Abstract
Background:
Evidence suggests that excessive inflammation of the immature intestine may predispose premature infants to necrotizing enterocolitis (NEC). We investigated the anti-inflammatory effects of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (ARA) in human fetal and adult intestinal epithelial cells (IEC) in primary culture.
Methods:
Human fetal IEC in culture were derived from a healthy fetal small intestine (H4) or resected small intestine of a neonate with NEC (NEC-IEC). Intestinal cell lines Caco2 and NCM460 in culture were used as models for mature IEC. IEC in culture were pretreated with 100 µmol/l palmitic acid (PAL), DHA, EPA, ARA, or ARA+DHA for 48 h and then stimulated with proinflammatory IL-1β.
Results:
DHA significantly attenuated IL-1β induced proinflammatory IL-8 and IL-6 protein and mRNA in fetal H4, NEC-IEC, and mature Caco2, NCM460 IEC, compared to control and PAL treatment. DHA downregulated IL-1R1 (IL-1β receptor) and NFk β1 mRNA expression in fetal and adult IEC. ARA had potent anti-inflammatory effects with lower IL-8 and IL-6 (protein and mRNA) in fetal H4 but not in NEC-IEC or adult IEC.
Conclusion:
The present study provides evidence that DHA and ARA may have important anti-inflammatory functions for prevention of NEC in premature infants.
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References
Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med 2011;364:255–64.
Henry MC, Moss RL. Necrotizing enterocolitis. Annu Rev Med 2009;60:111–24.
Gephart SM, McGrath JM, Effken JA, Halpern MD. Necrotizing enterocolitis risk: state of the science. Adv Neonatal Care 2012;12:77–87; quiz 88–9.
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.
Chan KY, Leung KT, Tam YH, et al. Genome-wide expression profiles of necrotizing enterocolitis versus spontaneous intestinal perforation in human intestinal tissues: dysregulation of functional pathways. Ann Surg 2014;260:1128–37.
De Plaen IG, Liu SX, Tian R, et al. Inhibition of nuclear factor-kappaB ameliorates bowel injury and prolongs survival in a neonatal rat model of necrotizing enterocolitis. Pediatr Res 2007;61:716–21.
Brenna JT, Varamini B, Jensen RG, Diersen-Schade DA, Boettcher JA, Arterburn LM. Docosahexaenoic and arachidonic acid concentrations in human breast milk worldwide. Am J Clin Nutr 2007;85:1457–64.
Zhang P, Lavoie PM, Lacaze-Masmonteil T, Rhainds M, Marc I. Omega-3 long-chain polyunsaturated fatty acids for extremely preterm infants: a systematic review. Pediatrics 2014;134:120–34.
Carlson SE, Montalto MB, Ponder DL, Werkman SH, Korones SB. Lower incidence of necrotizing enterocolitis in infants fed a preterm formula with egg phospholipids. Pediatr Res 1998;44:491–8.
Fewtrell MS, Morley R, Abbott RA, et al. Double-blind, randomized trial of long-chain polyunsaturated fatty acid supplementation in formula fed to preterm infants. Pediatrics 2002;110(1 Pt 1):73–82.
Ganguli K, Meng D, Rautava S, Lu L, Walker WA, Nanthakumar N. Probiotics prevent necrotizing enterocolitis by modulating enterocyte genes that regulate innate immune-mediated inflammation. Am J Physiol Gastrointest Liver Physiol 2013;304:G132–41.
Claud EC, Lu L, Anton PM, Savidge T, Walker WA, Cherayil BJ. Developmentally regulated IkappaB expression in intestinal epithelium and susceptibility to flagellin-induced inflammation. Proc Natl Acad Sci USA 2004;101:7404–8.
Liu Y, Chen F, Odle J, et al. Fish oil enhances intestinal integrity and inhibits TLR4 and NOD2 signaling pathways in weaned pigs after LPS challenge. J Nutr 2012;142:2017–24.
Innis SM, Dai C, Wu X, Buchan AM, Jacobson K. Perinatal lipid nutrition alters early intestinal development and programs the response to experimental colitis in young adult rats. Am J Physiol Gastrointest Liver Physiol 2010;299:G1376–85.
Kihara A. Very long-chain fatty acids: elongation, physiology and related disorders. J Biochem 2012;152:387–95.
Harkewicz R, Du H, Tong Z, et al. Essential role of ELOVL4 protein in very long chain fatty acid synthesis and retinal function. J Biol Chem 2012;287:11469–80.
Ohtsuka Y, Okada K, Yamakawa Y, et al. ω-3 fatty acids attenuate mucosal inflammation in premature rat pups. J Pediatr Surg 2011;46:489–95.
Lu J, Jilling T, Li D, Caplan MS. Polyunsaturated fatty acid supplementation alters proinflammatory gene expression and reduces the incidence of necrotizing enterocolitis in a neonatal rat model. Pediatr Res 2007;61:427–32.
Garlanda C, Mantovani A. Ligands and receptors of the interleukin-1 family in immunity and disease. Front Immunol 2013;4:396.
Nanthakumar NN, Fusunyan RD, Sanderson I, Walker WA. Inflammation in the developing human intestine: A possible pathophysiologic contribution to necrotizing enterocolitis. Proc Natl Acad Sci USA 2000;97:6043–8.
Massaro M, Habib A, Lubrano L, et al. The omega-3 fatty acid docosahexaenoate attenuates endothelial cyclooxygenase-2 induction through both NADP(H) oxidase and PKC epsilon inhibition. Proc Natl Acad Sci USA 2006;103:15184–9.
Jacobi SK, Moeser AJ, Corl BA, Harrell RJ, Blikslager AT, Odle J. Dietary long-chain PUFA enhance acute repair of ischemia-injured intestine of suckling pigs. J Nutr 2012;142:1266–71.
Norris PC, Dennis EA. Omega-3 fatty acids cause dramatic changes in TLR4 and purinergic eicosanoid signaling. Proc Natl Acad Sci USA 2012;109:8517–22.
Claud EC, Savidge T, Walker WA. Modulation of human intestinal epithelial cell IL-8 secretion by human milk factors. Pediatr Res 2003;53:419–25.
Reardon HT, Hsieh AT, Park WJ, et al. Dietary long-chain polyunsaturated fatty acids upregulate expression of FADS3 transcripts. Prostaglandins Leukot Essent Fatty Acids 2013;88:15–9.
Park WJ, Kothapalli KS, Lawrence P, Tyburczy C, Brenna JT. An alternate pathway to long-chain polyunsaturates: the FADS2 gene product Delta8-desaturates 20:2n-6 and 20:3n-3. J Lipid Res 2009;50:1195–202.
Acknowledgements
The authors acknowledge Nanda Shanmugam (Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Boston, MA) for assistance with qRT-PCR work; Maureen Garron and Suzette McCarron (Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Boston, MA) for administrative support.
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Wijendran, V., Brenna, J., Wang, D. et al. Long-chain polyunsaturated fatty acids attenuate the IL-1β-induced proinflammatory response in human fetal intestinal epithelial cells. Pediatr Res 78, 626–633 (2015). https://doi.org/10.1038/pr.2015.154
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DOI: https://doi.org/10.1038/pr.2015.154
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