Necrotizing Enterocolitis: Pathogenetic Features and Differential Diagnosis with Inflammatory Bowel Disease in Newborns

Necrotizing enterocolitis (NEC) is a disease primarily affecting premature infants. NEC pathogenesis is based on the development of inflammation damaging mucous membranes associated with bacterial colonization, intestinal epithelium immaturity, intestinal blood flow regulation, and excessive inflammatory response activation. Inflammatory bowel disease (IBD) with very early onset (VEO-IBD) can also manifest in the neonatal period. They are characterized by severe course, often resistant to traditional immunosuppressive therapy. This article discusses the features of NEC pathogenesis and differential diagnosis with VEO-IBD. Despite certain similarities in pathogenesis, NEC and IBD are different diseases. Infantile onset IBD is more often associated with monogenic diseases and primary immunodeficiency. VEO-IBD is a chronic disease characterized by damage to all intestinal layers and has a lower incidence compared to NEC. Its clinical manifestations may include chronic diarrhea, blood in stool, delayed physical development, perianal diseases, and ulcerations in the oral cavity. Infantile onset VEO-IBD usually affects the colon, while NEC affects the ileum in premature infants. The intestinal microbiome in VEO-IBD also has specific features. It has been reported that clinical cases of Crohn’s disease in patients who had NEC in the neonatal period are associated with NEC surgery. It is crucial to consider perinatal period features when assessing the IBD risk (prenatal effects of antibacterial therapy and smoking, several courses of antibacterial therapy during the first year of life, and formula feeding).

1. Niño DF, Sodhi CP, Hackam DJ. Necrotizing enterocolitis: new insights into pathogenesis and mechanisms. Nat Rev Gastroenterol Hepatol. 2016;13(10):590–600. doi: https://doi.org/10.1038/nrgastro.2016.119

2. Ginglen JG, Butki N. Necrotizing Enterocolitis. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024.

3. Alsaied A, Islam N, Thalib L. Global incidence of Necrotizing Enterocolitis: a systematic review and Meta-analysis. BMC Pediatr. 2020;20(1):344. doi: https://doi.org/10.1186/s12887-020-02231-5

4. Zozaya C, García González I, Avila-Alvarez A, et al. Incidence, Treatment, and Outcome Trends of Necrotizing Enterocolitis in Preterm Infants: A Multicenter Cohort Study. Front Pediatr. 2020;8:188. doi: https://doi.org/10.3389/fped.2020.00188

5. Ouahed J, Spencer E, Kotlarz D, et al. Very Early Onset Inflammatory Bowel Disease: A Clinical Approach With a Focus on the Role of Genetics and Underlying Immune Deficiencies. Inflamm Bowel Dis. 2020;26(6):820–842. doi: https://doi.org/10.1093/ibd/izz259.

6. Uhlig HH, Schwerd T, Koletzko S, et al. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology. 2014;147(5):990–1007.e3. https://doi.org/10.1053/j.gastro.2014.07.023

7. Kuenzig ME, Fung SG, Marderfeld L, et al. Twenty-first Century Trends in the Global Epidemiology of Pediatric-Onset Inflammatory Bowel Disease: Systematic Review. Gastroenterology. 2022;162(4):1147–1159.e4. doi: https://doi.org/10.1053/j.gastro.2021.12.282

8. Kornienko EA. Vospalitel’nyye zabolevaniya kishechnika u detey. Moscow: Prima Print; 2019. (In Russ).

9. Shapkina OA, Fedulova EN, Lavrova AE, Shabunina EI. Scientific and practical aspects of epidemiological studies of inflammatory bowel diseases in children living in Volga Federal District. Pediatria. Journal n.a. G.N. Speransky. 2016;95(6):50–55. (In Russ).

10. Belousova EA, Shelygin YA, Achkasov SI, et al. Clinical and Demographic Features and Treatment Approaches for Inflammatory Bowel Diseases (Crohn’s Disease, Ulcerative Colitis) in the Russia. The Primery Results of the Analysis of the National Register. Koloproktologia. 2023;22(1):65–82. (In Russ). doi: https://doi.org/10.33878/2073-7556-2023-22-1-65-82

11. Cannioto Z, Berti I, Martelossi S, et al. IBD and IBD mimicking enterocolitis in children younger than 2 years of age. Eur J Pediatr. 2009;168(2):149–155. doi: https://doi.org/10.1007/s00431-008-0721-2

12. Parente P, Pastore M, Grillo F, et al. Very Early Onset-IBD: evidence for the need of a multidisciplinary approach. Pathologica. 2022;114(1):3–11. doi: https://doi.org/10.32074/1591-951X-336

13. Underwood MA. Paneth cells and necrotizing enterocolitis. Gut Microbes. 2012;3(6):562–565. doi: https://doi.org/10.4161/gmic.21738

14. Demers-Mathieu V. The immature intestinal epithelial cells in preterm infants play a role in the necrotizing enterocolitis pathogenesis: A review. Health Sciences Review. 2022;4:100033. doi: https://doi.org/10.1016/j.hsr.2022.100033

15. Leaphart CL, Cavallo J, Gribar SC, et al. A critical role for TLR4 in the pathogenesis of necrotizing enterocolitis by modulating intestinal injury and repair. J Immunol. 2007;179(7):4808–4820. doi: https://doi.org/10.4049/jimmunol.179.7.4808

16. Gribar SC, Sodhi CP, Richardson WM, et al. Reciprocal expression and signaling of TLR4 and TLR9 in the pathogenesis and treatment of necrotizing enterocolitis. J Immunol. 2009;182(1):636–646. doi: https://doi.org/10.4049/jimmunol.182.1.636

17. Sodhi CP, Shi XH, Richardson WM, et al. Toll-like receptor-4 inhibits enterocyte proliferation via impaired beta-catenin signaling in necrotizing enterocolitis. Gastroenterology. 2010;138(1): 185–196. doi: https://doi.org/10.1053/j.gastro.2009.09.045

18. Hackam DJ, Sodhi CP. Toll-Like Receptor-Mediated Intestinal Inflammatory Imbalance in the Pathogenesis of Necrotizing Enterocolitis. Cell Mol Gastroenterol Hepatol. 2018;6(2): 229–238.e1. doi: https://doi.org/10.1016/j.jcmgh.2018.04.001

19. Good M, Sodhi CP, Yamaguchi Y, et al. The human milk oligosaccharide 2'-fucosyllactose attenuates the severity of experimental necrotising enterocolitis by enhancing mesenteric perfusion in the neonatal intestine. Br J Nutr. 2016;116(7): 1175–1187. doi: https://10.1017/S0007114516002944

20. Neal MD, Sodhi CP, Dyer M, et al. A critical role for TLR4 induction of autophagy in the regulation of enterocyte migration and the pathogenesis of necrotizing enterocolitis. J Immunol. 2013;190(7):3541–3551. doi: https://doi.org/10.4049/jimmunol.1202264

21. Sodhi CP, Wipf P, Yamaguchi Y, et al. The human milk oligosaccharides 2'-fucosyllactose and 6’-sialyllactose protect against the development of necrotizing enterocolitis by inhibiting toll-like receptor 4 signaling. Pediatr Res. 2021;89(1):91–101. doi: https://doi.org/10.1038/s41390-020-0852-3

22. Cai X, Golubkova A, Hunter CJ. Advances in our understanding of the molecular pathogenesis of necrotizing enterocolitis. BMC Pediatr. 2022;22(1):225. doi: https://doi.org/10.1186/s12887-022-03277-3

23. Xia X, Wang D, Yu L, et al. Activated M1 macrophages suppress c-kit expression via TNF-a-mediated upregulation of miR-222 in Neonatal Necrotizing Enterocolitis. Inflamm Res. 2021;70(3): 343–358. doi: https://doi.org/10.1007/s00011-021-01441-6

24. Schreurs RRCE, Baumdick ME, Sagebiel AF, et al. Human Fetal TNF-a-Cytokine-Producing CD4+ Effector Memory T Cells Promote Intestinal Development and Mediate Inflammation Early in Life. Immunity. 2019;50(2):462–476.e8. doi: https://doi.org/10.1016/j.immuni.2018.12.010

25. Pang Y, Du X, Xu X, et al. Impairment of regulatory T cells in patients with neonatal necrotizing enterocolitis. Int Immunopharmacol. 2018;63:19–25. doi: https://doi.org/10.1016/j.intimp.2018.07.029

26. 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(1):73–82. doi: https://doi.org/10.1136/gutjnl-2011-301551

27. Gephart SM, Gordon PV, Penn AH, et al. Changing the paradigm of defining, detecting, and diagnosing NEC: Perspectives on Bell’s stages and biomarkers for NEC. Semin Pediatr Surg. 2018;27(1): 3–10. doi: https://doi.org/10.1053/j.sempedsurg.2017.11.002

28. Patel RM, Ferguson J, McElroy SJ, et al. Defining necrotizing enterocolitis: current difficulties and future opportunities. Pediatr Res. 2020;88(Suppl 1):10–15. doi: https://doi.org/10.1038/s41390-020-1074-4

29. Gordon PV, Swanson JR, MacQueen BC, Christensen RD. A critical question for NEC researchers: Can we create a consensus definition of NEC that facilitates research progress? Semin Perinatol. 2017;41(1):7–14. doi: https://doi.org/10.1053/j.semperi.2016.09.013

30. Khashu M, Dame C, Lavoie PM, et al. Current Understanding of Transfusion-associated Necrotizing Enterocolitis: Review of Clinical and Experimental Studies and a Call for More Definitive Evidence. Newborn (Clarksville). 2022;1(1):201–208. doi: https://doi.org/10.5005/jp-journals-11002-0005

31. Nakib G, Sajwani S, Abusalah Z, et al. Recurrent supraventricular tachycardia and necrotizing enterocolitis: A causative role or a simple association? A case report and literature review. Pediatr Rep. 2018;10(3):7636. doi: https://doi.org/10.4081/pr.2018.7636

32. Mecarini F, Comitini F, Bardanzellu F, et al. Neonatal supraventricular tachycardia and necrotizing enterocolitis: case report and literature review. Ital J Pediatr. 2020;46(1):117. doi: https://doi.org/10.1186/s13052-020-00876-7

33. Fisher JG, Bairdain S, Sparks EA, et al. Serious congenital heart disease and necrotizing enterocolitis in very low birth weight neonates. J Am Coll Surg. 2015;220(6):1018–1026.e14. doi: https://doi.org/10.1016/j.jamcollsurg.2014.11.026

34. Siano E, Lauriti G, Ceccanti S, Zani A. Cardiogenic Necrotizing Enterocolitis: A Clinically Distinct Entity from Classical Necrotizing Enterocolitis. Eur J Pediatr Surg. 2019;29(1):14–22. doi: https://doi.org/10.1055/s-0038-1668144

35. Dorofeeva EI, Podurovskaya YuL, Burov AA, et al. Diagnostika i konservativnoye lecheniye novorozhdennykh s nekrotiziruyushchim enterokolitom: Clinical guidelines. 2014. (In Russ).] Доступно по: https://neonatology.pro/wp-content/uploads/2014/08/Protokol_NEC_2014.pdf. Ссылка активна на 17 июня 2024

36. Kappelman MD, Grand RJ. Does inflammatory bowel disease develop in infants? Inflamm Bowel Dis. 2008;14(Suppl 2):S6–S8. doi: https://doi.org/10.1002/ibd.20544

37. Feldens L, Souza JCK, Fraga JC. There is an association between disease location and gestational age at birth in newborns submitted to surgery due to necrotizing enterocolitis. J Pediatr (Rio J). 2018;94(3):320–324. doi: https://doi.org/10.1016/j.jped.2017.06.010

38. Ebrahimi S MS, Khademi G MD, Jafari SA MD, et al. Neonatal Presentation of Unremitting Inflammatory Bowel Disease. Iran J Med Sci. 2018;43(3):328–331.

39. Shumilov PV, Shchigoleva AE. Features of very early-onset inflammatory bowel disease: the experience of the Federal Pediatric Center. Pediatric Nutrition. 2021;19(3):5–13. (In Russ). doi: https://doi.org/10.20953/1727-5784-2021-3-5-13

40. Shchigoleva AE. Vospalitel’nye zabolevaniya kishechnika s ochen’ rannim nachalom u detei: osobennosti diagnostiki i lecheniya. [dissertation]. Moscow; 2020. (In Russ).

41. Yablokova EA, Dzhabarova AK, Lokhmatov MM, et al. Extraintestinal manifestations in inflammatory bowel diseases in children, a modern view of the problem. Exp Clin Gastroenterol. 2023;209(1):165–177. (In Russ). doi: https://doi.org/10.31146/1682-8658-ecg-209-1-165-177

42. Kaplina A, Kononova S, Zaikova E, et al. Necrotizing Enterocolitis: The Role of Hypoxia, Gut Microbiome, and Microbial Metabolites. Int J Mol Sci. 2023;24(3):2471. doi: https://doi.org/10.3390/ijms24032471

43. Conrad MA, Bittinger K, Ren Y, et al. The intestinal microbiome of inflammatory bowel disease across the pediatric age range. Gut Microbes. 2024;16(1):2317932. doi: https://doi.org/10.1080/19490976.2024.2317932

44. Kaplina AV, Azarov DV, Petrova NA, et al. Features of intestinal microbiome in necrotizing enterocolitis in preterm neonates and full-term neonates with congenital heart disease based on metagenomic sequencing. Voprosy prakticheskoi pediatrii = Clinical Practice in Pediatrics. 2023;18(6):68–83. (In Russ). doi: https://doi.org/10.20953/1817-7646-2023-6-68-8

45. Nakaya K, Iinuma Y, Hirayama Y, et al. A Case of a Two-MonthOld Boy Diagnosed with Infantile Crohn’s Disease Based on an Atypical Perianal Lesion. Case Rep Pediatr. 2020;2020:8832856. doi: https://doi.org/10.1155/2020/8832856

46. Iida C, Tatsumi A, Fujino H, et al. Infantile Inflammatory Bowel Disease in a Three-Month-Old-Boy. Cureus. 2021;13(1):e12743. doi: https://doi.org/10.7759/cureus.12743

47. Konovalova AM, Pechkurov DV, Tyazheva AA. Chronic Diarrhea as a Debut Manifestation of Crohn’s Disease in Infant: Clinical Case. Voprosy sovremennoi pediatrii — Current Pediatrics. 2023;22(1):68–72. (In Russ). doi: https://doi.org/10.15690/vsp.v22i1.2518

48. Xu L, Lochhead P, Ko Y, et al. Systematic review with metaanalysis: breastfeeding and the risk of Crohn’s disease and ulcerative colitis. Aliment Pharmacol Ther. 2017;46(9):780–789. doi: https://doi.org/10.1111/apt.14291

49. Canova C, Ludvigsson JF, Di Domenicantonio R, et al. Perinatal and Antibiotic Exposures and the Risk of Developing ChildhoodOnset Inflammatory Bowel Disease: A Nested Case-Control Study Based on a Population-Based Birth Cohort. Int J Environ Res Public Health. 2020;17(7):2409. doi: https://doi.org/10.3390/ijerph17072409

50. Agrawal M, Sabino J, Frias-Gomes C, et al. Early life exposures and the risk of inflammatory bowel disease: Systematic review and meta-analyses. EClinicalMedicine. 2021;36:100884. doi: https://doi.org/10.1016/j.eclinm.2021.100884

51. Miró-González ÁA, Maldonado-Chaar SM, ZambranaValenzuela R, et al. Development of Very-Early-Onset Inflammatory Bowel Disease After Multiple Early-Life Antibiotic Exposures: A Case Report and Literature Review. Cureus. 2023;15(1):e33813. doi: https://doi.org/10.7759/cureus.33813

52. Velosa M, Hochner H, Yerushalmi B, et al. Pre- and Perinatal Factors Predicting Inflammatory Bowel Disease: A PopulationBased Study with Fifty Years of Follow-Up. J Crohns Colitis. 2022;16(9):1397–1404. doi: https://doi.org/10.1093/ecco-jcc/jjac043

53. Kozuch P. Two Cases of Crohn’s Disease in the Setting of past Necrotizing Enterocolitis: 943. Am J Gastroenterol. 2008;103: S370–S371.

54. Carnell C, McHugh J, Lincango E, Holubar S. S18 Crohn’s Jejunoileitis in an Adult Patient With Prior Enterectomy After Necrotizing Enterocolitis: A Case Mandating Bowel Preserving Surgery. Am J Gastroenterol. 2022;117(1):S5. doi: https://doi.org/10.14309/01.ajg.0000897580.29305.ab

55. Ashcheulova AP, Levchuk LV. Sluchai bolezni Krona u rebenka s sindromom korotkoi kishki posle khirurgicheskoi korrektsii neirointestinal’noi displazii. Aktual’nye voprosy sovremennoi meditsinskoi nauki i zdravookhraneniya: Proceedings of the VI International Scientific and Practical Conference of Young Scientists and Students. Ekaterinburg: Publishing House Ural State Medical University; 2021. pp. 271–276. (In Russ).

56. Cuna A, George L, Sampath V. Genetic predisposition to necrotizing enterocolitis in premature infants: Current knowledge, challenges, and future directions. Semin Fetal Neonatal Med. 2018;23(6): 387–393. doi: https://doi.org/10.1016/j.siny.2018.08.006

57. Jilling T, Ambalavanan N, Cotten CM, et al. Surgical necrotizing enterocolitis in extremely premature neonates is associated with genetic variations in an intergenic region of chromosome 8. Pediatr Res. 2018;83(5):943–953. doi: https://doi.org/10.1038/pr.2018.33

58. Tremblay É, Thibault MP, Ferretti E, et al. Gene expression profiling in necrotizing enterocolitis reveals pathways common to those reported in Crohn’s disease. BMC Med Genomics. 2016;9:6. doi: https://doi.org/10.1186/s12920-016-0166-9

59. Kornienko EA, Krupina AN, Gabrusskaya TV, Kalinina NM. Inflammatory bowel disease with a very early onset. Almanac of Clinical Medicine. 2016;44(6):719–733. (In Russ). doi: https://doi.org/10.18786/2072-0505-2016-44-6-719-733

60. Zheng HB, de la Morena MT, Suskind DL. The Growing Need to Understand Very Early Onset Inflammatory Bowel Disease. Front Immunol. 2021;12:675186. doi: https://doi.org/10.3389/fimmu.2021.675186

61. Kornienko EA, Krupina AN, Kalinina NM, Bychkova NV. Osobennosti immunologicheskogo statusa u detey s vospalitel’nymi zabolevaniyami kishechnika. Gastroenterologiya Sankt-Peterburga. 2018;(2):73–73b. (In Russ).

62.