Necrotizing Enterocolitis and the Preterm Infant Microbiome

  • Jillian R. Baranowski
  • Erika C. ClaudEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1125)


Bacterial colonization patterns in preterm infants differ from those of their term counterparts due to maternal microbial diversity, delivery mode, feeding methods, antibiotic use, and exposure to commensal microbiota and pathogens in the neonatal intensive care unit (NICU). Early gut microbiome dysbiosis predisposes neonates to necrotizing enterocolitis (NEC), a devastating intestinal disease with high morbidity and mortality. Though mechanisms of NEC pathogenesis are not fully understood, the microbiome is a promising therapy target for prevention and treatment. Direct administration of probiotics to preterm infants has been shown to reduce the incidence of NEC, but is not without risk. The immature immune systems of preterm infants leave them vulnerable to even beneficial bacteria. Further research is required to investigate both short-term and long-term effects of probiotic administration to preterm infants. Other methods of altering the preterm infant microbiome must also be considered, including breastfeeding, prebiotics, and targeting the maternal microbiome.


Gastrointestinal microbiome Necrotizing enterocolitis Preterm birth Probiotics Very low birth weight infant 


  1. Ahle M, Drott P, Elfvin A, Andersson RE (2018) Maternal, fetal and perinatal factors associated with necrotizing enterocolitis in Sweden. A national case-control study. PLoS One 13:e0194352PubMedPubMedCentralGoogle Scholar
  2. Aloisio I, Mazzola G, Corvaglia LT et al (2014) Influence of intrapartum antibiotic prophylaxis against group B Streptococcus on the early newborn gut composition and evaluation of the anti-Streptococcus activity of Bifidobacterium strains. Appl Microbiol Biotechnol 98:6051–6060PubMedGoogle Scholar
  3. Autran CA, Schoterman MHC, Jantscher-Krenn E et al (2016) Sialylated galacto-oligosaccharides and 2′-fucosyllactose reduce necrotising enterocolitis in neonatal rats. Br J Nutr 116:294–299PubMedGoogle Scholar
  4. Azad MB, Konya T, Maughan H et al (2013) Gut microbiota of healthy Canadian infants: profiles by mode of delivery and infant diet at 4 months. CMAJ 185:385–394PubMedPubMedCentralGoogle Scholar
  5. Azad MB, Konya T, Guttman DS et al (2015) Infant gut microbiota and food sensitization: associations in the first year of life. Clin Exp Allergy 45:632–643PubMedGoogle Scholar
  6. Bäckhed F, Roswall J, Peng Y et al (2015) Dynamics and stabilization of the human gut microbiome during the first year of life. Cell Host Microbe 17:690–703Google Scholar
  7. Bell MJ, Ternberg JL, Feigin RD et al (1978) Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg 187:1–7PubMedPubMedCentralGoogle Scholar
  8. Bergström A, Skov TH, Bahl MI et al (2014) Establishment of intestinal microbiota during early life: a longitudinal, explorative study of a large cohort of Danish infants. Appl Environ Microbiol 80:2889–2900PubMedPubMedCentralGoogle Scholar
  9. Bertelsen RJ, Brantsæter AL, Magnus MC et al (2014) Probiotic milk consumption in pregnancy and infancy and subsequent childhood allergic diseases. J Allergy Clin Immunol 133:165–171PubMedGoogle Scholar
  10. Bilali A, Galanis P, Bartsocas C et al (2013) H2-blocker therapy and incidence of necrotizing enterocolitis in preterm infants: a case-control study. Pediatr Neonatol 54:141–142PubMedGoogle Scholar
  11. Bokulich NA, Mills DA, Underwood MA (2013) Surface microbes in the neonatal intensive care unit: changes with routine cleaning and over time. J Clin Microbiol 51:2617–2624PubMedPubMedCentralGoogle Scholar
  12. Brantsæter AL, Myhre R, Haugen M et al (2011) Intake of probiotic food and risk of preeclampsia in primiparous women the norwegian mother and child cohort study. Am J Epidemiol 174:807–815PubMedPubMedCentralGoogle Scholar
  13. Broe A, Pottegård A, Lamont RF et al (2014) Increasing use of antibiotics in pregnancy during the period 2000–2010: prevalence, timing, category, and demographics. BJOG 121:988–996PubMedGoogle Scholar
  14. Brooks B, Firek BA, Miller CS et al (2014) Microbes in the neonatal intensive care unit resemble those found in the gut of premature infants. Microbiome 2:1–16PubMedPubMedCentralGoogle Scholar
  15. Carr R, Modi N (1997) Haemopoietic colony stimulating factors for preterm neonates. Arch Dis Child Fetal Neonatal Ed 76:128–133Google Scholar
  16. Centers for Disease Control and Prevention (2018) Natality public-use data 2007–2016. In: CDC WONDER Online Database. Accessed 16 Apr 2018
  17. Chang H-Y, Chen J-H, Chang J-H et al (2017) Multiple strains probiotics appear to be the most effective probiotics in the prevention of necrotizing enterocolitis and mortality: An updated meta-analysis. PLoS One 12:e0171579PubMedPubMedCentralGoogle Scholar
  18. Clark RH, Bloom BT, Spitzer AR, Gerstmann DR (2006) Reported medication use in the neonatal intensive care unit: data from a large national data set. Pediatrics 117:1979–1987PubMedGoogle Scholar
  19. Clark RH, Gordon P, Walker WM et al (2012) Characteristics of patients who die of necrotizing enterocolitis. J Perinatol 32:199–204PubMedGoogle Scholar
  20. Claud EC, Walker WA (2001) Hypothesis: inappropriate colonization of the premature intestine can cause neonatal necrotizing enterocolitis. FASEB J 15:1398–1403PubMedGoogle Scholar
  21. Coggins SA, Wynn JL, Weitkamp J-H (2015) Infectious causes of necrotizing enterocolitis. Clin Perinatol 42(133–54):ixGoogle Scholar
  22. Costello EK, Carlisle EM, Bik EM et al (2013) Microbiome assembly across multiple body sites in low-birthweight infants. MBio 4:e00782–e00713PubMedPubMedCentralGoogle Scholar
  23. Cotten CM, Taylor S, Stoll B et al (2009) Prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants. Pediatrics 123:58–66PubMedPubMedCentralGoogle Scholar
  24. De Leoz MLA, Kalanetra KM, Bokulich NA et al (2014) Human milk glycomics and gut microbial genomics in infant feces show a correlation between human milk oligosaccharides and gut microbiota: a proof-of-concept study. J Proteome Res 14:491–502PubMedPubMedCentralGoogle Scholar
  25. Dodrill P, Donovan T, Cleghorn G et al (2008) Attainment of early feeding milestones in preterm neonates. J Perinatol 28:549–555PubMedGoogle Scholar
  26. Dolatkhah N, Hajifaraji M, Abbasalizadeh F et al (2015) Is there a value for probiotic supplements in gestational diabetes mellitus? A randomized clinical trial. J Health Popul Nutr 33:25–32PubMedPubMedCentralGoogle Scholar
  27. Dominguez-Bello MG, Costello EK, Contreras M et al (2010) Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A 107:11971–11975PubMedPubMedCentralGoogle Scholar
  28. Eckburg PB, Bik EM, Bernstein CN et al (2005) Diversity of the human intestinal microbial flora. Science 308:1635–1638PubMedPubMedCentralGoogle Scholar
  29. Ferraris L, Butel MJ, Campeotto F et al (2012) Clostridia in premature neonates’ gut: incidence, antibiotic susceptibility, and perinatal determinants influencing colonization. PLoS One 7:e30594PubMedPubMedCentralGoogle Scholar
  30. Fitzgibbons SC, Ching Y, Yu D et al (2009) Mortality of necrotizing enterocolitis expressed by birth weight categories. J Pediatr Surg 44:1072–1076PubMedGoogle Scholar
  31. Giovannini M, Verduci E, Gregori D et al (2014) Prebiotic effect of an infant formula supplemented with galacto-oligosaccharides: randomized multicenter trial. J Am Coll Nutr 33:385–393PubMedGoogle Scholar
  32. Good M, Sodhi CP, Yamaguchi Y et al (2016) The human milk oligosaccharide 2′-fucosyllactose attenuates the severity of experimental necrotising enterocolitis by enhancing mesenteric perfusion in the neonatal intestine. Br J Nutr 116:1175–1187PubMedPubMedCentralGoogle Scholar
  33. Gordon P, Christensen R, Weitkamp J-H, Maheshwari A (2012) mapping the new world of necrotizing enterocolitis (NEC): review and opinion. EJ Neonatol Res 2:145–172PubMedPubMedCentralGoogle Scholar
  34. Greenwood C, Morrow AL, Lagomarcino AJ et al (2014) Early empiric antibiotic use in preterm infants is associated with lower bacterial diversity and higher relative abundance of enterobacter. J Pediatr 165:23–29PubMedPubMedCentralGoogle Scholar
  35. Gregory KE, Deforge CE, Natale KM et al (2011) Necrotizing enterocolitis in the premature infant: neonatal nursing assessment, disease pathogenesis, and clinical presentation. Adv Neonatal Care 11:155–166PubMedPubMedCentralGoogle Scholar
  36. Grier A, Qiu X, Bandyopadhyay S et al (2017) Impact of prematurity and nutrition on the developing gut microbiome and preterm infant growth. Microbiome 5:158–176PubMedPubMedCentralGoogle Scholar
  37. Güney-Varal İ, Köksal N, Özkan H et al (2017) The effect of early administration of combined multi-strain and multi-species probiotics on gastrointestinal morbidities and mortality in preterm infants: A randomized controlled trial in a tertiary care unit. Turk J Pediatr 59:13–19PubMedGoogle Scholar
  38. Hsiao K-C, Ponsonby A-L, Axelrad C et al (2017) Long-term clinical and immunological effects of probiotic and peanut oral immunotherapy after treatment cessation: 4-year follow-up of a randomised, double-blind, placebo-controlled trial. Lancet Child Adolesc Health 1:97–105PubMedGoogle Scholar
  39. Hyman RW, Fukushima M, Jiang H et al (2014) Diversity of the vaginal microbiome correlates with preterm birth. Reprod Sci 21:32–40PubMedPubMedCentralGoogle Scholar
  40. Jinno S, Toshimitsu T, Nakamura Y et al (2017) Maternal prebiotic ingestion increased the number of fecal bifidobacteria in pregnant women but not in their neonates aged one month. Nutrients 9:196–207PubMedCentralGoogle Scholar
  41. Kalliomäki M, Carmen Collado M, Salminen S, Isolauri E (2008) Early differences in fecal microbiota composition in children may predict overweight. Am J Clin Nutr 87:534–538PubMedGoogle Scholar
  42. Kansagra K, Stoll B, Rognerud C et al (2003) Total parenteral nutrition adversely affects gut barrier function in neonatal piglets. Am J Physiol Gastrointest Liver Physiol 285:G1162–G1170PubMedGoogle Scholar
  43. Kosloske AM, Ulrich JA (1980) A bacteriologic basis for the clinical presentations of necrotizing enterocolitis. J Pediatr Surg 15:558–564PubMedGoogle Scholar
  44. Kosloske AM, Ulrich JA, Hoffman H (1978) Fulminant necrotising enterocolitis associated with Clostridia. Lancet 2:1014–1016PubMedGoogle Scholar
  45. Kostic AD, Gevers D, Siljander H et al (2015) The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes. Cell Host Microbe 17:260–273PubMedPubMedCentralGoogle Scholar
  46. Laursen MF, Zachariassen G, Bahl MI et al (2015) Having older siblings is associated with gut microbiota development during early childhood. BMC Microbiol 15:154–162PubMedPubMedCentralGoogle Scholar
  47. Lu L, Yu Y, Guo Y et al (2015) Transcriptional modulation of intestinal innate defense/inflammation genes by preterm infant microbiota in a humanized gnotobiotic mouse model. PLoS One 10:e0124504PubMedPubMedCentralGoogle Scholar
  48. Lu J, Lu L, Yu Y et al (2018) Effects of intestinal microbiota on brain development in humanized gnotobiotic mice. Sci Rep 8:5443–5458PubMedPubMedCentralGoogle Scholar
  49. Martin JA, Hamilton BE, Osterman MJK et al (2018) Births: final data for 2016. Natl Vital Stat Rep 67:1–55PubMedPubMedCentralGoogle Scholar
  50. McGreal EP, Hearne K, Spiller OB (2012) Off to a slow start: under-development of the complement system in term newborns is more substantial following premature birth. Immunobiology 217:176–186PubMedGoogle Scholar
  51. Meinzen-Derr J, Poindexter B, Wrage L et al (2009) Role of human milk in extremely low birth weight infants’ risk of necrotizing enterocolitis or death. J Perinatol 29:57–62PubMedGoogle Scholar
  52. Melville JM, Moss TJM (2013) The immune consequences of preterm birth. Front Neurosci 7:79–87PubMedPubMedCentralGoogle Scholar
  53. Murphy K, Curley D, O’Callaghan TF et al (2017) The composition of human milk and infant faecal microbiota over the first three months of life: a pilot study. Sci Rep 7:40597PubMedPubMedCentralGoogle Scholar
  54. Neu J (2014) Probiotics and necrotizing enterocolitis. Clin Perinatol 41:967–978PubMedPubMedCentralGoogle Scholar
  55. Ohishi A, Takahashi S, Ito Y et al (2010) Bifidobacterium septicemia associated with postoperative probiotic therapy in a neonate with omphalocele. J Pediatr 156:679–681PubMedGoogle Scholar
  56. Olm MR, Brown CT, Brooks B et al (2017) Identical bacterial populations colonize premature infant gut, skin, and oral microbiomes and exhibit different in situ growth rates. Genome Res 27:601–612PubMedPubMedCentralGoogle Scholar
  57. Pammi M, Cope J, Tarr PI et al (2017) Intestinal dysbiosis in preterm infants preceding necrotizing enterocolitis: a systematic review and meta-analysis. Microbiome 5:31–45PubMedPubMedCentralGoogle Scholar
  58. Pannaraj PS, Li F, Cerini C et al (2017) Association between breast milk bacterial communities and establishment and development of the infant gut microbiome. JAMA Pediatr 171:647–654PubMedPubMedCentralGoogle Scholar
  59. Perez-Muñoz ME, Arrieta M-C, Ramer-Tait AE, Walter J (2017) A critical assessment of the “sterile womb” and “in utero colonization” hypotheses: implications for research on the pioneer infant microbiome. Microbiome 5:48–66PubMedPubMedCentralGoogle Scholar
  60. Romero R, Hassan SS, Gajer P et al (2014) The composition and stability of the vaginal microbiota of normal pregnant women is different from that of non-pregnant women. Microbiome 2:4–22PubMedPubMedCentralGoogle Scholar
  61. Saldanha LG (2008) US food and drug administration regulations governing label claims for food products, including probiotics. Clin Infect Dis 46:S119–S121PubMedGoogle Scholar
  62. Sender R, Fuchs S, Milo R (2016) Revised estimates for the number of human and bacteria cells in the body. PLoS Biol 14:e1002533PubMedPubMedCentralGoogle Scholar
  63. Sjögren YM, Jenmalm MC, Böttcher MF et al (2009) Altered early infant gut microbiota in children developing allergy up to 5 years of age. Clin Exp Allergy 39:518–526PubMedGoogle Scholar
  64. Sohn K, Underwood MA (2017) Prenatal and postnatal administration of prebiotics and probiotics. Semin Fetal Neonatal Med 22:284–289PubMedPubMedCentralGoogle Scholar
  65. Srinivasjois R, Rao S, Patole S (2013) Prebiotic supplementation in preterm neonates: updated systematic review and meta-analysis of randomised controlled trials. Clin Nutr 32:958–965PubMedGoogle Scholar
  66. Stearns JC, Zulyniak MA, de Souza RJ et al (2017) Ethnic and diet-related differences in the healthy infant microbiome. Genome Med 9:32–43PubMedPubMedCentralGoogle Scholar
  67. Stewart CJ, Marrs ECL, Magorrian S et al (2012) The preterm gut microbiota: changes associated with necrotizing enterocolitis and infection. Acta Paediatr 101:1121–1127PubMedGoogle Scholar
  68. Stokholm J, Schjørring S, Pedersen L et al (2013) Prevalence and predictors of antibiotic administration during pregnancy and birth. PLoS One 8:e82932PubMedPubMedCentralGoogle Scholar
  69. Stoll BJ, Hansen NI, Bell EF et al (2015) Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993–2012. JAMA 314:1039–1051PubMedPubMedCentralGoogle Scholar
  70. Stout MJ, Zhou Y, Wylie KM et al (2017) Early pregnancy vaginal microbiome trends and preterm birth. Am J Obstet Gynecol 217:356.e1–356.e18Google Scholar
  71. Tilg H, Kaser A (2011) Gut microbiome, obesity, and metabolic dysfunction. J Clin Invest 121:2126–2132PubMedPubMedCentralGoogle Scholar
  72. U.S. Food & Drug Administration (2010) Dietary Supplements – Guidance for Industry: Current Good Manufacturing Practice in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements; Small Entity Compliance GuideGoogle Scholar
  73. Vallabhaneni S, Walker TA, Lockhart SR et al (2015) Fatal gastrointestinal mucormycosis in a premature infant associated with a contaminated dietary supplement. Morb Mortal Wkly Rep 64:634–653Google Scholar
  74. van den Berg JP, Westerbeek EAM, van der Klis FRM et al (2011) Transplacental transport of IgG antibodies to preterm infants: a review of the literature. Early Hum Dev 87:67–72PubMedGoogle Scholar
  75. Venugopalan V, Shriner KA, Wong-Beringer A (2010) Regulatory oversight and safety of probiotic use. Emerg Infect Dis 16:1661–1665PubMedPubMedCentralGoogle Scholar
  76. Walenkamp MJE, Karperien M, Pereira AM et al (2005) Homozygous and heterozygous expression of a novel insulin-like growth factor-I mutation. J Clin Endocrinol Metab 90:2855–2864PubMedGoogle Scholar
  77. Walsh MC, Kliegman RM (1986) Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin N Am 33:179–201Google Scholar
  78. Wang Y, Hoenig JD, Malin KJ et al (2009) 16S rRNA gene-based analysis of fecal microbiota from preterm infants with and without necrotizing enterocolitis. ISME J 3:944–954PubMedPubMedCentralGoogle Scholar
  79. Westerbeek EAM, Slump RA, Lafeber HN et al (2013) The effect of enteral supplementation of specific neutral and acidic oligosaccharides on the faecal microbiota and intestinal microenvironment in preterm infants. Eur J Clin Microbiol Infect Dis 32:269–276PubMedGoogle Scholar
  80. White JR, Gong H, Pope B et al (2017) Paneth-cell-disruption-induced necrotizing enterocolitis in mice requires live bacteria and occurs independently of TLR4 signaling. Dis Model Mech 10:727–736PubMedPubMedCentralGoogle Scholar
  81. World Health Organization (2013) Pocket book of hospital care for children. World Health Organization, GenevaGoogle Scholar
  82. Wu W, Wang Y, Zou J et al (2017) Bifidobacterium adolescentis protects against necrotizing enterocolitis and upregulates TOLLIP and SIGIRR in premature neonatal rats. BMC Pediatr 17:1–8PubMedPubMedCentralGoogle Scholar
  83. Ya W, Reifer C, Miller LE (2010) Efficacy of vaginal probiotic capsules for recurrent bacterial vaginosis: a double-blind, randomized, placebo-controlled study. Am J Obstet Gynecol 203:120.e1–120.e6Google Scholar
  84. Yassour M, Vatanen T, Siljander H et al (2016) Natural history of the infant gut microbiome and impact of antibiotic treatment on bacterial strain diversity and stability. Sci Transl Med 8:343ra81PubMedPubMedCentralGoogle Scholar
  85. Yazdankhah SP, Narvhus JA, Eggesbø M et al (2008) Should long-term prophylactic use of probiotics for infants and young children give cause for concern? Microb Ecol Health Dis 20:171–176Google Scholar
  86. Zuccotti G, Meneghin F, Aceti A et al (2015) Probiotics for prevention of atopic diseases in infants: systematic review and meta-analysis. Allergy 70:1356–1371PubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Pritzker School of MedicineUniversity of ChicagoChicagoUSA
  2. 2.Department of PediatricsThe University of Chicago Pritzker School of MedicineChicagoUSA

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