Skip to content
1887

Abstract

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disorder in preterm infants with a high mortality rate. The aetiology of NEC appears to be multifaceted; however, gut microbiota dysbiosis likely plays a significant role. This systematic review aimed to describe how the gut microbiota of preterm infants with NEC differs from infants without NEC (PROSPERO: CRD42022344126). Databases were searched from inception to 22 June 2022 to identify eligible studies that examined the gut microbiota composition of preterm infants with and without NEC using sequencing methods. Results were described narratively. We identified 28 eligible studies. Overall, findings were heterogeneous and no single gut microbiota signature was associated with NEC in all studies. Importantly, 3 studies reported no difference in the gut microbiota composition between NEC and healthy infants, while studies reported a difference using one or more analytical method (i.e. alpha diversity, beta diversity or differential abundance analysis). Of note, NEC (or development of NEC) was positively associated with increased detection and/or abundance of (=11 studies), (=8) and Proteobacteria (=2). The taxa most frequently associated with NEC (, , and Proteobacteria) may play an important role in the pathogenesis of NEC and should be further explored.

Funding
This study was supported by the:
  • National Health and Medical Research Council (Award 1197951)
    • Principal Award Recipient: SuzanneGarland
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
Loading

Article metrics loading...

/content/journal/acmi/10.1099/acmi.0.001077.v3
2025-12-19
2026-02-18

Metrics

Loading full text...

Full text loading...

/deliver/fulltext/acmi/7/12/acmi001077.v3.html?itemId=/content/journal/acmi/10.1099/acmi.0.001077.v3&mimeType=html&fmt=ahah

References

  1. Coggins SA, Wynn JL, Weitkamp JH. Infectious causes of necrotizing enterocolitis. Clin Perinatol 2015; 42:133–154 [View Article] [PubMed]
    [Google Scholar]
  2. Fu X, Li S, Jiang Y, Hu X, Wu H. Necrotizing enterocolitis and intestinal microbiota: the timing of disease and combined effects of multiple species. Front Pediatr 2021; 9:657349 [View Article] [PubMed]
    [Google Scholar]
  3. Patel RM, Ferguson J, McElroy SJ, Khashu M, Caplan MS. Defining necrotizing enterocolitis: current difficulties and future opportunities. Pediatr Res 2020; 88:10–15 [View Article] [PubMed]
    [Google Scholar]
  4. Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med 2011; 364:255–264 [View Article] [PubMed]
    [Google Scholar]
  5. Hong L, Zhang L, Zhou Q, Li S, Han J et al. Impacts of enriched human milk cells on fecal metabolome and gut microbiome of premature infants with stage I necrotizing enterocolitis: a pilot study. Mol Nutr Food Res 2022; 66:e2100342 [View Article] [PubMed]
    [Google Scholar]
  6. Yang M, Du J, Yang Q, Dou W, Jiang M et al. Influence of family integrated care on the intestinal microbiome of preterm infants with necrotizing enterocolitis and enterostomy: a preliminary study. Front Pediatr 2021; 9:678254 [View Article] [PubMed]
    [Google Scholar]
  7. Niño DF, Sodhi CP, Hackam DJ. Necrotizing enterocolitis: new insights into pathogenesis and mechanisms. Nat Rev Gastroenterol Hepatol 2016; 13:590–600 [View Article] [PubMed]
    [Google Scholar]
  8. Brown CT, Xiong W, Olm MR, Thomas BC, Baker R et al. Hospitalized premature infants are colonized by related bacterial strains with distinct proteomic profiles. mBio 2018; 9:e00441-18 [View Article] [PubMed]
    [Google Scholar]
  9. Kaelin EA, Rodriguez C, Hall-Moore C, Hoffmann JA, Linneman LA et al. Longitudinal gut virome analysis identifies specific viral signatures that precede necrotizing enterocolitis onset in preterm infants. Nat Microbiol 2022; 7:653–662 [View Article] [PubMed]
    [Google Scholar]
  10. Masi AC, Embleton ND, Lamb CA, Young G, Granger CL et al. Human milk oligosaccharide DSLNT and gut microbiome in preterm infants predicts necrotising enterocolitis. Gut 2021; 70:2273–2282 [View Article] [PubMed]
    [Google Scholar]
  11. Pammi M, Cope J, Tarr PI, Warner BB, Morrow AL et al. Intestinal dysbiosis in preterm infants preceding necrotizing enterocolitis: a systematic review and meta-analysis. Microbiome 2017; 5:31 [View Article] [PubMed]
    [Google Scholar]
  12. Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 2015; 4:1 [View Article] [PubMed]
    [Google Scholar]
  13. Howson CP, Kinney MV, McDougall L, Lawn JE, Born Too Soon Preterm Birth Action G. Born too soon: preterm birth matters. Reprod Health 2013; 10 Suppl 1:S1 [View Article] [PubMed]
    [Google Scholar]
  14. Murad MH, Mustafa RA, Schünemann HJ, Sultan S, Santesso N. Rating the certainty in evidence in the absence of a single estimate of effect. Evid Based Med 2017; 22:85–87 [View Article]
    [Google Scholar]
  15. Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011; 64:401–406 [View Article] [PubMed]
    [Google Scholar]
  16. Moschino L, Verlato G, Duci M, Cavicchiolo ME, Guiducci S et al. The metabolome and the gut microbiota for the prediction of necrotizing enterocolitis and spontaneous intestinal perforation: a systematic review. Nutrients 2022; 14:3859 [View Article] [PubMed]
    [Google Scholar]
  17. Mshvildadze M, Neu J, Shuster J, Theriaque D, Li N et al. Intestinal microbial ecology in premature infants assessed with non-culture-based techniques. J Pediatr 2010; 156:20–25 [View Article] [PubMed]
    [Google Scholar]
  18. Normann E, Fahlén A, Engstrand L, Lilja HE. Intestinal microbial profiles in extremely preterm infants with and without necrotizing enterocolitis. Acta Paediatr 2013; 102:129–136 [View Article] [PubMed]
    [Google Scholar]
  19. Wandro S, Osborne S, Enriquez C, Bixby C, Arrieta A et al. The microbiome and metabolome of preterm infant stool are personalized and not driven by health outcomes, including necrotizing enterocolitis and late-onset sepsis. mSphere 2018; 3:e00104-18 [View Article] [PubMed]
    [Google Scholar]
  20. Brehin C, Dubois D, Dicky O, Breinig S, Oswald E et al. Evolution of gut microbiome and metabolome in suspected necrotizing enterocolitis: a case-control study. J Clin Med 2020; 9:2278 [View Article] [PubMed]
    [Google Scholar]
  21. Claud EC, Keegan KP, Brulc JM, Lu L, Bartels D et al. Bacterial community structure and functional contributions to emergence of health or necrotizing enterocolitis in preterm infants. Microbiome 2013; 1:20 [View Article] [PubMed]
    [Google Scholar]
  22. Dobbler PT, Procianoy RS, Mai V, Silveira RC, Corso AL et al. Low microbial diversity and abnormal microbial succession is associated with necrotizing enterocolitis in preterm infants. Front Microbiol 2017; 8:2243 [View Article] [PubMed]
    [Google Scholar]
  23. Gopalakrishna KP, Macadangdang BR, Rogers MB, Tometich JT, Firek BA et al. Maternal IgA protects against the development of necrotizing enterocolitis in preterm infants. Nat Med 2019; 25:1110–1115 [View Article] [PubMed]
    [Google Scholar]
  24. Heida FH, van Zoonen AGJF, Hulscher JBF, Te Kiefte BJC, Wessels R et al. A necrotizing enterocolitis-associated gut microbiota is present in the meconium: results of a prospective study. Clin Infect Dis 2016; 62:863–870 [View Article] [PubMed]
    [Google Scholar]
  25. Itani T, Ayoub Moubareck C, Mangin I, Butel MJ, Karam Sarkis D. Individual variations in intestinal microbiota were higher in preterm infants with necrotising enterocolitis than healthy controls. Acta Paediatr 2019; 108:2294–2295 [View Article] [PubMed]
    [Google Scholar]
  26. Lindberg TP, Caimano MJ, Hagadorn JI, Bennett EM, Maas K et al. Preterm infant gut microbial patterns related to the development of necrotizing enterocolitis. J Matern Fetal Neonatal Med 2020; 33:349–358 [View Article] [PubMed]
    [Google Scholar]
  27. Liu J, Li Y, Feng Y, Pan L, Xie Z et al. Patterned progression of gut microbiota associated with necrotizing enterocolitis and late onset sepsis in preterm infants: a prospective study in a Chinese neonatal intensive care unit. PeerJ 2019; 7:e7310 [View Article]
    [Google Scholar]
  28. Mai V, Young CM, Ukhanova M, Wang X, Sun Y et al. Fecal microbiota in premature infants prior to necrotizing enterocolitis. PLoS One 2011; 6:e20647 [View Article] [PubMed]
    [Google Scholar]
  29. McMurtry VE, Gupta RW, Tran L, Blanchard EE 4th, Penn D et al. Bacterial diversity and Clostridia abundance decrease with increasing severity of necrotizing enterocolitis. Microbiome 2015; 3:11 [View Article] [PubMed]
    [Google Scholar]
  30. Morrow AL, Lagomarcino AJ, Schibler KR, Taft DH, Yu Z et al. Early microbial and metabolomic signatures predict later onset of necrotizing enterocolitis in preterm infants. Microbiome 2013; 1:13 [View Article] [PubMed]
    [Google Scholar]
  31. Olm MR, Bhattacharya N, Crits-Christoph A, Firek BA, Baker R et al. Necrotizing enterocolitis is preceded by increased gut bacterial replication, Klebsiella, and fimbriae-encoding bacteria. Sci Adv 2019; 5:eaax5727 [View Article] [PubMed]
    [Google Scholar]
  32. Ravi A, Estensmo ELF, Abée-Lund TML, Foley SL, Allgaier B et al. Association of the gut microbiota mobilome with hospital location and birth weight in preterm infants. Pediatr Res 2017; 82:829–838 [View Article] [PubMed]
    [Google Scholar]
  33. Rozé J-C, Ancel P-Y, Lepage P, Martin-Marchand L, Al Nabhani Z et al. Nutritional strategies and gut microbiota composition as risk factors for necrotizing enterocolitis in very-preterm infants. Am J Clin Nutr 2017; 106:821–830 [View Article] [PubMed]
    [Google Scholar]
  34. Shaw AG, Sim K, Rose G, Wooldridge DJ, Li M-S et al. Premature neonatal gut microbial community patterns supporting an epithelial TLR-mediated pathway for necrotizing enterocolitis. BMC Microbiol 2021; 21:225 [View Article] [PubMed]
    [Google Scholar]
  35. Sim K, Shaw AG, Randell P, Cox MJ, McClure ZE et al. Dysbiosis anticipating necrotizing enterocolitis in very premature infants. Clin Infect Dis 2015; 60:389–397 [View Article] [PubMed]
    [Google Scholar]
  36. Stewart CJ, Embleton ND, Marrs ECL, Smith DP, Nelson A et al. Temporal bacterial and metabolic development of the preterm gut reveals specific signatures in health and disease. Microbiome 2016; 4:67 [View Article] [PubMed]
    [Google Scholar]
  37. Torrazza RM, Ukhanova M, Wang X, Sharma R, Hudak ML et al. Intestinal microbial ecology and environmental factors affecting necrotizing enterocolitis. PLoS One 2013; 8:e83304 [View Article] [PubMed]
    [Google Scholar]
  38. Ward DV, Scholz M, Zolfo M, Taft DH, Schibler KR et al. Metagenomic sequencing with strain-level resolution implicates uropathogenic E. coli in necrotizing enterocolitis and mortality in preterm infants. Cell Rep 2016; 14:2912–2924 [View Article]
    [Google Scholar]
  39. Warner BB, Deych E, Zhou Y, Hall-Moore C, Weinstock GM et al. Gut bacteria dysbiosis and necrotising enterocolitis in very low birthweight infants: a prospective case-control study. Lancet 2016; 387:1928–1936 [View Article]
    [Google Scholar]
  40. Zhou Y, Shan G, Sodergren E, Weinstock G, Walker WA et al. Longitudinal analysis of the premature infant intestinal microbiome prior to necrotizing enterocolitis: a case-control study. PLoS ONE 2015; 10:e0118632 [View Article]
    [Google Scholar]
  41. Cassir N, Benamar S, Khalil JB, Croce O, Saint-Faust M et al. Clostridium butyricum strains and dysbiosis linked to necrotizing enterocolitis in preterm neonates. Clin Infect Dis 2015; 61:1107–1115 [View Article] [PubMed]
    [Google Scholar]
  42. Feng J, He Y, Liu D, Li L, Chen J et al. The constitution and functional prediction of the microbiota in necrotizing enterocolitis with a gestational age of over 28 weeks. Medicine (Baltimore) 2019; 98:e17206 [View Article] [PubMed]
    [Google Scholar]
  43. Taft DH, Ambalavanan N, Schibler KR, Yu Z, Newburg DS et al. Intestinal microbiota of preterm infants differ over time and between hospitals. Microbiome 2014; 2:36 [View Article] [PubMed]
    [Google Scholar]
  44. Mosca A, Leclerc M, Hugot JP. Gut microbiota diversity and human diseases: should we reintroduce key predators in our ecosystem?. Front Microbiol 2016; 7:455 [View Article] [PubMed]
    [Google Scholar]
  45. Pisani A, Rausch P, Bang C, Ellul S, Tabone T et al. Dysbiosis in the gut microbiota in patients with inflammatory bowel disease during remission. Microbiol Spectr 2022; 10:e0061622 [View Article] [PubMed]
    [Google Scholar]
  46. Fan Y, Pedersen O. Gut microbiota in human metabolic health and disease. Nat Rev Microbiol 2021; 19:55–71 [View Article] [PubMed]
    [Google Scholar]
  47. Afrazi A, Sodhi CP, Richardson W, Neal M, Good M et al. New insights into the pathogenesis and treatment of necrotizing enterocolitis: toll-like receptors and beyond. Pediatr Res 2011; 69:183–188 [View Article] [PubMed]
    [Google Scholar]
  48. Cho SX, Berger PJ, Nold-Petry CA, Nold MF. The immunological landscape in necrotising enterocolitis. Expert Rev Mol Med 2016; 18:e12 [View Article] [PubMed]
    [Google Scholar]
  49. Ferraris L, Balvay A, Bellet D, Delannoy J, Maudet C et al. Neonatal necrotizing enterocolitis: Clostridium butyricum and Clostridium neonatale fermentation metabolism and enteropathogenicity. Gut Microbes 2023; 15:2172666 [View Article] [PubMed]
    [Google Scholar]
  50. Jeong S. Factors influencing development of the infant microbiota: from prenatal period to early infancy. Clin Exp Pediatr 2022; 65:439–447 [View Article] [PubMed]
    [Google Scholar]
  51. Mirzayi C, Renson A. Genomic Standards ConsortiumMassive Analysis and Quality Control Society Zohra F et al. Reporting guidelines for human microbiome research: the STORMS checklist. Nat Med 2021; 27:1885–1892 [View Article] [PubMed]
    [Google Scholar]
/content/journal/acmi/10.1099/acmi.0.001077.v3
Loading
/content/journal/acmi/10.1099/acmi.0.001077.v3
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF

Supplementary material 2

EXCEL
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An error occurred
Approval was partially successful, following selected items could not be processed due to error