Advertisement

Recent Advances in Prevention and Therapies for Clinical or Experimental Necrotizing Enterocolitis

  • Kewei WangEmail author
  • Guozhong Tao
  • Karl G. Sylvester
Review

Abstract

Necrotizing enterocolitis (NEC) is one of the most severe diseases of preterm neonates and has a high mortality rate. With the development of inspection techniques and new biomarkers, the diagnostic accuracy of NEC is constantly improving. The most recognized potential risk factors include prematurity, formula-feeding, infection, and microbial dysbiosis. With further understanding of the pathogenesis, more effective prevention and therapies will be applied to clinical or experimental NEC. At present, such new potential prevention and therapies for NEC are mainly focused on the Toll-like receptor 4 inflammatory signaling pathway, the repair of intestinal barrier function, probiotics, antioxidative stress, breast-feeding, and immunomodulatory agents. Many new studies have changed our understanding of the pathogenesis of NEC and improve our approaches for preventing and treating of NEC each year. This review provides an overview of the recent researches focused on clinical or experimental NEC and highlights the advances made within the past 5 years toward the development of new potential preventive approaches and therapies for this disease.

Keywords

Necrotizing enterocolitis NEC Toll-like receptor Treatment Preterm neonate Prevention 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Fitzgibbons SC, Ching Y, Yu D, et al. Mortality of necrotizing enterocolitis expressed by birth weight categories. J Pediatr Surg. 2009;44:1072–1075; discussion 1075–1076.CrossRefGoogle Scholar
  2. 2.
    McElroy SJ. Unraveling the enigma that is neonatal necrotizing enterocolitis. J Perinatol. 2014;34:729–730.CrossRefGoogle Scholar
  3. 3.
    Sankaran K, Puckett B, Lee DS, et al. Variations in incidence of necrotizing enterocolitis in Canadian neonatal intensive care units. J Pediatr Gastroenterol Nutr. 2004;39:366–372.CrossRefGoogle Scholar
  4. 4.
    Good M, Sodhi CP, Hackam DJ. Evidence-based feeding strategies before and after the development of necrotizing enterocolitis. Expert Rev Clin Immunol. 2014;10:875–884.CrossRefGoogle Scholar
  5. 5.
    Berkhout D, Klaassen P, Niemarkt HJ, et al. Risk factors for necrotizing enterocolitis: a prospective multicenter case-control study. Neonatology. 2018;114:277–284.CrossRefGoogle Scholar
  6. 6.
    Neu J, Pammi M. Pathogenesis of NEC: impact of an altered intestinal microbiome. Semin Perinatol. 2017;41:29–35.CrossRefGoogle Scholar
  7. 7.
    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;387:1928–1936.CrossRefGoogle Scholar
  8. 8.
    Elgin TG, Kern SL, McElroy SJ. Development of the neonatal intestinal microbiome and its association with necrotizing enterocolitis. Clin Ther. 2016;38:706–715.CrossRefGoogle Scholar
  9. 9.
    Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med. 2011;364:255–264.CrossRefGoogle Scholar
  10. 10.
    Sharma R, Hudak ML. A clinical perspective of necrotizing enterocolitis: past, present, and future. Clin Perinatol. 2013;40:27–51.CrossRefGoogle Scholar
  11. 11.
    Hunter CJ, De Plaen IG. Inflammatory signaling in NEC: role of NF-κB, cytokines and other inflammatory mediators. Pathophysiology. 2014;21:55–65.CrossRefGoogle Scholar
  12. 12.
    Egan CE, Sodhi CP, Good M, et al. Toll-like receptor 4-mediated lymphocyte influx induces neonatal necrotizing enterocolitis. J Clin Invest. 2016;126:495–508.CrossRefGoogle Scholar
  13. 13.
    Lu P, Sodhi CP, Hackam DJ. Toll-like receptor regulation of intestinal development and inflammation in the pathogenesis of necrotizing enterocolitis. Pathophysiology. 2014;21:81–93.CrossRefGoogle Scholar
  14. 14.
    Hackam DJ, Sodhi CP, Good M. New insights into necrotizing enterocolitis: from laboratory observation to personalized prevention and treatment. J Pediatr Surg. 2019;54:398–404.CrossRefGoogle Scholar
  15. 15.
    Zhou Y, Li Y, Zhou B, et al. Inflammation and apoptosis: dual mediator role for toll-like receptor 4 in the development of necrotizing enterocolitis. Inflamm Bowel Dis. 2017;23:44–56.CrossRefGoogle Scholar
  16. 16.
    Huang K, Mukherjee S, DesMarais V, et al. Targeting the PXR-TLR4 signaling pathway to reduce intestinal inflammation in an experimental model of necrotizing enterocolitis. Pediatr Res. 2018;83:1031–1040.CrossRefGoogle Scholar
  17. 17.
    Hou Y, Lu X, Zhang Y. IRAK inhibitor protects the intestinal tract of necrotizing enterocolitis by inhibiting the toll-like receptor (TLR) inflammatory signaling pathway in rats. Med Sci Monit. 2018;24:3366–3373.CrossRefGoogle Scholar
  18. 18.
    Tian F, Liu GR, Li N, Yuan G. Insulin-like growth factor I reduces the occurrence of necrotizing enterocolitis by reducing inflammatory response and protecting intestinal mucosal barrier in neonatal rats model. Eur Rev Med Pharmacol Sci. 2017;21:4711–4719.Google Scholar
  19. 19.
    Shi Y, Liu T, Zhao X, et al. Vitamin D ameliorates neonatal necrotizing enterocolitis via suppressing TLR4 in a murine model. Pediatr Res. 2018;83:1024–1030.CrossRefGoogle Scholar
  20. 20.
    Qi W, Shen Q, Zhang L, Han LP, Wang S. Study on the inflammatory intervention of erythropoietin on NEC. Exp Ther Med. 2016;11:2221–2224.CrossRefGoogle Scholar
  21. 21.
    Wipf P, Eyer BR, Yamaguchi Y, et al. Synthesis of anti-inflammatory α-and β-linked acetamidopyranosides as inhibitors of toll-like receptor 4 (TLR4). Tetrahedron Lett. 2015;56:3097–3100.CrossRefGoogle Scholar
  22. 22.
    Bein A, Eventov-Friedman S, Arbell D, Schwartz B. Intestinal tight junctions are severely altered in NEC preterm neonates. Pediatr Neonatol. 2018;59:464–473.CrossRefGoogle Scholar
  23. 23.
    Halpern MD, Denning PW. The role of intestinal epithelial barrier function in the development of NEC. Tissue Barriers. 2015;3:e1000707.CrossRefGoogle Scholar
  24. 24.
    Grothaus JS, Ares G, Yuan C, Wood DR, Hunter CJ. Rho kinase inhibition maintains intestinal and vascular barrier function by upregulation of occludin in experimental necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol. 2018;315:G514–G528.CrossRefGoogle Scholar
  25. 25.
    Xiao S, Li Q, Hu K, et al. Vitamin A and retinoic acid exhibit protective effects on necrotizing enterocolitis by regulating intestinal flora and enhancing the intestinal epithelial barrier. Arch Med Res. 2018;49:1–9.CrossRefGoogle Scholar
  26. 26.
    Denkel LA, Schwab F, Garten L, Geffers C, Gastmeier P, Piening B. Dual-strain probiotics reduce NEC, mortality and neonatal bloodstream infections among extremely low birthweight infants. Arch Dis Child Fetal Neonatal Ed. 2017;102:F559–F560.CrossRefGoogle Scholar
  27. 27.
    Denkel LA, Schwab F, Garten L, Geffers C, Gastmeier P, Piening B. Protective effect of dual-strain probiotics in preterm infants: a multi-center time series analysis. PLoS ONE. 2016;11:e0158136.CrossRefGoogle Scholar
  28. 28.
    Wu W, Wang Y, Zou J, et al. Bifidobacterium adolescentis protects against necrotizing enterocolitis and upregulates TOLLIP and SIGIRR in premature neonatal rats. BMC Pediatr. 2017;17:1.CrossRefGoogle Scholar
  29. 29.
    Ling X, Linglong P, Weixia D, Hong W. Protective effects of bifidobacterium on intestinal barrier function in LPS-induced enterocyte barrier injury of Caco-2 monolayers and in a rat NEC model. PLoS ONE. 2016;11:e0161635.CrossRefGoogle Scholar
  30. 30.
    Zhu XL, Tang XG, Qu F, Zheng Y, Zhang WH, Diao YQ. Bifidobacterium may benefit the prevention of necrotizing enterocolitis in preterm infants: a systematic review and meta-analysis. Int J Surg. 2019;61:17–25.CrossRefGoogle Scholar
  31. 31.
    Olson JK, Navarro JB, Allen JM, et al. An enhanced Lactobacillus reuteri biofilm formulation that increases protection against experimental necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol. 2018;315:G408–G419.CrossRefGoogle Scholar
  32. 32.
    Fleming P, Hall NJ, Eaton S. Probiotics and necrotizing enterocolitis. Pediatr Surg Int. 2015;31:1111–1118.CrossRefGoogle Scholar
  33. 33.
    Olson JK, Rager TM, Navarro JB, Mashburn-Warren L, Goodman SD, Besner GE. Harvesting the benefits of biofilms: a novel probiotic delivery system for the prevention of necrotizing enterocolitis. J Pediatr Surg. 2016;51:936–941.CrossRefGoogle Scholar
  34. 34.
    Singh B, Shah PS, Afifi J, et al. Probiotics for preterm infants: a national retrospective cohort study. J Perinatol. 2019;28:1.Google Scholar
  35. 35.
    Floch MH, Walker WA, Sanders ME, et al. Recommendations for probiotic use–2015 update: proceedings and consensus opinion. J Clin Gastroenterol. 2015;49:S69–73.CrossRefGoogle Scholar
  36. 36.
    Underwood MA. Probiotics and the prevention of necrotizing enterocolitis. J Pediatr Surg. 2019;54:405–412.CrossRefGoogle Scholar
  37. 37.
    Kane AF, Bhatia AD, Denning PW, Shane AL, Patel RM. Routine supplementation of Lactobacillus rhamnosus GG and risk of necrotizing enterocolitis in very low birth weight infants. J Pediatr. 2018;195:e2.CrossRefGoogle Scholar
  38. 38.
    Perrone S, Tataranno ML, Santacroce A, Negro S, Buonocore G. The role of oxidative stress on necrotizing enterocolitis in very low birth weight infants. Curr Pediatr Rev. 2014;10:202–207.Google Scholar
  39. 39.
    Buyuktiryaki M, Tayman C, Koyuncu I, et al. Therapeutic and preventative effects of ankaferd blood stopper in an experimental necrotizing enterocolitis model. Biomed Pharmacother. 2019;110:105–110.CrossRefGoogle Scholar
  40. 40.
    Yazıcı S, Ozcan CU, Hismiogullari AA, et al. Protective effects of quercetin on necrotizing enterocolitis in a neonatal rat model. Am J Perinatol. 2018;35:434–440.CrossRefGoogle Scholar
  41. 41.
    Cigsar EB, Ali Karadag C, Tanik C, Fatih Aydin A, Ihsan Dokucu A. The protective effects of sesamol in a neonatal rat model of necrotizing enterocolitis. J Matern Fetal Neonatal Med. 2018;2018:1–6.CrossRefGoogle Scholar
  42. 42.
    Cakir U, Tayman C, Serkant U, et al. Ginger (Zingiber officinale Roscoe) for the treatment and prevention of necrotizing enterocolitis. J Ethnopharmacol. 2018;225:297–308.CrossRefGoogle Scholar
  43. 43.
    Zhang L, Fan J, He J, et al. Regulation of ROS-NF-κB axis by tuna backbone derived peptide ameliorates inflammation in necrotizing enterocolitis. J Cell Physiol. 2019.  https://doi.org/10.1002/jcp.28133.Google Scholar
  44. 44.
    Niemarkt HJ, de Meij TG, van de Velde ME, et al. Necrotizing enterocolitis: a clinical review on diagnostic biomarkers and the role of the intestinal microbiota. Inflamm Bowel Dis. 2015;21:436–444.CrossRefGoogle Scholar
  45. 45.
    Li X, Li X, Shang Q, 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.CrossRefGoogle Scholar
  46. 46.
    Cacho NT, Parker LA, Neu J. Necrotizing enterocolitis and human milk feeding: a systematic review. Clin Perinatol. 2017;44:49–67.CrossRefGoogle Scholar
  47. 47.
    Aceti A, Beghetti I, Martini S, Faldella G, Corvaglia L. Oxidative stress and necrotizing enterocolitis: pathogenetic mechanisms, opportunities for intervention, and role of human milk. Oxid Med Cell Longev. 2018;2018:7397659.CrossRefGoogle Scholar
  48. 48.
    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 Perinatol. 2016;36:221–224.CrossRefGoogle Scholar
  49. 49.
    Autran CA, Kellman BP, Kim JH, et al. Human milk oligosaccharide composition predicts risk of necrotising enterocolitis in preterm infants. Gut. 2018;67:1064–1070.CrossRefGoogle Scholar
  50. 50.
    Armanian AM, Sadeghnia A, Hoseinzadeh M, et al. The effect of neutral oligosaccharides on reducing the incidence of necrotizing enterocolitis in preterm infants: a randomized clinical trial. Int J Prev Med. 2014;5:1387–1395.Google Scholar
  51. 51.
    Isani MA, Delaplain PT, Grishin A, Ford HR. Evolving understanding of neonatal necrotizing enterocolitis. Curr Opin Pediatr. 2018;30:417–423.CrossRefGoogle Scholar
  52. 52.
    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;8:1166–1179.CrossRefGoogle Scholar
  53. 53.
    Isani M, Illingworth L, Herman E, et al. Soybean-derived recombinant human epidermal growth factor protects against experimental necrotizing enterocolitis. J Pediatr Surg. 2018;53:1203–1207.CrossRefGoogle Scholar
  54. 54.
    Pammi M, Suresh G. Enteral lactoferrin supplementation for prevention of sepsis and necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev. 2017;6:CD007137.Google Scholar
  55. 55.
    Pammi M, Abrams SA. Oral lactoferrin for the prevention of sepsis and necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev. 2015;2015:CD007137.Google Scholar
  56. 56.
    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;31:1111–1120.CrossRefGoogle Scholar
  57. 57.
    He Y, Cao L, Yu J. Prophylactic lactoferrin for preventing late-onset sepsis and necrotizing enterocolitis in preterm infants: a PRISMA-compliant systematic review and meta-analysis. Medicine (Baltimore). 2018;97:e11976.CrossRefGoogle Scholar
  58. 58.
    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:S60–65.CrossRefGoogle Scholar
  59. 59.
    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:G310–323.CrossRefGoogle Scholar
  60. 60.
    Li B, Hock A, Wu RY, et al. Bovine milk-derived exosomes enhance goblet cell activity and prevent the development of experimental necrotizing enterocolitis. PLoS ONE. 2019;14:e0211431.CrossRefGoogle Scholar
  61. 61.
    Matheson PJ, Walker SK, Maki AC, Shaheen SP, Neal Garrison R, Downard CD. Oral relaxin maintains intestinal blood flow in a rat model of NEC. J Pediatr Surg. 2014;49:961–964; discussion 964–965.CrossRefGoogle Scholar
  62. 62.
    McElroy SJ, Castle SL, Bernard JK, et al. The ErbB4 ligand neuregulin-4 protects against experimental necrotizing enterocolitis. Am J Pathol. 2014;184:2768–2778.CrossRefGoogle Scholar
  63. 63.
    Maheshwari A. Immunologic and hematological abnormalities in necrotizing enterocolitis. Clin Perinatol. 2015;42:567–585.CrossRefGoogle Scholar
  64. 64.
    Feng Z, Zhou H, Ma S, et al. FTY720 attenuates intestinal injury and suppresses inflammation in experimental necrotizing enterocolitis via modulating CXCL5/CXCR64 axis. Biochem Biophys Res Commun. 2018;505:1032–1037.CrossRefGoogle Scholar
  65. 65.
    Zhou P, Li Y, Ma LY, Lin HC. The role of immunonutrients in the prevention of necrotizing enterocolitis in preterm very low birth weight infants. Nutrients. 2015;7:7256–7270.CrossRefGoogle Scholar
  66. 66.
    Garg BD, Kabra NS. Role of amino acid supplementation in the prevention of necrotizing enterocolitis in preterm neonates—a review of current evidences. J Matern Fetal Neonatal Med. 2018;31:2349–2366.CrossRefGoogle Scholar
  67. 67.
    Shah PS, Shah VS, LE Kelly. Arginine supplementation for prevention of necrotising enterocolitis in preterm infants. Cochrane Database Syst Rev. 2017;4:CD004339.Google Scholar
  68. 68.
    El-Shimi MS, Awad HA, Abdelwahed MA, Mohamed MH, Khafagy SM, Saleh G. Enteral l-arginine and glutamine supplementation for prevention of NEC in preterm neonates. Int J Pediatr. 2015;2015:856091.CrossRefGoogle Scholar
  69. 69.
    Zani A, Cananzi M, Fascetti-Leon F, et al. Amniotic fluid stem cells improve survival and enhance repair of damaged intestine in necrotising enterocolitis via a COX-2 dependent mechanism. Gut. 2014;63:300–309.CrossRefGoogle Scholar
  70. 70.
    Wei J, Zhou Y, Besner GE. Heparin-binding EGF-like growth factor and enteric neural stem cell transplantation in the prevention of experimental necrotizing enterocolitis in mice. Pediatr Res. 2015;78:29–37.CrossRefGoogle Scholar
  71. 71.
    Bowker RM, Yan X, Managlia E, et al. Dimethyloxalylglycine preserves the intestinal microvasculature and protects against intestinal injury in a neonatal mouse NEC model: role of VEGF signaling. Pediatr Res. 2018;83:545–553.CrossRefGoogle Scholar
  72. 72.
    Corsini I, Polvani S, Tarocchi M, et al. Peroxisome proliferator-activated receptor-γ agonist pioglitazone reduces the development of necrotizing enterocolitis in a neonatal preterm rat model. Pediatr Res. 2017;81:364–368.CrossRefGoogle Scholar
  73. 73.
    Klinke M, Vincent D, Trochimiuk M, et al. Degradation of extracellular DNA significantly ameliorates necrotizing enterocolitis severity in mice. J Surg Res. 2019;235:513–520.CrossRefGoogle Scholar
  74. 74.
    Yin Y, Qin Z, Xu X, et al. Inhibition of miR-124 improves neonatal necrotizing enterocolitis via an MYPT1 and TLR9 signal regulation mechanism. J Cell Physiol. 2019;234:10218–10224.CrossRefGoogle Scholar
  75. 75.
    Blackwood BP, Wood DR, Yuan C, et al. A role for cAMP and protein kinase a in experimental necrotizing enterocolitis. Am J Pathol. 2017;187:401–417.CrossRefGoogle Scholar
  76. 76.
    Al-Wassia H, Shah PS. Efficacy and safety of umbilical cord milking at birth: a systematic review and meta-analysis. JAMA Pediatr. 2015;169:18–25.CrossRefGoogle Scholar
  77. 77.
    Sekhon MK, Yoder BA. Impact of umbilical cord milking and pasteurized donor human milk on necrotizing enterocolitis: a retrospective review. BMC Pediatr. 2018;18:155.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Gastrointestinal SurgeryThe First Hospital of China Medical UniversityShenyangChina
  2. 2.Department of SurgeryStanford University School of MedicineStanfordUSA

Personalised recommendations