Impact of Docosahexaenoic acid supplementation on proinflammatory cytokines release and the development of Necrotizing enterocolitis in preterm Neonates: A randomized controlled study

Dina Khaled Abou El Fadl, Marwa Adel Ahmed, Yasmin Af Aly, Ebtissam Abdel Ghaffar Darweesh, Nagwa A Sabri, Dina Khaled Abou El Fadl, Marwa Adel Ahmed, Yasmin Af Aly, Ebtissam Abdel Ghaffar Darweesh, Nagwa A Sabri

Abstract

Introduction: Preterm neonates have under-developed immune-regulatory system; consequently, there is a risk for developing chronic inflammation. Necrotizing enterocolitis (NEC) is an acute devastating neonatal intestinal inflammatory disorder. Due to the obscure multifactorial etiology, early diagnosis and effective treatment of NEC are limited. Consequently, effective strategies in the prevention of NEC, including nutritional approaches, are critically needed. The current study was conducted to assess the potential immunomodulatory effect of Docosahexaenoic Acid (DHA) supplementation in preterm neonates at neonatal intensive care unit (NICU) and subsequently its effect on preventing or reducing NEC incidence.

Methods: This was a prospective randomized controlled study. A total of 67 neonates, with gestational age equal or less than 32 weeks at birth and weight less than or equal 1500 g, were randomly assigned to either DHA group or the control group. Modified Bell's staging criteria for NEC was used as an objective tool for diagnosis and staging of NEC. Levels of Interleukin 1 beta (IL-1β) were measured at baseline and after 10 days. Mortality and NICU length of stay (LOS) were also monitored.

Results: Thirty neonates of each group completed the study. A statistically significant difference was observed between the two groups regarding diagnosis and staging of NEC (p = 0.0001). There was also a statistically significant difference between DHA group 22(73.3), 95% CI [55.9, 86.5] and the control group 8 (26.7), 95% CI [13.5, 44.1] in the percentage change in IL-1β levels (p = 0.0001).A statistically significant association was found between IL and 1 β change and NEC diagnosis (p = 0.001). NICU LOS was significantly lower among DHA group 21.63 ± 6.67 compared to the control group 25.07 ± 4.67 (p = 0.025). Mortality n (%) among the control group 4 (11.8) was higher than DHA group 3 (9.1), however, no significant difference was detected (p = 1.0).

Conclusion: Findings of this study suggest that enteral DHA supplementation can reduce NEC incidence in preterm neonates through its immunoregulatory effect that modulates production of regulatory cytokines.Trial registration: Registered at clinical trials.gov (NCT03700957), 6 October 2018.

Keywords: DHA, Docosahexaenoic acid; IL-1β, Interleukin 1 beta; Immunomodulation; Inflammation; Interleukin 1 beta; LOS, Length of stay; Long-chain polyunsaturated fatty acids; NEC, Necrotizing enterocolitis; NICU, Neonatal intensive care unit; Neonatal intensive care unit; Prematurity; n-3 LCPUFA, Omega-3 long-chain polyunsaturated.

Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

© 2021 The Authors.

Figures

Fig. 1
Fig. 1
Modified Bell’s Staging Criteria for NEC.
Fig. 2
Fig. 2
CONSORT flow chart diagram of study selection.
Fig. 3
Fig. 3
Diagnosis and staging of NEC on day 10 for both groups.
Fig. 4
Fig. 4
NICU length of stay.

References

    1. Al-Biltagi M.A.M., Abo-Elezz A.A.E., Abd-Elhafez M.A., Mabrouk M.M., Suliman G.A. Beneficial Effects of Omega-3 Supplement to the Enteral Feeding in Children with Mild to Moderate Sepsis. J. Intensive Care Med. 2017 doi: 10.1177/0885066615623927.
    1. Andersen, A.D., Mølbak, L., Thymann, T., Michaelsen, K.F., Lauritzen, L., 2011. Dietary long-chain n-3 PUFA, gut microbiota and fat mass in early postnatal piglet development-exploring a potential interplay. Prostaglandins Leukot. Essent. Fat. Acids. 10.1016/j.plefa.2011.08.004.
    1. Baack M.L., Puumala S.E., Messier S.E., Pritchett D.K., Harris W.S. Daily Enteral DHA Supplementation Alleviates Deficiency in Premature Infants. Lipids. 2016 doi: 10.1007/s11745-016-4130-4.
    1. Barbosa V.M., Miles E.A., Calhau C., Lafuente E., Calder P.C. Effects of a fish oil containing lipid emulsion on plasma phospholipid fatty acids, inflammatory markers, and clinical outcomes in septic patients: A randomized, controlled clinical trial. Crit. Care. 2010 doi: 10.1186/cc8844.
    1. Beck, S., Wojdyla, D., Say, L., Betran, A.P., Merialdi, M., Requejo, J.H., Rubens, C., Menon, R., Van Look, P.F.A., 2010. 1. Owen J, Mancuso M. Cervical Cerclage for the Prevention of Preterm Birth. Vol. 39, Obstetrics and Gynecology Clinics of North America. 2012. p. 25–33. Bull. World Health Organ.
    1. Bell, M.J., Ternberg, J.L., Feigin, R.D., Keating, J.P., Marshall, R., Barton, L., Brotherton, T., 1978. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann. Surg. 10.1097/00000658-197801000-00001.
    1. Bernabe-García M., Calder P.C., Villegas-Silva R., Rodríguez-Cruz M., Chávez-Sánchez L., Cruz-Reynoso L., Mateos-Sánchez L., Lara-Flores G., Aguilera-Joaquín A.R., Sánchez-García L. Efficacy of Docosahexaenoic Acid for the Prevention of Necrotizing Enterocolitis in Preterm Infants: A Randomized Clinical Trial. Nutrients. 2021;13:648.
    1. Bernabe-Garcia, M., Lopez-Alarcon, M., Mansilla- Olivares, A., Maldonado-Hernandez, J., Blanco-Favela, F., Chavez-Sanchez, L., Chavez-Rueda, K., Mancilla-Ramirez, J., Arriaga-Pizano, L., Riera-Kinkel, C., 2014. Oral administration of n-3 long-chain fatty acids reduce inflammatory response and improve clinical outcomes in patients with cardiovascular surgery. Exp. Clin. Cardiol.
    1. Bernabe-Garcia M., Lopez-Alarcon M., Villegas-Silva R., Mancilla-Ramirez J., Rodriguez-Cruz M., Maldonado-Hernandez J., Chavez-Rueda K.A., Blanco-Favela F., Espinoza-Garcia L., Lagunes-Salazar S. Beneficial Effects of Enteral Docosahexaenoic Acid on the Markers of Inflammation and Clinical Outcomes of Neonates Undergoing Cardiovascular Surgery: An Intervention Study. Ann. Nutr. Metab. 2016 doi: 10.1159/000447498.
    1. Calder P.C. Mechanisms of action of (n-3) fatty acids. J. Nutr. 2012 doi: 10.3945/jn.111.155259.
    1. Carlson S.E., Montalto M.B., Ponder D.L., Werkman S.H., Korones S.B. Lower incidence of necrotizing enterocolitis in infants fed a preterm formula with egg phospholipids. Pediatr. Res. 1998 doi: 10.1203/00006450-199810000-00005.
    1. Chen A.C., Chung M.Y., Chang J.H., Lin H.C. Pathogenesis implication for necrotizing enterocolitis prevention in preterm very-low-birth-weight infants. J. Pediatr. Gastroenterol. Nutr. 2014 doi: 10.1097/MPG.0b013e3182a7dc74.
    1. Chen B., Zhou Y., Yang P., Wan H.W., Wu X.T. Safety and efficacy of fish oil-enriched parenteral nutrition regimen on postoperative patients undergoing major abdominal surgery: A meta-analysis of randomized controlled trials. J. Parenter. Enter. Nutr. 2010 doi: 10.1177/0148607110362532.
    1. Collins, C.T., Gibson, R.A., Makrides, M., McPhee, A.J., Sullivan, T.R., Davis, P.G., Thio, M., Simmer, K., Rajadurai, V.S., Team, N.I., Ryan, P., Morris, S., Stark, M., Travadi, J., Wright, I., Tan, K., Holberton, J., Opie, G., Callander, I., Stack, J., Shein, D., Bellhouse, S., Bolisetty, S., Lui, K., Liley, H., Berry, M., Harris, D., Chua, M.C., Agarwal, P., 2017. Docosahexaenoic acid and bronchopulmonary dysplasia in preterm infants. N. Engl. J. Med.
    1. Collins, C.T., Sullivan, T.R., McPhee, A.J., Stark, M.J., Makrides, M., Gibson, R.A., 2015. A dose response randomised controlled trial of docosahexaenoic acid (DHA) in preterm infants. Prostaglandins Leukot. Essent. Fat. Acids. 10.1016/j.plefa.2015.04.003.
    1. DeSena H.C., Nelson D.P., Cooper D.S. Cardiac intensive care for the neonate and child after cardiac surgery. Curr. Opin. Cardiol. 2015 doi: 10.1097/HCO.0000000000000127.
    1. Dunstan J.A., Mori T.A., Barden A., Beilin L.J., Taylor A.L., Holt P.G., Prescott S.L. Fish oil supplementation in pregnancy modifies neonatal allergen-specific immune responses and clinical outcomes in infants at high risk of atopy: A randomized, controlled trial. J. Allergy Clin. Immunol. 2003 doi: 10.1016/j.jaci.2003.09.009.
    1. Ellard, D.M., Anderson, D.M., Cloherty, J.P., Eichenwald, E.C., Stark, A.R., 2012. Manual of neonatal care.
    1. Espiritu M.M., Lin H., Foley E., Tsang V., Rhee E., Perlman J., Cunningham-Rundles S. Omega-3 fatty acids modulate neonatal cytokine response to endotoxin. J. Perinat. Med. 2016 doi: 10.1515/jpm-2015-0248.
    1. Field C.J., Van Aerde J.E., Robinson L.E., Clandinin M.T. Effect of providing a formula supplemented with long-chain polyunsaturated fatty acids on immunity in full-term neonates. Br. J. Nutr. 2008 doi: 10.1017/S0007114507791845.
    1. Fink N.H., Collins C.T., Gibson R.A., Makrides M., Penttila I.A. Targeting inflammation in the preterm infant: The role of the omega-3 fatty acid docosahexaenoic acid. J. Nutr. Intermed. Metab. 2016 doi: 10.1016/j.jnim.2016.03.004.
    1. Gagliani N., Palm N.W., de Zoete M.R., Flavell R.A. Inflammasomes and intestinal homeostasis: Regulating and connecting infection, inflammation and the microbiota. Int. Immunol. 2014 doi: 10.1093/intimm/dxu066.
    1. Ganapathy, V., Hay, J.W., Kim, J.H., 2012. Costs of necrotizing enterocolitis and cost-effectiveness of exclusively human milk-based products in feeding extremely premature infants. Breastfeed. Med. 10.1089/bfm.2011.0002.
    1. Good, M., Sodhi, C.P., Hackam, D.J., 2014. Evidence-based feeding strategies before and after the development of necrotizing enterocolitis. Expert Rev. Clin. Immunol. 10.1586/1744666X.2014.913481.
    1. Harris W.S., Baack M.L. Beyond building better brains: Bridging the docosahexaenoic acid (DHA) gap of prematurity. J. Perinatol. 2015 doi: 10.1038/jp.2014.195.
    1. Henriksen C., Haugholt K., Lindgren M., Aurvåg A.K., Rønnestad A., Grønn M., Solberg R., Moen A., Nakstad B., Berge R.K., Smith L., Iversen P.O., Drevon C.A. Improved cognitive development among preterm infants attributable to early supplementation of human milk with docosahexaenoic acid and arachidonic acid. Pediatrics. 2008 doi: 10.1542/peds.2007-1511.
    1. Ilardi L., Proto A., Ceroni F., Morniroli D., Martinelli S., Mosca F., Giannì M.L. Overview of Important Micronutrients Supplementation in Preterm Infants after Discharge: A Call for Consensus. Life. 2021;11:331.
    1. Johnson T.J., Patel A.L., Bigger H.R., Engstrom J.L., Meier P.P. Cost savings of human milk as a strategy to reduce the incidence of necrotizing enterocolitis in very low birth weight infants. Neonatology. 2015 doi: 10.1159/000370058.
    1. Kang J.X., Weylandt K.H. Modulation of inflammatory cytokines by omega-3 fatty acids. Subcell. Biochem. 2008 doi: 10.1007/978-1-4020-8831-5_5.
    1. Kawano, A., Ariyoshi, W., Yamasaki, R., Yoshioka, Y., Kashiwagi, K., Namikawa, D., Nishihara, T., Okinaga, T., 2020. Docosahexaenoic acid attenuates cell death and interleukin-1beta secretion in THP-1 cells responded to Aggregatibacter actinomycetemcomitans invasion.
    1. Khashana, A., Moussa, R., 2016. Incidence of feeding intolerance in preterm neonates in neonatal intensive care units, Port Said, Egypt. J. Clin. Neonatol. 10.4103/2249-4847.194165.
    1. Klevebro S., Juul S.E., Wood T.R. A More Comprehensive Approach to the Neuroprotective Potential of Long-Chain Polyunsaturated Fatty Acids in Preterm Infants Is Needed—Should We Consider Maternal Diet and the n-6: n-3 Fatty Acid Ratio? Front. Pediatr. 2020;7:533.
    1. Lapillonne A., Moltu S.J. Long-chain polyunsaturated fatty acids and clinical outcomes of preterm infants. Ann. Nutr. Metab. 2016 doi: 10.1159/000448265.
    1. Larsen B.M.K., Goonewardene L.A., Joffe A.R., Van Aerde J.E., Field C.J., Olstad D.L., Clandinin M.T. Pre-treatment with an intravenous lipid emulsion containing fish oil (eicosapentaenoic and docosahexaenoic acid) decreases inflammatory markers after open-heart surgery in infants: A randomized, controlled trial. Clin. Nutr. 2012 doi: 10.1016/j.clnu.2011.11.006.
    1. Lee J.Y., Plakidas A., Lee W.H., Heikkinen A., Chanmugam P., Bray G., Hwang D.H. Differential modulation of Toll-like receptors by fatty acids: Preferential inhibition by n-3 polyunsaturated fatty acids. J. Lipid Res. 2003 doi: 10.1194/jlr.M200361-JLR200.
    1. Lee J.Y., Zhao L., Youn H.S., Weatherill A.R., Tapping R., Feng L., Lee W.H., Fitzgerald K.A., Hwang D.H. Saturated Fatty Acid Activates but Polyunsaturated Fatty Acid Inhibits Toll-like Receptor 2 Dimerized with Toll-like Receptor 6 or 1. J. Biol. Chem. 2004 doi: 10.1074/jbc.M312990200.
    1. Lien V.W., Clandinin M.T. Dietary assessment of arachidonic acid and docosahexaenoic acid intake in 4–7 year-old children. J. Am. Coll. Nutr. 2009 doi: 10.1080/07315724.2009.10719755.
    1. Lin P.W., Stoll B.J. Necrotising enterocolitis. Lancet. 2006 doi: 10.1016/S0140-6736(06)69525-1.
    1. López-Alarcón M., Bernabe-García M., Del Valle O., González-Moreno G., Martínez-Basilea A., Villegas R. Oral administration of docosahexaenoic acid attenuates interleukin-1β response and clinical course of septic neonates. Nutrition. 2012 doi: 10.1016/j.nut.2011.07.016.
    1. Maheshwari A., Schelonka R.L., Dimmitt R.A., Carlo W.A., Munoz-Hernandez B., Das A., McDonald S.A., Thorsen P., Skogstrand K., Hougaard D.M., Higgins R.D. Cytokines associated with necrotizing enterocolitis in extremely-low-birth- weight infants. Pediatr. Res. 2014 doi: 10.1038/pr.2014.48.
    1. Martin C.R., Dasilva D.A., Cluette-Brown J.E., Dimonda C., Hamill A., Bhutta A.Q., Coronel E., Wilschanski M., Stephens A.J., Driscoll D.F., Bistrian B.R., Ware J.H., Zaman M.M., Freedman S.D. Decreased postnatal docosahexaenoic and arachidonic acid blood levels in premature infants are associated with neonatal morbidities. J. Pediatr. 2011 doi: 10.1016/j.jpeds.2011.04.039.
    1. Mizrahi A., Barlow O., Berdon W., Blanc W.A., Silverman W.A. Necrotizing enterocolitis in premature infants. J. Pediatr. 1965 doi: 10.1016/S0022-3476(65)80003-8.
    1. Myles I.A., Pincus N.B., Fontecilla N.M., Datta S.K. Effects of parental omega-3 fatty acid intake on offspring microbiome and immunity. PLoS One. 2014 doi: 10.1371/journal.pone.0087181.
    1. Ohtsuka Y., Okada K., Yamakawa Y., Ikuse T., Baba Y., Inage E., Fujii T., Izumi H., Oshida K., Nagata S., Yamashiro Y., Shimizu T. ω-3 fatty acids attenuate mucosal inflammation in premature rat pups. J. Pediatr. Surg. 2011 doi: 10.1016/j.jpedsurg.2010.07.032.
    1. Ramirez-Ramirez, V., Macias-Islas, M.A., Ortiz, G.G., Pacheco-Moises, F., Torres-Sanchez, E.D., Sorto-Gomez, T.E., Cruz-Ramos, J.A., Orozco-Aviña, G., Celis De La Rosa, A.J., 2013. Efficacy of fish oil on serum of TNF α, IL-1 β, and IL-6 oxidative stress markers in multiple sclerosis treated with interferon beta-1b. Oxid. Med. Cell. Longev. 10.1155/2013/709493.
    1. Rasiah V., Yajamanyam P.K., Ewer A.K. Necrotizing enterocolitis: current perspectives. Res. Reports Neonatol. 2014 doi: 10.2147/rrn.s36576.
    1. Richard C., Lewis E.D., Field C.J. Evidence for the essentiality of arachidonic and docosahexaenoic acid in the postnatal maternal and infant diet for the development of the infant’s immune system early in life. Appl. Physiol. Nutr. Metab. 2016 doi: 10.1139/apnm-2015-0660.
    1. Rodriguez-Santana, Y., Ochoa, J.J., Lara-Villoslada, F., Kajarabille, N., Saavedra-Santana, P., Hurtado, J.A., Peña, M., Diaz-Castro, J., Sebastian-Garcia, I., Machin-Martin, E., Villanueva, M., Ramirez-Garcia, O., Peña-Quintana, L., 2017. Cytokine distribution in mothers and breastfed children after omega-3 LCPUFAs supplementation during the last trimester of pregnancy and the lactation period: A randomized, controlled trial. Prostaglandins Leukot. Essent. Fat. Acids. 10.1016/j.plefa.2017.09.006.
    1. Sharma A.A., Jen R., Butler A., Lavoie P.M. The developing human preterm neonatal immune system: A case for more research in this area. Clin. Immunol. 2012 doi: 10.1016/j.clim.2012.08.006.
    1. Shulhan, J., Dicken, B., Hartling, L., Larsen, B.M.K., 2017. Current knowledge of necrotizing enterocolitis in preterm infants and the impact of different types of enteral nutrition products. Adv. Nutr. 10.3945/an.116.013193.
    1. Skouroliakou, M., Konstantinou, D., Agakidis, C., Delikou, N., Koutri, K., Antoniadi, M., Karagiozoglou-Lampoudi, T., 2012. Cholestasis, bronchopulmonary dysplasia, and lipid profile in preterm infants receiving MCT/ω-3-PUFA-containing or soybean-based lipid emulsions. Nutr. Clin. Pract. 10.1177/0884533612454547.
    1. Skouroliakou, M., Konstantinou, D., Agakidis, C., Kaliora, A., Kalogeropoulos, N., Massara, P., Antoniadi, M., Panagiotakos, D., Karagiozoglou-Lampoudi, T., 2016. Parenteral MCT/ω-3 Polyunsaturated Fatty Acid-Enriched Intravenous Fat Emulsion is Associated with Cytokine and Fatty Acid Profiles Consistent with Attenuated Inflammatory Response in Preterm Neonates: A Randomized, Double-Blind Clinical Trial. Nutr. Clin. Pract. 10.1177/0884533615602011.
    1. Smithers, L.G., Gibson, R.A., McPhee, A., Makrides, M., 2008. Effect of long-chain polyunsaturated fatty acid supplementation of preterm infants on disease risk and neurodevelopment: A systematic review of randomized controlled trials. Am. J. Clin. Nutr. 10.1093/ajcn/87.4.912.
    1. Strunk T., Currie A., Richmond P., Simmer K., Burgner D. Innate immunity in human newborn infants: Prematurity means more than immaturity. J. Matern. Neonatal Med. 2011 doi: 10.3109/14767058.2010.482605.
    1. Turner J.M., Josephson J., Field C.J., Wizzard P.R., Ball R.O., Pencharz P.B., Wales P.W. Liver Disease, Systemic Inflammation, and Growth Using a Mixed Parenteral Lipid Emulsion, Containing Soybean Oil, Fish Oil, and Medium Chain Triglycerides, Compared with Soybean Oil in Parenteral Nutrition-Fed Neonatal Piglets. J. Parenter. Enter. Nutr. 2016 doi: 10.1177/0148607115579711.
    1. Valentine C.J., Dingess K.A., Kleiman J., Morrow A.L., Rogers L.K. A Randomized Trial of Maternal Docosahexaenoic Acid Supplementation to Reduce Inflammation in Extremely Preterm Infants. J. Pediatr. Gastroenterol. Nutr. 2019 doi: 10.1097/MPG.0000000000002375.
    1. Vedin I., Cederholm T., Levi Y.F., Basun H., Garlind A., Irving G.F., Jönhagen M.E., Vessby B., Wahlund L.O., Palmblad J. Effects of docosahexaenoic acid-rich n-3 fatty acid supplementation on cytokine release from blood mononuclear leukocytes: The OmegAD study. Am. J. Clin. Nutr. 2008 doi: 10.1093/ajcn/87.6.1616.
    1. Walsh M.C., Kliegman R.M. Necrotizing enterocolitis: Treatment based on staging criteria. Pediatr. Clin. North Am. 1986 doi: 10.1016/S0031-3955(16)34975-6.
    1. Xu, F., Song, Y., Guo, A., 2019. Anti-apoptotic effects of docosahexaenoic acid in il-1β-induced human chondrosarcoma cell death through involvement of the mapk signaling pathway. Cytogenet. Genome Res. 10.1159/000500290.
    1. Yuan, S., Li, H., Yang, C., Xie, Wenyi, Wang, Y., Zhang, J., Mao, Z., Xie, Weibing, Lü, T., 2020. DHA attenuates Aβ-induced necroptosis through the RIPK1/RIPK3 signaling pathway in THP-1 monocytes. Biomed. Pharmacother. 126, 110102.
    1. Zhang P., Lavoie P.M., Lacaze-Masmonteil T., Rhainds M., Marc I. Omega-3 long-chain polyunsaturated fatty acids for extremely preterm infants: A systematic review. Pediatrics. 2014 doi: 10.1542/peds.2014-0459.
    1. Zhou P., Li Y., Ma L.Y., Lin H.C. The role of immunonutrients in the prevention of necrotizing enterocolitis in preterm very low birth weight infants. Nutrients. 2015 doi: 10.3390/nu7095334.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner