Abstract
Necrotizing enterocolitis (NEC) is a poorly defined disease that primarily affects preterm infants. There has not been much progress in the prevention or treatment of NEC since it became recognized as a common problem in preterm infants. Reasons for this lack of progress include the likelihood that different diseases are being put under the same moniker of “NEC,” similar to using “diabetes” for the different diseases it represents. In order to make progress, better delineation of the phenotypes that present as NEC will be necessary to clearly establish their pathophysiology, find specific and sensitive biomarkers, and establish preventative regimens. In this review, we summarize some of the entities that are being called NEC, discuss the pathophysiology of the most classic form of NEC, and provide an overview of how we might proceed in the future to make progress in this field.
Similar content being viewed by others
References
Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med. 2011;364:255–264.
Obladen M. Necrotizing enterocolitis—150 years of fruitless search for the cause. Neonatology. 2009;96:203–210.
Mizrahi A, Barlow O, Berdon W, Blanc WA, Silverman WA. Necrotizing enterocolitis in premature infants. J Pediatr. 1965;66:697–705.
Bell MJ, Ternberg JL, Feigin RD, et al. Neonatal necrotizing enterocolitis: therapeutic decisions based upon clinical staging. Ann Surg. 1978;187:1–6.
Fitzgibbons SC, Ching Y, Yu D, et al. Mortality of necrotizing enterocolitis expressed by birth weight categories. J Pediatr Surg. 2009;44:1072–1075.
Neu J, Modi N, Caplan M. Necrotizing enterocolitis comes in different forms: Historical perspectives and defining the disease. Semin Fetal Neonatal Med. 2018;23:370–373.
Bazacliu C, Neu J. Pathophysiology of necrotizing enterocolitis: an update. Curr Pediatr Rev. 2019;15:68–87.
Sulistyo A, Rahman A, Biouss G, Antounians L, Zani A. Animal models of necrotizing enterocolitis: review of the literature and state of the art. Innov Surg Sci. 2018;3:87–92.
Ares GJ, McElroy SJ, Hunter CJ. The science and necessity of using animal models in the study of necrotizing enterocolitis. Semin Pediatr Surg. 2018;27:29–33.
Pitt J, Barlow B, Heird WC. Protection against experimental necrotizing enterocolitis by maternal milk. I. Role of milk leukocytes. Pediatr Res. 1977;11:906–909.
Cuna A, Sampath V. Genetic alterations in necrotizing enterocolitis. Semin Perinatol. 2017;41:61–69.
Sampath V, Menden H, Helbling D, et al. SIGIRR genetic variants in premature infants with necrotizing enterocolitis. Pediatrics. 2015;135:e1530–e1534.
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:e51-7.
Helander HF, Fandriks L. Surface area of the digestive tract—revisited. Scand J Gastroenterol. 2014;49:681–689.
Lenfestey MW, Neu J. Gastrointestinal development: implications for management of preterm and term infants. Gastroenterol Clin N Am. 2018;47:773–791.
Bergstrom KS, Kissoon-Singh V, Gibson DL, et al. Muc2 protects against lethal infectious colitis by disassociating pathogenic and commensal bacteria from the colonic mucosa. PLoS Pathog. 2010;6:e1000902.
McElroy SJ, Prince LS, Weitkamp JH, 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:G656–G666.
Vieten D, Corfield A, Carroll D, Ramani P, Spicer R. Impaired mucosal regeneration in neonatal necrotising enterocolitis. Pediatr Surg Int. 2005;21:153–160.
Camilleri M. Leaky gut: mechanisms, measurement and clinical implications in humans. Gut. 2019;68:1516–1526.
Odenwald MA, Turner JR. The intestinal epithelial barrier: A therapeutic target? Nat Rev Gastroenterol Hepatol. 2017;14:9–21.
Waisman A, Lukas D, Clausen BE, Yogev N. Dendritic cells as gatekeepers of tolerance. Semin Immunopathol. 2017;39:153–163.
Funes SC, Manrique de Lara A, Altamirano-Lagos MJ, Mackern-Oberti JP, Escobar-Vera J, Kalergis AM. Immune checkpoints and the regulation of tolerogenicity in dendritic cells: implications for autoimmunity and immunotherapy. Autoimmun Rev. 2019;18:359–368.
Weitkamp JH, Rudzinski E, Koyama T, et al. Ontogeny of FOXP3(+) regulatory T cells in the postnatal human small intestinal and large intestinal lamina propria. Pediatr Dev Pathol. 2009;12:443–449.
Cong Y, Feng T, Fujihashi K, Schoeb TR, Elson CO. A dominant, coordinated T regulatory cell-IgA response to the intestinal microbiota. Proc Natl Acad Sci USA. 2009;106:19256–19261.
Egan CE, Sodhi CP, Good M, et al. Toll-like receptor 4-mediated lymphocyte influx induces neonatal necrotizing enterocolitis. J Clin Investig. 2016;126:495–508.
Weitkamp JH, Koyama T, Rock MT, et al. Necrotising enterocolitis is characterised by disrupted immune regulation and diminished mucosal regulatory (FOXP3)/effector (CD4, CD8) T cell ratios. Gut. 2013;62:73–82.
Clevers HC, Bevins CL. Paneth cells: maestros of the small intestinal crypts. Annu Rev Physiol. 2013;75:289–311.
McElroy SJ, Underwood MA, Sherman MP. Paneth cells and necrotizing enterocolitis: a novel hypothesis for disease pathogenesis. Neonatology. 2013;103:10–20.
Brandtzaeg P. The mucosal immune system and its integration with the mammary glands. J Pediatr. 2010;156:S8–S15.
Sterlin D, Fadlallah J, Slack E, Gorochov G. The antibody/microbiota interface in health and disease. Mucosal Immunol. 2019;13:3–11.
Gopalakrishna KP, Macadangdang BR, Rogers MB, et al. Maternal IgA protects against the development of necrotizing enterocolitis in preterm infants. Nat Med. 2019;25:1110–1115.
Stinson LF, Boyce MC, Payne MS, Keelan JA. The not-so-sterile womb: evidence that the human fetus is exposed to bacteria prior to birth. Front Microbiol. 2019;10:1124.
O’Callaghan JL, Turner R, Dekker Nitert M, Barrett HL, Clifton V, Pelzer ES. Re-assessing microbiomes in the low-biomass reproductive niche. BJOG. 2019;127:147–158. https://doi.org/10.1111/1471-0528.15974.
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;156:20–25.
Ardissone AN, Cruz DM, Davis-Richardson AG, et al. Meconium microbiome analysis identifies bacteria correlated with premature birth. PLoS ONE. 2014;9:e90784.
Borghi E, Massa V, Severgnini M, et al. Antenatal microbial colonization of mammalian gut. Reprod Sci. 2019;26:1045–1053.
Tapiainen T, Paalanne N, Tejesvi MV, et al. Maternal influence on the fetal microbiome in a population-based study of the first-pass meconium. Pediatr Res. 2018;84:371–379.
Younge N, McCann JR, Ballard J, et al. Fetal exposure to the maternal microbiota in humans and mice. JCI Insight. 2019;4:e127806.
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:e17776.
Pannaraj PS, Li F, Cerini C, et al. Association between breast milk bacterial communities and establishment and development of the infant gut microbiome. JAMA Pediatr. 2017;171:647–654.
Liu Z, Subbaraj A, Fraser K, et al. Human milk and infant formula differentially alters the microbiota composition and functional gene relative abundance in the small and large intestines in weanling rats. Eur J Nutr. 2019. https://doi.org/10.1007/s00394-019-02062-w.
Cesare Marincola F, Corbu S, Lussu M, et al. Impact of early postnatal nutrition on the NMR urinary metabolic profile of infant. J Proteome Res. 2016;15:3712–3723.
Liu H, Wang J, He T, et al. Butyrate: A double-edged sword for health? Adv Nutr. 2018;9:21–29.
Hackam DJ, Afrazi A, Good M, Sodhi CP. Innate immune signaling in the pathogenesis of necrotizing enterocolitis. Clin Dev Immunol. 2013;2013:475415.
Lepage P, Leclerc MC, Joossens M, et al. A metagenomic insight into our gut’s microbiome. Gut. 2013;62:146–158.
Maccaferri S, Biagi E, Brigidi P. Metagenomics: key to human gut microbiota. Dig Dis. 2011;29:525–530.
Mai V, Young CM, Ukhanova M, et al. Fecal microbiota in premature infants prior to necrotizing enterocolitis. PLoS ONE. 2011;6:e20647.
Claud EC, Keegan KP, Brulc JM, et al. Bacterial community structure and functional contributions to emergence of health or necrotizing enterocolitis in preterm infants. Microbiome. 2013;1:20.
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.
Pammi M, Cope J, Tarr PI, et al. Intestinal dysbiosis in preterm infants preceding necrotizing enterocolitis: a systematic review and meta-analysis. Microbiome. 2017;5:31.
Round JL, Mazmanian SK. Inducible Foxp3 + regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci USA. 2010;107:12204–12209.
Mayneris-Perxachs J, Fernandez-Real JM. Exploration of the microbiota and metabolites within body fluids could pinpoint novel disease mechanisms. FEBS J. 2019. https://doi.org/10.1111/febs.15130.
Neu J. Multiomics-based strategies for taming intestinal inflammation in the neonate. Curr Opin Clin Nutr Metab Care. 2019;22:217–222.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
Dr. Neu has a grant from Infant Bacterial Therapeutics and serves on the Scientific Advisory Boards of Astarte and Medela.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Neu, J. Necrotizing Enterocolitis: A Multi-omic Approach and the Role of the Microbiome. Dig Dis Sci 65, 789–796 (2020). https://doi.org/10.1007/s10620-020-06104-w
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10620-020-06104-w