Abstract
Necrotizing enterocolitis (NEC) remains among the most common and devastating diseases in neonates. Despite advances in neonatal clinical care, specific treatment strategies and diagnostic modalities remain lacking. As a result, morbidity and mortality remain high. Improved understanding of the pathogenesis of NEC has the potential for improved therapeutics. Some of the areas of research leading to promising discoveries include inhibition of Toll-like receptor signaling, modulation of vascular endothelial growth factor signal pathways, defining metabolomic alterations in NEC to discover potential biomarkers, probing for genetic predispositions to NEC susceptibility, determining mechanistic relations between anemia and NEC, and microflora modulation through the use of probiotics. All of these areas may represent novel promising approaches to the prevention and treatment of NEC. This review will focus on these current and possible therapeutic perspectives.
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References
Wang, K., Tao, G. & Sylvester, K. G. Recent Advances in prevention and therapies for clinical or experimental necrotizing enterocolitis. Dig. Dis. Sci. 64, 3078–3085 (2019).
Good, M., Sodhi, C. P. & Hackam, D. J. Evidence-based feeding strategies before and after the development of necrotizing enterocolitis. Expert Rev. Clin. Immunol. 10, 875–884 (2014).
Elgin, T. G., Kern, S. L. & McElroy, S. J. Development of the neonatal intestinal microbiome and its association with necrotizing enterocolitis. Clin. Ther. 38, 706–715 (2016).
Sankaran, K. et al. Variations in incidence of necrotizing enterocolitis in Canadian neonatal intensive care units. J. Pediatr. Gastroenterol. Nutr. 39, 366–372 (2004).
Bowker, R. M., Yan, X. & De Plaen, I. G. Intestinal microcirculation and necrotizing enterocolitis: the vascular endothelial growth factor system. Semin. Fetal Neonatal Med. 23, 411–415 (2018).
Arthur, C. M. et al. Anemia induces gut inflammation and injury in an animal model of preterm infants. Transfusion 59, 1233–1245 (2019).
Perrone, S., Tataranno, M. L., Santacroce, A., Negro, S. & Buonocore, G. The role of oxidative stress on necrotizing enterocolitis in very low birth weight infants. Curr. Pediatr. Rev. 10, 202–207 (2014).
Patel, R. M. et al. Association of red blood cell transfusion, anemia, and necrotizing enterocolitis in very low-birth-weight infants. JAMA 315, 889–897 (2016).
Yan, X. et al. Lack of VEGFR2 signaling causes maldevelopment of the intestinal microvasculature and facilitates necrotizing enterocolitis in neonatal mice. Am. J. Physiol. Gastrointest. Liver Physiol. 310, G716–G725 (2016).
Bowker, R. M. et al. Dimethyloxalylglycine preserves the intestinal microvasculature and protects against intestinal injury in a neonatal mouse NEC model: role of VEGF signaling. Pediatr. Res. 83, 545–553 (2018).
MohanKumar, K. et al. A murine neonatal model of necrotizing enterocolitis caused by anemia and red blood cell transfusions. Nat. Commun. 10, 3494 (2019).
Sabnis, A. et al. Intestinal vascular endothelial growth factor is decreased in necrotizing enterocolitis. Neonatology 107, 191–198 (2015).
Robinson, J. R. et al. Neurodevelopmental considerations in surgical necrotizing enterocolitis. Semin. Pediatr. Surg. 27, 52–56 (2018).
Rees, C. M., Pierro, A. & Eaton, S. Neurodevelopmental outcomes of neonates with medically and surgically treated necrotizing enterocolitis. Arch. Dis. Child Fetal Neonatal Ed. 92, F193–F198 (2007).
Hintz, S. R. et al. Neurodevelopmental and growth outcomes of extremely low birth weight infants after necrotizing enterocolitis. Pediatrics 115, 696–703 (2005).
Adams-Chapman, I. Necrotizing enterocolitis and neurodevelopmental outcome. Clin. Perinatol. 45, 453–466 (2018).
Nino, D. F. et al. Cognitive impairments induced by necrotizing enterocolitis can be prevented by inhibiting microglial activation in mouse brain. Sci. Transl. Med. 10, eaan0237. https://doi.org/10.1126/scitranslmed.aan0237 (2018).
Egan, C. E. et al. Toll-like receptor 4-mediated lymphocyte influx induces neonatal necrotizing enterocolitis. J. Clin. Invest. 126, 495–508 (2016).
Niño, D. F., Sodhi, C. P. & Hackam, D. J. Necrotizing enterocolitis: new insights into pathogenesis and mechanisms. Nat. Rev. Gastroenterol. Hepatol. 13, 590–600 (2016).
Good, M. et al. Breast milk protects against the development of necrotizing enterocolitis through inhibition of Toll-like receptor 4 in the intestinal epithelium via activation of the epidermal growth factor receptor. Mucosal Immunol. 8, 1166–1179 (2015).
Shin, S. H. et al. Surgical necrotizing enterocolitis versus spontaneous intestinal perforation in white matter injury on brain magnetic resonance imaging. Neonatology 110, 148–154 (2016).
Merhar, S. L., Ramos, Y., Meinzen-Derr, J. & Kline-Fath, B. M. Brain magnetic resonance imaging in infants with surgical necrotizing enterocolitis or spontaneous intestinal perforation versus medical necrotizing enterocolitis. J. Pediatr. 164, 410–412.e411 (2014).
Martin, C. R. et al. Neurodevelopment of extremely preterm infants who had necrotizing enterocolitis with or without late bacteremia. J. Pediatr. 157, 751–756.e751 (2010).
Biouss, G. et al. Experimental necrotizing enterocolitis induces neuroinflammation in the neonatal brain. J. Neuroinflamm. 16, 97 (2019).
Hackam, D. J., Sodhi, C. P. & Good, M. New insights into necrotizing enterocolitis: from laboratory observation to personalized prevention and treatment. J. Pediatr. Surg. 54, 398–404 (2019).
Jilling, T. et al. Surgical necrotizing enterocolitis in extremely premature neonates is associated with genetic variations in an intergenic region of chromosome 8. Pediatr. Res. 83, 943–953 (2018).
Cuna, A. & Sampath, V. Genetic alterations in necrotizing enterocolitis. Semin. Perinatol. 41, 61–69 (2017).
Cuna, A., George, L. & Sampath, V. Genetic predisposition to necrotizing enterocolitis in premature infants: current knowledge, challenges, and future directions. Semin. Fetal Neonatal Med. 23, 387–393 (2018).
Sampath, V. et al. SIGIRR genetic variants in premature infants with necrotizing enterocolitis. Pediatrics 135, e1530–e1534 (2015).
Hackam, D. J. & Sodhi, C. P. Toll-like receptor-mediated intestinal inflammatory imbalance in the pathogenesis of necrotizing enterocolitis. Cell. Mol. Gastroenterol. Hepatol. 6, 229–238 e221 (2018).
Fawley, J. et al. Single-immunoglobulin interleukin-1-related receptor regulates vulnerability to TLR4-mediated necrotizing enterocolitis in a mouse model. Pediatr. Res. 83, 164–174 (2018).
Wang, S. L. et al. Intestinal autophagy links psychosocial stress with gut microbiota to promote inflammatory bowel disease. Cell Death Dis. 10, 391 (2019).
Lavoie, S. et al. The Crohn’s disease polymorphism, ATG16L1 T300A, alters the gut microbiota and enhances the local Th1/Th17 response. Elife 8, e39982. https://doi.org/10.7554/eLife.39982 (2019).
Liu, J. Z. et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat. Genet. 47, 979–986 (2015).
Iida, T., Onodera, K. & Nakase, H. Role of autophagy in the pathogenesis of inflammatory bowel disease. World J. Gastroenterol. 23, 1944–1953 (2017).
Yuan, Y. et al. TNF-alpha induces autophagy through ERK1/2 pathway to regulate apoptosis in neonatal necrotizing enterocolitis model cells IEC-6. Cell Cycle 17, 1390–1402 (2018).
Neal, M. D. et al. A critical role for TLR4 induction of autophagy in the regulation of enterocyte migration and the pathogenesis of necrotizing enterocolitis. J. Immunol. 190, 3541–3551 (2013).
Sampath, V. et al. A functional ATG16L1 (T300A) variant is associated with necrotizing enterocolitis in premature infants. Pediatr. Res. 81, 582–588 (2017).
Strimbu, K. & Tavel, J. A. What are biomarkers? Curr. Opin. HIV AIDS 5, 463–466 (2010).
Sylvester, K. G. et al. Acylcarnitine profiles reflect metabolic vulnerability for necrotizing enterocolitis in newborns born premature. J. Pediatr. 181, 80–85.e81 (2017).
Sylvester, K. G. et al. A novel urine peptide biomarker-based algorithm for the prognosis of necrotising enterocolitis in human infants. Gut 63, 1284–1292 (2014).
Nakayuenyongsuk, W. et al. Point-of-care fecal calprotectin monitoring in preterm infants at risk for necrotizing enterocolitis. J. Pediatr. 196, 98–103.e101 (2018).
MacQueen, B. C. et al. Reference intervals for stool calprotectin in preterm neonates and their utility for the diagnosis of necrotizing enterocolitis. J. Perinatol. 38, 1379–1385 (2018).
van Zoonen, A. et al. Serial fecal calprotectin in the prediction of necrotizing enterocolitis in preterm neonates. J. Pediatr. Surg. 54, 455–459 (2019).
Jiang, P. et al. Antibiotic treatment preventing necrotising enterocolitis alters urinary and plasma metabolomes in preterm pigs. J. Proteome Res. 16, 3547–3557 (2017).
Call, L. et al. Metabolomic signatures distinguish the impact of formula carbohydrates on disease outcome in a preterm piglet model of NEC. Microbiome 6, 111 (2018).
Underwood, M. A. Probiotics and the prevention of necrotizing enterocolitis. J. Pediatr. Surg. 54, 405–412 (2019).
Patel, R. M. & Underwood, M. A. Probiotics and necrotizing enterocolitis. Semin. Pediatr. Surg. 27, 39–46 (2018).
Underwood, M. A. Arguments for routine administration of probiotics for NEC prevention. Curr. Opin. Pediatr. 31, 188–194 (2019).
Underwood, M. A. et al. Bifidobacterium longum subsp. infantis in experimental necrotizing enterocolitis: alterations in inflammation, innate immune response, and the microbiota. Pediatr. Res. 76, 326–333 (2014).
Olson, J. K. et al. An enhanced Lactobacillus reuteri biofilm formulation that increases protection against experimental necrotizing enterocolitis. Am. J. Physiol. Gastrointest. Liver Physiol. 315, G408–G419 (2018).
Olson, J. K. et al. Harvesting the benefits of biofilms: a novel probiotic delivery system for the prevention of necrotizing enterocolitis. J. Pediatr. Surg. 51, 936–941 (2016).
Kersey, J. H. Fifty years of studies of the biology and therapy of childhood leukemia. Blood 90, 4243–4251 (1997).
Caplan, M. S. et al. Necrotizing enterocolitis: using regulatory science and drug development to improve outcomes. J. Pediatr. 212, 208–215.e1. https://doi.org/10.1016/j.jpeds.2019.05.032 (2019).
Gordon, P. V. & Swanson, J. R. Necrotizing enterocolitis is one disease with many origins and potential means of prevention. Pathophysiology 21, 13–19 (2014).
Gephart, S. M. et al. Changing the paradigm of defining, detecting, and diagnosing NEC: Perspectives on Bell’s stages and biomarkers for NEC. Semin. Pediatr. Surg. 27, 3–10 (2018).
Ares, G. J., McElroy, S. J. & Hunter, C. J. The science and necessity of using animal models in the study of necrotizing enterocolitis. Semin. Pediatr. Surg. 27, 29–33 (2018).
Acknowledgements
This publication of this article was sponsored by the Necrotizing Enterocolitis (NEC) Society, Patient-Centered Outcomes Research Institute, and National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development.
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R.D.S., R.R., G.E.B., and S.J.M. all made substantial contributions to conception, drafting, critical revisions, and approval of the manuscript.
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G.E.B. receives support from Scioto Biosciences, holds stock options in the company, and receives royalties for US Patent No. 5811393. S.J.M. has received consulting and lecture fees from Abbott, and grant support from Evolve Biosystems and the Carver College of Medicine at the University of Iowa. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. R.D.S. and R.R. declared no competing interests.
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Shelby, R.D., Raab, R., Besner, G.E. et al. Hope on the horizon: promising novel therapies for necrotizing enterocolitis. Pediatr Res 88 (Suppl 1), 30–34 (2020). https://doi.org/10.1038/s41390-020-1077-1
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DOI: https://doi.org/10.1038/s41390-020-1077-1
