et al. Depth of bacterial invasion in resected intestinal tissue predicts mortality in surgical necrotizing enterocolitis. J Perinatol 2015; 35(9): 755-62.
[251]
Tremblay É, Thibault M-P, Ferretti E, Babakissa C, Bertelle V, Bettolli M, et al. Gene expression profiling in necrotizing enterocolitis reveals pathways common to those reported in Crohn’s disease. BMC Med Genomics 2016; 9: 6.
[252]
MohanKumar K, Kaza N, Jagadeeswaran R, et al. Gut mucosal injury in neonates is marked by macrophage infiltration in contrast to pleomorphic infiltrates in adult: evidence from an animal model.. Am J Physiol Gastrointest Liver Physiol 2012; 303(1): G93-102.
[253]
Emami CN, Mittal R, Wang L, Ford HR, Prasadarao NV. Role of neutrophils and macrophages in the pathogenesis of necrotizing enterocolitis caused by Cronobacter sakazakii. J Surg Res 2012; 172(1): 18-28.
[254]
Schüller SS, Sadeghi K, Wisgrill L, Dangl A, Diesner SC, Prusa AR, et al. Preterm neonates display altered plasmacytoid dendritic cell function and morphology. J Leukoc Biol 2013; 93(5): 781-8.
[255]
Merrill JD, Sigaroudinia M, Kohl S. Characterization of natural killer and antibody-dependent cellular cytotoxicity of preterm infants against human immunodeficiency virus-infected cells. Pediatr Res 1996; 40(3): 498-503.
[256]
MohanKumar K, Namachivayam K, Chapalamadugu KC, et al. Smad7 interrupts TGF-β signaling in intestinal macrophages and promotes inflammatory activation of these cells during necrotizing enterocolitis.. Pediatr Res 2016; 79(6): 951-61. Available from:.http://www.ncbi.nlm.nih.gov/pubmed/26859364
[257]
Remon J, Kampanatkosol R, Kaul RR, Muraskas JK, Christensen RD, Maheshwari A. Acute drop in blood monocyte count differentiates NEC from other causes of feeding intolerance. J Perinatol 2014; 34(7): 549-54.
[258]
Denning TW, Bhatia AM, Kane AF, Patel RM, Denning PW. Pathogenesis of NEC: Role of the innate and adaptive immune response. Semin Perinatol 2017; 41(1): 15-28.
[259]
Weitkamp J-H, Rosen MJ, Zhao Z, Koyama T, Geem D, Denning TL, et al. Small intestinal intraepithelial TCRγδ+ T lymphocytes are present in the premature intestine but selectively reduced in surgical necrotizing enterocolitis. PLoS One 2014; 9(6)e99042
[260]
Hui L, Dai Y, Guo Z, Zhang J, Zheng F, Bian X, et al. Immunoregulation effects of different γδT cells and toll-like receptor signaling pathways in neonatal necrotizing enterocolitis. Medicine (Baltimore) 2017; 96(8)e6077
[261]
Bochennek K, Fryns E, Wittekindt B, Buxmann H, Quaiser A, Fischer D, et al. Immune cell subsets at birth may help to predict risk of late-onset sepsis and necrotizing enterocolitis in preterm infants. Early Hum Dev 2016; 93: 9-16.
[262]
Vignali DAA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol 2008; 8(7): 523-32.
[263]
Dingle BM, Liu Y, Fatheree NY, Min J, Rhoads JM, Tran DQ. FoxP3+ regulatory T cells attenuate experimental necrotizing enterocolitis. PLoS One 2013; 8(12)e82963
[264]
Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol 2010; 10(7): 490-500.
[265]
Lu P, Struijs M-C, Mei J, Witte-Bouma J, Korteland-van Male AM, de Bruijn ACJM, et al. Endoplasmic reticulum stress, unfolded protein response and altered T cell differentiation in necrotizing enterocolitis. PLoS One 2013; 8(10)e78491
[266]
Ohlsson A, Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2013; (7): CD000361
[267]
Bush TG, Savidge TC, Freeman TC, Cox HJ, Campbell EA, Mucke L, et al. Fulminant jejuno-ileitis following ablation of enteric glia in adult transgenic mice. Cell 1998; 93(2): 189-201.
[268]
Zhou Y, Yang J, Watkins DJ, Boomer LA, Matthews MA, Su Y, et al. Enteric nervous system abnormalities are present in human necrotizing enterocolitis: potential neurotransplantation therapy. Stem Cell Res Ther 2013; 4(6): 157.
[269]
Bhandari V, Bizzarro MJ, Shetty A, Zhong X, Page GP, Zhang H, et al. Familial and genetic susceptibility to major neonatal morbidities in preterm twins. Pediatrics 2006; 117(6): 1 901-6.
[270]
Bhandari V, Gruen JR. What is the basis for a genetic approach in neonatal disorders? Semin Perinatol 2015; 39(8): 568-73.
[271]
Sampath V, Bhandari V, Berger J, et al. A functional ATG16L1 (T300A) variant is associated with necrotizing enterocolitis in premature infants. Pediatr Res 2017; 81(4): 582-8.
[272]
Sampath V, Helbling D, Menden H, et al. Necrotizing Enterocolitis Is Not Associated With Sequence Variants in Antioxidant Response Genes in Premature Infants. J Pediatr Gastroenterol Nutr 2016; 62(3): 420-3.
[273]
Demmert M, Schaper A, Pagel J, et al. FUT 2 polymorphism and outcome in very-low-birth-weight infants. Pediatr Res 2015; 77(4): 586-90.
[274]
Moonen RM, Cavallaro G, Huizing MJ, González-Luis GE, Mosca F, Villamor E. Association between the p.Thr1406Asn polymorphism of the carbamoyl-phosphate synthetase 1 gene and necrotizing enterocolitis: A prospective multicenter study. Sci Rep 2016; 6: 36999.
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