Intestinal Development and Permeability: Role in Nutrition of Preterm Infants

  • Sarah N. Taylor
  • Julie Ross
  • Carol L. Wagner
Part of the Nutrition and Health book series (NH)


Preterm birth necessitates that fetal organ development occur in the extra-uterine environment. This circumstance poses significant risk for gastrointestinal (GI) system development as this system doubles in length from 25 to 40 weeks’ gestation. The most severe consequence of preterm intestinal development is necrotizing enterocolitis (NEC)—an inflammatory cascade that leads to ischemia/necrosis of the intestines. This disease is found in 7–10 % of very low birth weight (VLBW) infants and is associated with 33 % mortality and 33 % long-term GI and/or neurodevelopmental morbidity. The two protective factors consistently identified to decrease risk for NEC are prolonged gestation and human milk feeds. Investigation into the mechanism of NEC has dominated the study of preterm infant intestinal development. Within this context, intestinal maturation and specifically intestinal permeability have been studied for 20 years.


Preterm infants Intestinal permeability Human milk Intestinal maturation Intestinal development 


  1. 1.
    Behrens RH, Docherty H, Elia M, et al. A simple enzymatic method for the assay of urinary lactulose. Clin Chim Acta. 1984;137:361–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Lunn PG, Northrop CA, Northrop AJ. Automated enzymatic assays for the determination of intestinal permeability probes in urine. 2. Mannitol. Clin Chim Acta. 1989;183:163–70.PubMedCrossRefGoogle Scholar
  3. 3.
    Shulman RJ, Schanler RJ, Lau C, et al. Early feeding, antenatal glucocorticoids, and human milk decrease intestinal permeability in preterm infants. Pediatr Res. 1998;44:519–23.PubMedCrossRefGoogle Scholar
  4. 4.
    Catassi C, Bonucci A, Coppa V, et al. Intestinal permeability changes during the first month: effect of natural versus artificial feeding. J Pediatr Gastroenterol Nutr. 1995;21:383–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Weaver LT, Laker MF, Nelson R. Intestinal permeability in the newborn. Arch Dis Child. 1984;59:236–41.PubMedCrossRefGoogle Scholar
  6. 6.
    Van Elburg RM, Fetter WP, Bunkers CM, Heymans HS. Intestinal permeability in relation to birth weight and gestational and postnatal age. Arch Dis Child Fetal Neonatal Ed. 2003;88:F52–5.PubMedCrossRefGoogle Scholar
  7. 7.
    Corpeleijn WE, van Elburg RM, Kema IP, van Goudovever JB. Assessment of intestinal permeability in (premature) neonates by sugar absorption tests. Methods Mol Biol. 2011;763:95–104.PubMedCrossRefGoogle Scholar
  8. 8.
    Van Goudoever JB, Corpeleijn W, Riedijk M, Schaart M, Renes I, van der Schoor S. The impact of enteral insulin-like growth factor 1 and nutrition on gut permeability and amino acid utilization. J Nutr. 2008;138:1829S–33.PubMedGoogle Scholar
  9. 9.
    Ulluwishewa D, Anderson RC, McNabb WC, Moughan PJ, Wells JM, Roy NC. Regulation of tight junction permeability by intestinal bacteria and dietary compounds. J Nutr. 2011;141:769–76.PubMedCrossRefGoogle Scholar
  10. 10.
    Suenaert P, Bulteel V, Lemmens L, et al. Anti-tumor necrosis factor treatment restores the gut barrier in Crohn’s disease. Am J Gastroenterol. 2002;97:2000–4.PubMedCrossRefGoogle Scholar
  11. 11.
    Vogelsang H, Schwarzenhofer M, Oberhuber G. Changes in gastrointestinal permeability in celiac disease. Dig Dis. 1998;16:333–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Damci T, Nuhoglu I, Devranoglu G, et al. Increased intestinal permeability as a cause of fluctuating postprandial blood glucose levels in Type 1 diabetic patients. Eur J Clin Invest. 2003;33:397–401.PubMedCrossRefGoogle Scholar
  13. 13.
    Davin JC, Forget P, Mahieu PR. Increased intestinal permeability to (51 Cr) EDTA is correlated with IgA immune complex-plasma levels in children with IgA-associated nephropathies. Acta Paediatr Scand. 1988;77:118–24.PubMedCrossRefGoogle Scholar
  14. 14.
    Yacyshyn B, Meddings J, Sadowski D, et al. Multiple sclerosis patients have peripheral blood CD45RO  +  B cells and increased intestinal permeability. Dig Dis Sci. 1996;41:2493–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Wagner CL, Taylor SN, Johnson D. Host factors in amniotic fluid and breast milk that contribute to gut maturation. Clin Rev Allergy Immunol. 2008;34:191–204.PubMedCrossRefGoogle Scholar
  16. 16.
    Mulvihill SJ, Stone MM, Debas HT, et al. The role of amniotic fluid in fetal nutrition. J Pediatr Surg. 1985;20:668–72.PubMedCrossRefGoogle Scholar
  17. 17.
    Pitkin R, Reynolds W. Fetal ingestion and metabolism of amniotic fluid protein. Am J Obstet Gynecol. 1975;123:356–63.PubMedGoogle Scholar
  18. 18.
    Maheshwari A. Role of cytokines in human intestinal villous development. Clin Perinatol. 2004;31:1–11.CrossRefGoogle Scholar
  19. 19.
    Van den Berg A, Fetter WP, Westerbeek EA, et al. The effect of glutamine-enriched enteral nutrition on intestinal permeability in very-low-birth-weight infants: a randomized controlled trial. JPEN J Parenter Enteral Nutr. 2006;30:408–14.PubMedCrossRefGoogle Scholar
  20. 20.
    Sevastiadou S, Malamitsi-Puchner A, Costalos C, et al. The impact of oral glutamine supplementation on the intestinal permeability and incidence of NEC/septicemia in premature neonates. J Matern Fetal Neonatal Med. 2011;24:1294–300. Epub 2011 Apr 4.PubMedCrossRefGoogle Scholar
  21. 21.
    Corpeleijn WE, van Vliet I, de Gast-Bakker DA, et al. Effect of enteral IGF-1 supplementation on feeding tolerance, growth, and gut permeability in enterally fed premature neonates. J Pediatr Gastroenterol Nutr. 2008;46:184–90.PubMedCrossRefGoogle Scholar
  22. 22.
    Barney CK, Lambert DK, Alder SC, et al. Treating feeding intolerance with an enteral solution patterned after human amniotic fluid: a randomized, controlled, masked trial. J Perinatol. 2007;27:28–31.PubMedCrossRefGoogle Scholar
  23. 23.
    Neu J. Gastrointestinal maturation and implications for infant feeding. Early Hum Dev. 2007;83:767–75.PubMedCrossRefGoogle Scholar
  24. 24.
    Bourlioux P, Koletzko B, Guarner F, et al. The intestine and its microflora are partners for the protection of the host: report on the Danone Symposium “The Intelligent Intestine” held in Paris, June 14, 2002. Am J Clin Nutr. 2003;78:675–83.PubMedGoogle Scholar
  25. 25.
    Westerbeek EA, van den Berg A, Lafeber HN, et al. The effect of enteral supplementation of a prebiotic mixture of non-human milk galacto-, fructo-, and acidic oligosaccharides on intestinal permeability in preterm infants. Br J Nutr. 2011;105:268–74.PubMedCrossRefGoogle Scholar
  26. 26.
    Boehm G, Moro G. Structural and functional aspects of prebiotics used in infant nutrition. J Nutr. 2008;138:1818S–28.PubMedGoogle Scholar
  27. 27.
    Burger-van Paassen N, Vincent A, Puiman PJ, et al. The regulation of intestinal mucin MUC2 expression by short-chain fatty acids: implications for epithelia protection. Biochem J. 2009;420:211–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Sharma R, Young C, Neu J. Molecular modulaton of intestinal epithelial barrier: contribution of microbiota. J Biomed Biotechnol. 2010;2010:305879.PubMedGoogle Scholar
  29. 29.
    Cani PD, Possemiers S, Van de Wiele T, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2 driven improvement of gut permeability. Gut. 2009;58:1091–103.PubMedCrossRefGoogle Scholar
  30. 30.
    Beach R, Menzies IS, Clayden GS, et al. Gastrointestinal permeability changes in the preterm neonate. Arch Dis Child. 1982;57:141–5.PubMedCrossRefGoogle Scholar
  31. 31.
    Taylor SN, Basile LA, Ebeling M, Wagner CL. Intestinal permeability in preterm infants by feeding type: mother’s milk versus formula. Breastfeed Med. 2009;4:11–5.PubMedCrossRefGoogle Scholar
  32. 32.
    Stratiki Z, Costalos C, Sevastiadou S, et al. The effect of a bifidobacter supplemented bovine milk on intestinal permeability of preterm infants. Early Hum Dev. 2007;83:575–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Rouwet EV, Heineman E, Buurman WA, et al. Intestinal permeability and carrier-mediated monosaccharide absorption in preterm neonates during the early postnatal period. Pediatr Res. 2002;51:64–70.PubMedCrossRefGoogle Scholar
  34. 34.
    Van Elburg RM, van den Berg A, Bunkers CM, et al. Minimal enteral feeding, fetal blood flow pulsatility, and postnatal intestinal permeability in preterm infants with intrauterine growth retardation. Arch Dis Child Fetal Neonatal Ed. 2004;89(4):F293–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Insoft RM, Sanderson IR, Walker WA. Development of immune function in the intestine and its role in neonatal diseases. Pediatr Clin North Am. 1996;43:551–71.PubMedCrossRefGoogle Scholar
  36. 36.
    Simmer K. Aggressive nutrition for preterm infants—benefits and risks. Early Hum Dev. 2007;83:631–4.PubMedCrossRefGoogle Scholar
  37. 37.
    Ronnestad A, Abrahmsen TG, Medbo S, et al. Late onset septicarmia in a Norwegian national cohort of extremely premature infants receiving very early full human milk feeding. Pediatrics. 2005;115:269–76.CrossRefGoogle Scholar
  38. 38.
    Morgan J, Young L, McGuire W. Delayed introduction of progressive enteral feeds to prevent necrotizing enterocolitis in very low birth weight infants. Cochrane Database Syst Rev. 2011;(issue 3):CD001970.Google Scholar
  39. 39.
    Tyson JE, Kennedy KA. Trophic feedings for parenterally fed infants. Cochrane Database Syst Rev. 2005;(issue 3):CD000504.Google Scholar
  40. 40.
    Hylander MA, Strobino DM, Dhanireddy R. Human milk feedings and infection among very low birth weight infants. Pediatrics. 1998;102:E38.PubMedCrossRefGoogle Scholar
  41. 41.
    Schanler RJ, Shulman RJ, Lau C. Feeding strategies for premature infants: beneficial outcomes of feeding fortified human milk versus preterm formula. Pediatrics. 1999;103:1150–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Meinzen-Derr J, Poindexter B, Wrage L, et al. Role of human milk in extremely low birth weight infants’ risk of necrotizing enterocolitis or death. J Perinatol. 2009;29:57–62.PubMedCrossRefGoogle Scholar
  43. 43.
    Palmer C, Bik EM, DiGiulio DB, et al. Development of the human infant intestinal microbiota. PLoS Biol. 2007;5:e177.PubMedCrossRefGoogle Scholar
  44. 44.
    Favier CF, Vaughan EE, De Vos WM, et al. Molecular monitoring of succession of bacterial communities in human neonates. Appl Environ Microbiol. 2002;68:219–26.PubMedCrossRefGoogle Scholar
  45. 45.
    Martin CR, Walker WA. Intestinal immune defences and the inflammatory response in necrotizing entercolitis. Semin Fetal Neonatal Med. 2006;11:369–77.PubMedCrossRefGoogle Scholar
  46. 46.
    Claud EC, Walker WA. Bacterial colonization, probiotics, and necrotizing enterocolitis. J Clin Gastroenterol. 2008;42(suppl):S46–52.PubMedCrossRefGoogle Scholar
  47. 47.
    Alfaleh K, Anabrees J, Basseler D et al. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev 2011;(issue 3):CD005496.Google Scholar
  48. 48.
    Van Zwol A, Neu J, van Elburg RM. Long-term effects of neonatal glutamine-enriched nutrition in very-low-birth-weight infants. Nutr Rev. 2011;69:2–8.PubMedCrossRefGoogle Scholar
  49. 49.
    Neu J, Li N. Pathophysiology of glutamine and glutamate metabolism in premature infants. Curr Opin Clin Nutr Metab Care. 2007;10:75–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Panigrahi P, Gewolb IH, Bamford P, et al. Role of glutamine in bacterial transcytosis and epithelia cell injury. J Parenter Enteral Nutr. 1997;21:75–80.CrossRefGoogle Scholar
  51. 51.
    Khan J, Lliboshi Y, Cui L, et al. Alanyl-glutamine-supplemented parenteral nutrition increases luminal mucus gel and decreases permeability in the rat small intestine. J Parenter Enteral Nutr. 1999;23:24–31.CrossRefGoogle Scholar
  52. 52.
    van der Hulst RR, van Kreel BK, von Meyenfeldt MR, et al. Glutamine and the preservation of gut integrity. Lancet. 1993;341:1363–5.PubMedCrossRefGoogle Scholar
  53. 53.
    Tubman TR, Thompson SW, McGuire W. Glutamine supplementation to prevent morbidity and mortality in preterm infants. Cochrane Database Syst Rev. 2008;(issue 1):CD001457.Google Scholar
  54. 54.
    Chokshi NK, Guner YS, Hunter CJ, Upperman JS, Grishin A, Ford HR. The role of nitric oxide in intestinal epithelial injury and restitution in neonatal NEC. Semin Perinatol. 2008;32:92–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Upperman JS, Potoka D, Grishin A, Hackam D, Zamora R, Ford HR. Mechanisms of nitric oxide-mediatred intestinal barrier failure in NEC. Semin Pediatr Surg. 2005;14:159–66.PubMedCrossRefGoogle Scholar
  56. 56.
    Arslanoglu S, Ziegler EE, Moro GE, World Association of Perinatal Medicine Working Group on Nutrition. Donor human milk in preterm infant feeding: evidence and recommendations. J Perinat Med. 2010;38:347–51.PubMedGoogle Scholar
  57. 57.
    Sullivan S, Schanler RJ, Kim JH, et al. An exclusively human milk-based diet is associated with a lower rate of NEC than a diet of human milk and bovine milk-based products. J Pediatr. 2010;156:562–7.PubMedCrossRefGoogle Scholar
  58. 58.
    Bjornvad CR, Thymann T, Deutz NE, et al. Enteral feeding induces diet-dependent mucosal dysfunction, bacterial proliferation, and necrotizing enterocolitis in preterm pigs on parenteral nutrition. Am J Physiol Gastrointest Liver Physiol. 2008;295:G1092–103.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Sarah N. Taylor
    • 1
  • Julie Ross
    • 2
  • Carol L. Wagner
    • 2
  1. 1.Department of Pediatrics, NeonatologyMUSC Children’s HospitalCharlestonUSA
  2. 2.Department of PediatricsMedical University of South CarolinaCharlestonUSA

Personalised recommendations