Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2024; 23: 119-126
Цитокиновый профиль кала недоношенных новорожденных в диагностике некротизирующего энтероколита: результаты пилотного исследования
https://doi.org/10.24287/1726-1708-2024-23-1-119-126Аннотация
Цель исследования: определить уровень фекальных цитокинов у глубоко недоношенных новорожденных при развитии неспецифичных клинических проявлений некротизирующего энтероколита (НЭК) и дискинезии желудочно-кишечного тракта (ЖКТ).
Исследование одобрено этическим комитетом и утверждено решением ученого совета ФГБУ «НМИЦ АГП им. акад. В. И. Кулакова» Минздрава России. Информированное согласие об участии в исследовании было получено от родителей всех пациентов. Исследование проведено на базе ФГБУ «НМИЦ АГП им. акад. В. И. Кулакова» Минздрава России в период с июня 2020 г. по декабрь 2022 г. Образцы кала недоношенных новорожденных гестационного возраста 32 недели и менее, проходивших лечение в отделении реанимации и интенсивной терапии им. проф. А. Г. Антонова, собирались ежедневно на протяжении первых 14 дней жизни. Для анализа были выбраны образцы от 46 новорожденных: образцы кала в день возникновения эпизода интолерантности к энтеральной нагрузке и контрольные образцы кала новорожденных, не развивших неспецифичные клинические проявления НЭК и дискинезии ЖКТ, соответствующие дню достижения объема энтерального питания 100 мл/кг/сут. Ретроспективно по результатам диагностики НЭК и дискинезии ЖКТ образцы кала были разделены на 3 группы: группа НЭК (n = 8), группа дискинезии ЖКТ (n = 14) и группа контроля (n = 24). В образцах кала глубоко недоношенных новорожденных с НЭК II стадии и выше в день возникновения начальных симптомов заболевания отмечается значимое повышение уровней IL-6, IL-8, IL-10, TNF-a. При этом цитокиновый профиль кала новорожденных из группы дискинезии ЖКТ достоверно не отличался от группы контроля ни по одному показателю. При развитии НЭК на стадии возникновения интолерантности к энтеральному питанию в кале выявляются высокие уровни IL-6, IL-8, IL-10 и TNF-a, что может свидетельствовать о перспективности метода определения про- и противовоспалительного профиля цитокинов кала в дифференциальной диагностике НЭК и дискинезии ЖКТ у глубоко недоношенных новорожденных.
Список литературы
1. Fitzgibbons S.C., Ching Y., Yu D., Carpenter J., Kenny M., Weldon C., et al. Mortality of necrotizing enterocolitis expressed by birth weight categories. J Pediatr Surg 2009; 44 (6): 1072–5: discussion 1075–6. DOI: 10.1016/j.jpedsurg.2009.02.013
2. MohanKumar K., Namachivayam K., Ho T.T.B., Torres B.A., Ohls R.K., Maheshwari A. Cytokines and growth factors in the developing intestine and during necrotizing enterocolitis. Vol. 41, Seminars in Perinatology. W.B. Saunders; 2017. Рp. 52–60.
3. Lodha A., Howlett A., Ahmed T., Moore A.M. The Role of Interleukin-6 and Interleukin-8 Circulating Cytokines in Differentiating between Feeding Intolerance and Necrotizing Enterocolitis in Preterm Infants. Am J Perinatol 2017; 34 (13): 1286–92. DOI: 10.1055/s-0037-1603329
4. Benkoe T.M., Mechtler T.P., Weninger M., Pones M., Rebhandl W., Kasper D.C. Serum levels of interleukin-8 and gut-associated biomarkers in diagnosing necrotizing enterocolitis in preterm infants. J Pediatr Surg 2014; 49 (10): 1446–51. DOI: 10.1016/j.jpedsurg.2014.03.012
5. Martin C.R., Bellomy M., Allred E.N., Fichorova R.N., Leviton A. Systemic inflammation associated with severe intestinal injury in extremely low gestational age newborns. Fetal Pediatr Pathol 2013; 32 (3): 222–34. DOI: 10.3109/15513815.2012.721477
6. Seo Y.-mi, Lin Y.K., Im S.A., Sung I.K., Youn Y.A. Interleukin 8 may predict surgical necrotizing enterocolitis in infants born less than 1500 g. Cytokine 2021; 137: 155–63. DOI: 10.1016/j.cyto.2020.155343
7. Wisgrill L., Weinhandl A., Unterasinger L., Amann G., Oehler R., Metzelder M.L., et al. Interleukin-6 serum levels predict surgical intervention in infants with necrotizing enterocolitis. J Pediatr Surg 2019; 54 (3): 449–54. DOI: 10.1016/j.jpedsurg.2018.08.003
8. Duffy L.C., Zielezny M.A., Carrion V., Griffiths E., Dryja D., Hilty M., et al. Concordance of bacterial cultures with endotoxin and interleukin-6 in necrotizing enterocolitis. Dig Dis Sci 1997; 42 (2): 359–65. DOI: 10.1023/a:1018826204819
9. Gómez M., Moles L., Espinosa-Martos I., Bustos G., de Vos W.M., Fernández L., et al. Bacteriological and Immunological Profiling of Meconium and Fecal Samples from Preterm Infants: A Two-Year Follow-Up Study. Nutrients 2017; 9 (12): 1293. DOI: 10.3390/nu9121293
10. Lemme-Dumit J.M., Song Y., Lwin H.W., Hernandez-Chavez C., Sundararajan S., Viscardi R.M., et al. Altered Gut Microbiome and Fecal Immune Phenotype in Early Preterm Infants With Leaky Gut. Front Immunol 2022; 13: 815046. DOI: 10.3389/fimmu.2022.815046
11. Richter M., Topf H.G., Gröschl M., Fröhlich T., Tzschoppe A., Wenzl T.G., Köhler H. Influence of gestational age, cesarean section, and type of feeding on fecal human b-defensin 2 and tumor necrosis factor-a. J Pediatr Gastroenterol Nutr 2010; 51 (1): 103–5. DOI: 10.1097/MPG.0b013e3181cd26f9
12. Indrio F., Riezzo G., Tafuri S., Ficarella M., Carlucci B., Bisceglia M., et al. Probiotic supplementation in preterm: Feeding intolerance and hospital cost. Nutrients 2017; 9 (9): 965. DOI: 10.3390/nu9090965
13. Balachandran B., Dutta S., Singh R., Prasad R., Kumar P. Bovine colostrum in prevention of necrotizing enterocolitis and sepsis in very low birth weight neonates: A randomized, double-blind, placebo-controlled pilot trial. J Trop Pediatr 2017; 63 (1): 10–7. DOI: 10.1093/tropej/fmw029
14. Zenner C., Chalklen L., Adjei H., Dalby M.J., Mitra S., Cornwell E., et al. Noninvasive Fecal Cytokine and Microbiota Profiles Predict Commencement of Necrotizing Enterocolitis in a Proof-of-Concept Study. Gastro Hep Adv 2023; 2 (5): 666–75. DOI: 10.1016/j.gastha.2023.03.003
15. Дорофеева Е.И., Подуровская Ю.Л., Буров А.А., Рюмина И.И., Нароган М.В., Грошева Е.В. и др. Диагностика и консервативное лечение новорожденных с некротизирующим энтероколитом (проект клинических рекомендаций). Неонатология: Новости. Мнения. Обучение 2014; 2 (4): 84–92.
16. Walsh M.C., Kliegman R.M. Necrotizing enterocolitis: Treatment based on staging criteria. Pediatr Clin North Am 1986; 33 (1): 179–201. DOI: 10.1016/s0031-3955(16)34975-6
17. van Belkum M., Mendoza Alvarez L., Neu J. Preterm neonatal immunology at the intestinal interface. Cell Mol Life Sci 2020; 26 (7):1209–27. DOI: 10.1007/s00018-019-03316-w
18. Westerbeek E.A.M., Mørch E., Lafeber H.N., Fetter W.P.F., Twisk J.W.R., van Elburg R.M. Effect of Neutral and Acidic Oligosaccharides on Fecal IL-8 and Fecal Calprotectin in Preterm Infants. 2011. [Electronic resource] URL: www.controlled-trials.com (accessed 02. 02. 2024).
19. Harris M.C., D’Angio C.T., Gallagher P.R., Kaufman D., Evans J., Kilpatrick L. Cytokine elaboration in critically ill infants with bacterial sepsis, necrotizing entercolitis, or sepsis syndrome: Correlation with clinical parameters of inflammation and mortality. J Pediatri 2005; 147 (4): 462–8. DOI: 10.1016/j.jpeds.2005.04.037
20. Ebach D.R., Newberry R., Stenson W.F. Differential Role of Tumor Necrosis Factor Receptors in TNBS Colitis. Inflamm Bowel Dis 2005; 11 (6): 533–40. DOI: 10.1097/01.mib.0000163698.34592.30
21. Tatiya-Aphiradee N., Chatuphonprasert W., Jarukamjorn K. Immune response and inflammatory pathway of ulcerative colitis. J Basic Clin Physiol Pharmacol 2018; 30 (1): 1–10. DOI: 10.1515/jbcpp-2018-0036
22. Duess J.W., Sampah M.E., Lopez C.M., Tsuboi K., Scheese D.J., Sodhi C.P., Hackam D.J. Necrotizing enterocolitis, gut microbes, and sepsis. Gut Microbes 2023; 15 (1): 2221470. DOI: 10.1080/19490976.2023.2221470
23. Pott J., Kabat A.M., Maloy K.J. Intestinal Epithelial Cell Autophagy Is Required to Protect against TNF-Induced Apoptosis during Chronic Colitis in Mice. Cell Host Microbe 2018; 23 (2): 191–202.e4. DOI: 10.1016/j.chom.2017.12.017
24. Baregamian N., Song J., Bailey C.E., Papaconstantinou J., Evers B.M., Chung D.H. Tumor Necrosis Factor-a and Apoptosis Signal-Regulating Kinase 1 Control Reactive Oxygen Species Release, Mitochondrial Autophagy and C-Jun N-Terminal Kinase/P38 Phosphorylation During Necrotizing Enterocolitis. Oxid Med Cell Longev 2009; 2 (5): 297–306. DOI: 10.4161/oxim.2.5.9541
25. Hui L., Dai Y., Guo Z., Zhang J., Zheng F., Bian X., et al. Immunoregulation effects of different gdT cells and toll-like receptor signaling pathways in neonatal necrotizing enterocolitis. Medicine (Baltimore) 2017; 96 (8): e6077. Doi: 10.1097/MD.0000000000006077
26. Friedrich M., Pohin M., Powrie F. Cytokine Networks in the Pathophysiology of Inflammatory Bowel Disease. Immunity 2019; 50 (4): 992–1006. DOI: 10.1016/j.immuni.2019.03.017
27. Gareb B., Otten A.T., Frijlink H.W., Dijkstra G., Kosterink J.G.W. Review: Local Tumor Necrosis Factor-a Inhibition in Inflammatory Bowel Disease. Pharmaceutics 2020; 12 (6): 539. DOI: 10.3390/pharmaceutics12060539
28. Tayman C., Aydemir S., Yakut I., Serkant U., Ciftci A., Arslan E., Koç O. TNF-a Blockade Efficiently Reduced Severe Intestinal Damage in Necrotizing Enterocolitis. J Invest Surg 2016; 29 (4): 209–17. DOI: 10.3109/08941939.2015.1127449
29. Emami C.N., Chokshi N., Wang J., Hunter C., Guner Y., Goth K., et al. Role of interleukin-10 in the pathogenesis of necrotizing enterocolitis. Am J Surg 2012; 203 (4): 428–35. DOI: 10.1016/j.amjsurg.2011.08.016
30. Konnikova Y., Zaman M.M., Makda M., D’Onofrio D., Freedman S.D., Martin C.R. Late enteral feedings are associated with intestinal inflammation and adverse neonatal outcomes. PLoS One 2015; 10 (7): e0132924. DOI: 10.1371/journal.pone.0132924
Pediatric Hematology/Oncology and Immunopathology. 2024; 23: 119-126
Fecal cytokine profile in preterm infants in the diagnosis of necrotizing enterocolitis: pilot study results
https://doi.org/10.24287/1726-1708-2024-23-1-119-126Abstract
In this study, we sought to determine fecal cytokine levels in very preterm newborns at the onset of non-specific clinical symptoms of necrotizing enterocolitis (NEC) and decreased gastrointestinal (GI) motility. The study was approved by the Ethics Committee and the Scientific Council of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after the Academician V. I. Kulakov of Ministry of Healthcare of the Russian Federation. Each patient’s parents gave their informed consent to their child’s participation in the study. The study was conducted at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after the Academician V. I. Kulakov over the period from June 2020 to December 2022. Fecal samples from preterm neonates with gestational age ≤ 32 weeks treated at the A.G. Antonov ICU were collected daily over their first 14 days of life. Samples from 46 newborns were selected for analysis: fecal samples collected on the day of an enteral feeding intolerance episode and fecal samples from controls who had not developed non-specific clinical symptoms of NEC or decreased GI motility, collected on the day when enteral intake reached 100 ml/kg/day. Based on the results of NEC and decreased GI motility diagnosis, stool samples were retrospectively divided into 3 groups: an NEC group (n = 8), a decreased GI motility group (n = 14) and a control group (n = 24). In the fecal samples of the very preterm newborns with NEC stage ≥ II, there was a significant increase in IL-6, IL-8, IL-10, TNF-a levels at the onset of initial symptoms of the disease. At the same time, the cytokine profile of the feces of the decreased GI motility patients did not differ significantly from the control group in any of the parameters. In cases of NEC, high IL-6, IL-8, IL-10 and TNF-a levels were detected in the patients’ stool at the onset of enteral feeding intolerance, suggesting that the method under investigation (aimed at determining the pro- and anti-inflammatory profile of fecal cytokines) may be a promising new tool for differentiating NEC from decreased GI motility in very preterm newborns.
References
1. Fitzgibbons S.C., Ching Y., Yu D., Carpenter J., Kenny M., Weldon C., et al. Mortality of necrotizing enterocolitis expressed by birth weight categories. J Pediatr Surg 2009; 44 (6): 1072–5: discussion 1075–6. DOI: 10.1016/j.jpedsurg.2009.02.013
2. MohanKumar K., Namachivayam K., Ho T.T.B., Torres B.A., Ohls R.K., Maheshwari A. Cytokines and growth factors in the developing intestine and during necrotizing enterocolitis. Vol. 41, Seminars in Perinatology. W.B. Saunders; 2017. Rp. 52–60.
3. Lodha A., Howlett A., Ahmed T., Moore A.M. The Role of Interleukin-6 and Interleukin-8 Circulating Cytokines in Differentiating between Feeding Intolerance and Necrotizing Enterocolitis in Preterm Infants. Am J Perinatol 2017; 34 (13): 1286–92. DOI: 10.1055/s-0037-1603329
4. Benkoe T.M., Mechtler T.P., Weninger M., Pones M., Rebhandl W., Kasper D.C. Serum levels of interleukin-8 and gut-associated biomarkers in diagnosing necrotizing enterocolitis in preterm infants. J Pediatr Surg 2014; 49 (10): 1446–51. DOI: 10.1016/j.jpedsurg.2014.03.012
5. Martin C.R., Bellomy M., Allred E.N., Fichorova R.N., Leviton A. Systemic inflammation associated with severe intestinal injury in extremely low gestational age newborns. Fetal Pediatr Pathol 2013; 32 (3): 222–34. DOI: 10.3109/15513815.2012.721477
6. Seo Y.-mi, Lin Y.K., Im S.A., Sung I.K., Youn Y.A. Interleukin 8 may predict surgical necrotizing enterocolitis in infants born less than 1500 g. Cytokine 2021; 137: 155–63. DOI: 10.1016/j.cyto.2020.155343
7. Wisgrill L., Weinhandl A., Unterasinger L., Amann G., Oehler R., Metzelder M.L., et al. Interleukin-6 serum levels predict surgical intervention in infants with necrotizing enterocolitis. J Pediatr Surg 2019; 54 (3): 449–54. DOI: 10.1016/j.jpedsurg.2018.08.003
8. Duffy L.C., Zielezny M.A., Carrion V., Griffiths E., Dryja D., Hilty M., et al. Concordance of bacterial cultures with endotoxin and interleukin-6 in necrotizing enterocolitis. Dig Dis Sci 1997; 42 (2): 359–65. DOI: 10.1023/a:1018826204819
9. Gómez M., Moles L., Espinosa-Martos I., Bustos G., de Vos W.M., Fernández L., et al. Bacteriological and Immunological Profiling of Meconium and Fecal Samples from Preterm Infants: A Two-Year Follow-Up Study. Nutrients 2017; 9 (12): 1293. DOI: 10.3390/nu9121293
10. Lemme-Dumit J.M., Song Y., Lwin H.W., Hernandez-Chavez C., Sundararajan S., Viscardi R.M., et al. Altered Gut Microbiome and Fecal Immune Phenotype in Early Preterm Infants With Leaky Gut. Front Immunol 2022; 13: 815046. DOI: 10.3389/fimmu.2022.815046
11. Richter M., Topf H.G., Gröschl M., Fröhlich T., Tzschoppe A., Wenzl T.G., Köhler H. Influence of gestational age, cesarean section, and type of feeding on fecal human b-defensin 2 and tumor necrosis factor-a. J Pediatr Gastroenterol Nutr 2010; 51 (1): 103–5. DOI: 10.1097/MPG.0b013e3181cd26f9
12. Indrio F., Riezzo G., Tafuri S., Ficarella M., Carlucci B., Bisceglia M., et al. Probiotic supplementation in preterm: Feeding intolerance and hospital cost. Nutrients 2017; 9 (9): 965. DOI: 10.3390/nu9090965
13. Balachandran B., Dutta S., Singh R., Prasad R., Kumar P. Bovine colostrum in prevention of necrotizing enterocolitis and sepsis in very low birth weight neonates: A randomized, double-blind, placebo-controlled pilot trial. J Trop Pediatr 2017; 63 (1): 10–7. DOI: 10.1093/tropej/fmw029
14. Zenner C., Chalklen L., Adjei H., Dalby M.J., Mitra S., Cornwell E., et al. Noninvasive Fecal Cytokine and Microbiota Profiles Predict Commencement of Necrotizing Enterocolitis in a Proof-of-Concept Study. Gastro Hep Adv 2023; 2 (5): 666–75. DOI: 10.1016/j.gastha.2023.03.003
15. Dorofeeva E.I., Podurovskaya Yu.L., Burov A.A., Ryumina I.I., Narogan M.V., Grosheva E.V. i dr. Diagnostika i konservativnoe lechenie novorozhdennykh s nekrotiziruyushchim enterokolitom (proekt klinicheskikh rekomendatsii). Neonatologiya: Novosti. Mneniya. Obuchenie 2014; 2 (4): 84–92.
16. Walsh M.C., Kliegman R.M. Necrotizing enterocolitis: Treatment based on staging criteria. Pediatr Clin North Am 1986; 33 (1): 179–201. DOI: 10.1016/s0031-3955(16)34975-6
17. van Belkum M., Mendoza Alvarez L., Neu J. Preterm neonatal immunology at the intestinal interface. Cell Mol Life Sci 2020; 26 (7):1209–27. DOI: 10.1007/s00018-019-03316-w
18. Westerbeek E.A.M., Mørch E., Lafeber H.N., Fetter W.P.F., Twisk J.W.R., van Elburg R.M. Effect of Neutral and Acidic Oligosaccharides on Fecal IL-8 and Fecal Calprotectin in Preterm Infants. 2011. [Electronic resource] URL: www.controlled-trials.com (accessed 02. 02. 2024).
19. Harris M.C., D’Angio C.T., Gallagher P.R., Kaufman D., Evans J., Kilpatrick L. Cytokine elaboration in critically ill infants with bacterial sepsis, necrotizing entercolitis, or sepsis syndrome: Correlation with clinical parameters of inflammation and mortality. J Pediatri 2005; 147 (4): 462–8. DOI: 10.1016/j.jpeds.2005.04.037
20. Ebach D.R., Newberry R., Stenson W.F. Differential Role of Tumor Necrosis Factor Receptors in TNBS Colitis. Inflamm Bowel Dis 2005; 11 (6): 533–40. DOI: 10.1097/01.mib.0000163698.34592.30
21. Tatiya-Aphiradee N., Chatuphonprasert W., Jarukamjorn K. Immune response and inflammatory pathway of ulcerative colitis. J Basic Clin Physiol Pharmacol 2018; 30 (1): 1–10. DOI: 10.1515/jbcpp-2018-0036
22. Duess J.W., Sampah M.E., Lopez C.M., Tsuboi K., Scheese D.J., Sodhi C.P., Hackam D.J. Necrotizing enterocolitis, gut microbes, and sepsis. Gut Microbes 2023; 15 (1): 2221470. DOI: 10.1080/19490976.2023.2221470
23. Pott J., Kabat A.M., Maloy K.J. Intestinal Epithelial Cell Autophagy Is Required to Protect against TNF-Induced Apoptosis during Chronic Colitis in Mice. Cell Host Microbe 2018; 23 (2): 191–202.e4. DOI: 10.1016/j.chom.2017.12.017
24. Baregamian N., Song J., Bailey C.E., Papaconstantinou J., Evers B.M., Chung D.H. Tumor Necrosis Factor-a and Apoptosis Signal-Regulating Kinase 1 Control Reactive Oxygen Species Release, Mitochondrial Autophagy and C-Jun N-Terminal Kinase/P38 Phosphorylation During Necrotizing Enterocolitis. Oxid Med Cell Longev 2009; 2 (5): 297–306. DOI: 10.4161/oxim.2.5.9541
25. Hui L., Dai Y., Guo Z., Zhang J., Zheng F., Bian X., et al. Immunoregulation effects of different gdT cells and toll-like receptor signaling pathways in neonatal necrotizing enterocolitis. Medicine (Baltimore) 2017; 96 (8): e6077. Doi: 10.1097/MD.0000000000006077
26. Friedrich M., Pohin M., Powrie F. Cytokine Networks in the Pathophysiology of Inflammatory Bowel Disease. Immunity 2019; 50 (4): 992–1006. DOI: 10.1016/j.immuni.2019.03.017
27. Gareb B., Otten A.T., Frijlink H.W., Dijkstra G., Kosterink J.G.W. Review: Local Tumor Necrosis Factor-a Inhibition in Inflammatory Bowel Disease. Pharmaceutics 2020; 12 (6): 539. DOI: 10.3390/pharmaceutics12060539
28. Tayman C., Aydemir S., Yakut I., Serkant U., Ciftci A., Arslan E., Koç O. TNF-a Blockade Efficiently Reduced Severe Intestinal Damage in Necrotizing Enterocolitis. J Invest Surg 2016; 29 (4): 209–17. DOI: 10.3109/08941939.2015.1127449
29. Emami C.N., Chokshi N., Wang J., Hunter C., Guner Y., Goth K., et al. Role of interleukin-10 in the pathogenesis of necrotizing enterocolitis. Am J Surg 2012; 203 (4): 428–35. DOI: 10.1016/j.amjsurg.2011.08.016
30. Konnikova Y., Zaman M.M., Makda M., D’Onofrio D., Freedman S.D., Martin C.R. Late enteral feedings are associated with intestinal inflammation and adverse neonatal outcomes. PLoS One 2015; 10 (7): e0132924. DOI: 10.1371/journal.pone.0132924
