MICROBIOTA

microbiotakapak

EXPLORING NECROTIZING ENTEROCOLITIS AND MICROBIOTA

Handan Bezirganoğlu

Trabzon Kanuni Training and Research Hospital, Department of Neonatology, Trabzon, Türkiye

Bezirganoğlu H. Exploring Necrotizing Enterocolitis and Microbiota. Melek İM, Aydoğan S, ed. Microbiota. 1st ed. Ankara: Türkiye Klinikleri; 2025. p.63-71.

ABSTRACT

Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease in preterm infants, often leading to significant complications and high mortality. Despite advancements in neonatal care, the incidence of NEC and its associated mortality rates have remained unchanged over time. The disease is characterized by inflammation, intestinal ischemia, and bacterial invasion, often progressing to sepsis. NEC’s pathophysiology is not yet fully understood; however, its multifaceted pathogenesis is thought to involve the immaturity of the immune system and gut barrier, coupled with exaggerated inflammatory responses to triggers such as gut hypoxia, enteral feeding, and microbial dysbiosis. Emerging evidence indicates that gut microbiota plays a critical role in NEC development, and identifying specific microbial patterns or pathogens associated with the disease could potentially expand therapeutic options. In this chapter, we aim to review the current knowledge regarding the role of the intestinal microbiota in the pathogenesis of NEC.

Keywords: Gut microbiota; NEC; Dysbiosis; Prematurity

Referanslar

  1. Lin PW, Stoll BJ. Necrotising enterocolitis. Lancet. 2006;368(9543):1271-83. [Crossref]  [PubMed]
  2. Stoll BJ, Hansen NI, Bell EF, Walsh MC, Carlo WA, Shankaran S,et al. ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993-2012. JAMA.2015;314(10):1039-51. [Link]
  3. Alsaied A, Islam N, Thalib L. Global incidence of Necrotizing Enterocolitis: a systematic review and Meta-analysis. BMC Pediatr. 2020;20(1):344. [Crossref]  [PubMed]  [PMC]
  4. Fitzgibbons SC, Ching Y, Yu D, Carpenter J, Kenny M, Weldon C, et al. Mortality of necrotizing enterocolitis expressed by birth weight categories. J Pediatr Surg. 2009;44(6):1072-5 [Crossref]  [PubMed]
  5. Shah TA, Meinzen-Derr J, Gratton T, Steichen J, Donovan EF, Yolton K, et al. Hospital and neurodevelopmental outcomes of extremely low-birth-weight infants with necrotizing enterocolitis and spontaneous intestinal perforation. J Perinatol. 2012;32(7):552-8. [Crossref]  [PubMed]  [PMC]
  6. Hackam DJ, Sodhi CP. Bench to bedside - new insights into the pathogenesis of necrotizing enterocolitis. Nat Rev Gastroenterol Hepatol. 2022;19(7):468-479. [Crossref]  [PubMed]
  7. Tanner SM, Berryhill TF, Ellenburg JL, Jilling T, Cleveland DS, Lorenz RG, et al. Pathogenesis of necrotizing enterocolitis: modeling the innate immune response. Am J Pathol. 2015;185(1):4-16. [Crossref]  [PubMed]  [PMC]
  8. Maheshwari A, Traub TM, Garg PM, Ethawi Y, Buonocore G. Necrotizing Enterocolitis: Clinical Features, Histopathological Characteristics, and Genetic Associations. Curr Pediatr Rev. 2022;18(3):210-225 [Crossref]  [PubMed]
  9. Ahle M, Drott P, Elfvin A, Andersson RE. Maternal, fetal and perinatal factors associated with necrotizing enterocolitis in Sweden. A national case-control study. PLoS One. 2018;13(3):e0194352 [Crossref]  [PubMed]  [PMC]
  10. Duci M, Frigo AC, Visentin S, Verlato G, Gamba P, Fascetti-Leon F. Maternal and placental risk factors associated with the development of necrotizing enterocolitis (NEC) and its severity. J Pediatr Surg. 2019;54(10):2099-2102. [Crossref]  [PubMed]
  11. Rose AT, Patel RM. A critical analysis of risk factors for necrotizing enterocolitis. Semin Fetal Neonatal Med. 2018;23(6):374-379 [Crossref]  [PubMed]  [PMC]
  12. Samuels N, van de Graaf RA, de Jonge RCJ, Reiss IKM, Vermeulen MJ. Risk factors for necrotizing enterocolitis in neonates: a systematic review of prognostic studies. BMC Pediatr. 2017;17(1):105. [Crossref]  [PubMed]  [PMC]
  13. Altobelli E, Angeletti PM, Verrotti A, Petrocelli R. The Impact of Human Milk on Necrotizing Enterocolitis: A Systematic Review and Meta-Analysis. Nutrients. 2020;12(5):1322. [Crossref]  [PubMed]  [PMC]
  14. Bresesti I, Salvatore S, Valetti G, Baj A, Giaroni C, Agosti M. The Microbiota-Gut Axis in Premature Infants: Physio-Pathological Implications. Cells. 2022;11(3):379. [Crossref]  [PubMed]  [PMC]
  15. Lee JS, Polin RA. Treatment and prevention of necrotizing enterocolitis. Semin Neonatol. 2003;8(6):449-59. [Crossref]  [PubMed]
  16. Kaplina A, Kononova S, Zaikova E, Pervunina T, Petrova N, Sitkin S. Necrotizing Enterocolitis: The Role of Hypoxia, Gut Microbiome, and Microbial Metabolites. Int J Mol Sci. 2023;24(3):2471. [Crossref]  [PubMed]  [PMC]
  17. Hackam D, Caplan M. Necrotizing enterocolitis: Pathophysiology from a historical context. Semin Pediatr Surg. 2018;27(1):11-18 [Crossref]  [PubMed]  [PMC]
  18. Sodhi CP, Neal MD, Siggers R, Sho S, Ma C, Branca MF, et al. Intestinal epithelial Toll-like receptor 4 regulates goblet cell development and is required for necrotizing enterocolitis in mice. Gastroenterology. 2012;143(3):708-718.e5. [Crossref]  [PubMed]  [PMC]
  19. Neal MD, Leaphart C, Levy R, Prince J, Billiar TR, Watkins S, et al. Enterocyte TLR4 mediates phagocytosis and translocation of bacteria across the intestinal barrier. J Immunol. 2006;176(5):3070-9. [Crossref]  [PubMed]
  20. Yazji I, Sodhi CP, Lee EK, Good M, Egan CE, Afrazi A, et al. Endothelial TLR4 activation impairs intestinal microcirculatory perfusion in necrotizing enterocolitis via eNOS-NO-nitrite signaling. Proc Natl Acad Sci U S A. 2013;110(23):9451-6. [Crossref]  [PubMed]  [PMC]
  21. Ciesielska A, Matyjek M, Kwiatkowska K. TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling. Cell Mol Life Sci. 2021;78(4):1233-1261. [Crossref]  [PubMed]  [PMC]
  22. Chen Y, Koike Y, Chi L, Ahmed A, Miyake H, Li B, et al. Formula feeding and immature gut microcirculation promote intestinal hypoxia, leading to necrotizing enterocolitis. Dis Model Mech. 2019;12(12):dmm040998. [Crossref]  [PubMed]  [PMC]
  23. Stappenbeck TS, Hooper LV, Gordon JI. Developmental regulation of intestinal angiogenesis by indigenous microbes via Paneth cells. Proc Natl Acad Sci U S A. 2002;99(24):15451-5. [Crossref]  [PubMed]  [PMC]
  24. Chen Y, Chang KT, Lian DW, Lu H, Roy S, Laksmi NK, et al. The role of ischemia in necrotizing enterocolitis. J Pediatr Surg. 2016;51(8):1255-61 [Crossref]  [PubMed]
  25. Park AM, Sanders TA, Maltepe E. Hypoxia-inducible factor (HIF) and HIF-stabilizing agents in neonatal care. Semin Fetal Neonatal Med. 2010;15(4):196-202. [Crossref]  [PubMed]  [PMC]
  26. Bowker RM, Yan X, De Plaen IG. Intestinal microcirculation and necrotizing enterocolitis: The vascular endothelial growth factor system. Semin Fetal Neonatal Med. 2018;23(6):411-415. [Crossref]  [PubMed]
  27. Thursby E, Juge N. Introduction to the human gut microbiota. Biochem J. 2017;474(11):1823-1836. [Crossref]  [PubMed]  [PMC]
  28. Walter J, Hornef MW. A philosophical perspective on the prenatal in utero microbiome debate. Microbiome. 2021;9(1):5. [Crossref]  [PubMed]  [PMC]
  29. Jost T, Lacroix C, Braegger CP, Chassard C. New insights in gut microbiota establishment in healthy breast fed neonates. PLoS One. 2012;7(8):e44595. [Crossref]  [PubMed]  [PMC]
  30. La Rosa PS, Warner BB, Zhou Y, Weinstock GM, Sodergren E, Hall-Moore CM, et al. Patterned progression of bacterial populations in the premature infant gut. Proc Natl Acad Sci U S A. 2014;111(34):12522-7. [Crossref]  [PubMed]  [PMC]
  31. Dominguez-Bello MG, Costello EK, Contreras M, Magris M, Hidalgo G, Fierer N, et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A. 2010;107(26):11971-5. [Crossref]  [PubMed]  [PMC]
  32. Vilchez-Vargas R, Skieceviciene J, Lehr K, Varkalaite G, Thon C, Urba M, et al. A. Gut microbial similarity in twins is driven by shared environment and aging. EBioMedicine. 2022;79:104011. [Crossref]  [PubMed]  [PMC]
  33. Claud EC, Keegan KP, Brulc JM, Lu L, Bartels D, Glass E,et al. Bacterial community structure and functional contributions to emergence of health or necrotizing enterocolitis in preterm infants. Microbiome. 2013;1(1):20. [Crossref]  [PubMed]  [PMC]
  34. Arboleya S, Martinez-Camblor P, Solís G, Suárez M, Fernández N, de Los Reyes-Gavilán CG, et al. Intestinal Microbiota and Weight-Gain in Preterm Neonates. Front Microbiol. 2017;8:183 [Crossref]  [PubMed]  [PMC]
  35. Arboleya S, Sánchez B, Milani C, Duranti S, Solís G, Fernández N, et al. Intestinal microbiota development in preterm neonates and effect of perinatal antibiotics. J Pediatr. 2015;166(3):538-44. [Crossref]  [PubMed]
  36. Cong X, Judge M, Xu W, Diallo A, Janton S, Brownell EA, et al. Influence of Feeding Type on Gut Microbiome Development in Hospitalized Preterm Infants. Nurs Res. 2017;66(2):123-133. [Crossref]  [PubMed]  [PMC]
  37. Singh A, Mittal M. Neonatal microbiome - a brief review. J Matern Fetal Neonatal Med. 2020;33(22):3841-3848. [Crossref]  [PubMed]
  38. Marcobal A, Barboza M, Froehlich JW, Block DE, German JB, Lebrilla CB, et al. Consumption of human milk oligosaccharides by gut-related microbes. J Agric Food Chem. 2010;58(9):5334-40. [Crossref]  [PubMed]  [PMC]
  39. Neu J, Pammi M. Pathogenesis of NEC: Impact of an altered intestinal microbiome. Semin Perinatol. 2017;41(1):29-35. [Crossref]  [PubMed]
  40. Claud EC, Walker WA. Hypothesis: inappropriate colonization of the premature intestine can cause neonatal necrotizing enterocolitis. FASEB J. 2001;15(8):1398-403. [Crossref]  [PubMed]
  41. Afrazi A, Sodhi CP, Richardson W, Neal M, Good M, Siggers R, Hackam DJ. New insights into the pathogenesis and treatment of necrotizing enterocolitis: Toll-like receptors and beyond. Pediatr Res. 2011;69(3):183-8. [Crossref]  [PubMed]  [PMC]
  42. Stanikova A, Jouza M, Bohosova J, et al. Role of the microbiome in pathophysiology of necrotising enterocolitis in preterm neonates. BMJ Paediatrics Open 2023;7:e002172. [Crossref]  [PubMed]  [PMC]
  43. Wang Y, Hoenig JD, Malin KJ, Qamar S, Petrof EO, Sun J, et al. 16S rRNA gene-based analysis of fecal microbiota from preterm infants with and without necrotizing enterocolitis. ISME J. 2009;3(8):944-54. [Crossref]  [PubMed]  [PMC]
  44. Hourigan SK, Ta A, Wong WS, Clemency NC, Provenzano MG, et al.The Microbiome in Necrotizing Enterocolitis: A Case Report in Twins and Minireview. Clin Ther. 2016;38(4):747-53. [Crossref]  [PubMed]
  45. Mai V, Young CM, Ukhanova M, Wang X, Sun Y, Casella G, et al. Fecal microbiota in premature infants prior to necrotizing enterocolitis. PLoS One. 2011;6(6):e20647. [Crossref]  [PubMed]  [PMC]
  46. Brower-Sinning R, Zhong D, Good M, Firek B, Baker R, Sodhi CP, et al. Mucosa-associated bacterial diversity in necrotizing enterocolitis. PLoS One. 2014;9(9):e105046. [Crossref]  [PubMed]  [PMC]
  47. Heida FH, van Zoonen AGJF, Hulscher JBF, Te Kiefte BJC, Wessels R, Kooi EMW, et al. A Necrotizing Enterocolitis-Associated Gut Microbiota Is Present in the Meconium: Results of a Prospective Study. Clin Infect Dis. 2016;62(7):863-870. [Crossref]  [PubMed]
  48. 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.PLoSOne.2015;10(3):e0118632. [Crossref]  [PubMed]  [PMC]
  49. Smith B, Bodé S, Skov TH, Mirsepasi H, Greisen G, Krogfelt KA. Investigation of the early intestinal microflora in premature infants with/without necrotizing enterocolitis using two different methods. Pediatr Res. 2012;71(1):115-20. [Crossref]  [PubMed]
  50. Torrazza RM, Ukhanova M, Wang X, Sharma R, Hudak ML, Neu J, et al. Intestinal microbial ecology and environmental factors affecting necrotizing enterocolitis. PLoS One. 2013;8(12):e83304. [Crossref]  [PubMed]  [PMC]
  51. Olm MR, Bhattacharya N, Crits-Christoph A, Firek BA, Baker R, Song YS, et al. Necrotizing enterocolitis is preceded by increased gut bacterial replication, Klebsiella, and fimbriae-encoding bacteria. Sci Adv. 2019;5(12):eaax5727. [Crossref]  [PubMed]  [PMC]
  52. Hooven TA, Lin AYC, Salleb-Aouissi A. Multiple Instance Learning for Predicting Necrotizing Enterocolitis in Premature Infants Using Microbiome Data. Proc ACM Conf Health Inference Learn. 2020;2020:99-109 [Crossref]  [PubMed]  [PMC]
  53. Ji J, Ling XB, Zhao Y, Hu Z, Zheng X, Xu Z, et al. A data-driven algorithm integrating clinical and laboratory features for the diagnosis and prognosis of necrotizing enterocolitis. PLoS One. 2014;9(2):e89860. [Crossref]  [PubMed]  [PMC]
  54. Stewart CJ, Cummings SP. Gut bacteria and necrotizing enterocolitis: cause or effect? Trends Microbiol. 2015;23(6):332-3. [Crossref]  [PubMed]