Skip to main content

Advertisement

Log in

The Effects of Formula Feeding on Physiological and Immunological Parameters in the Gut of Neonatal Rats

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

A unique model of formula feeding in the neonatal rat was utilized to investigate the effects of an enterally delivered artificial milk formula on clinically relevant immunological and biological characteristics in the gut, compared to naturally reared pups. Hooded Wistar rat pups were randomly allocated to two treatment groups: formula-fed (FF) or naturally suckled (NS). A flexible silastic intra-gastric cannula was surgically implanted into the FF pups, through which an artificial rat milk supplement was continuously delivered from day 4 to day 10 of life. Rat pups were sacrificed at 10 days of age. Body weight, small intestinal weight, mucosal CD8+ cell numbers, and ileal lactase activity in FF animals were significantly decreased compared to their NS counterparts (P < 0.05). Numbers of eosinophils, mucosal mast cells, CD4+ T-cells, ileal villus height and gastric emptying times were significantly increased in FF pups (P < 0.05). We have developed a new rat model of artificial feeding which possesses important immunological and biological similarities to the premature human infant.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Clark JA, Doelle SM, Halpern MD, et al. Intestinal barrier failure during experimental necrotizing enterocolitis: protective effect of EGF treatment. Am J Physiol Gastrointest Liver Physiol. 2006;291:G938–G949. doi:10.1152/ajpgi.00090.2006.

    Article  PubMed  CAS  Google Scholar 

  2. Halpern MD, Clark JA, Saunders TA, et al. Reduction of experimental necrotizing enterocolitis with anti-TNF-alpha. Am J Physiol Gastrointest Liver Physiol. 2006;290:G757–G764. doi:10.1152/ajpgi.00408.2005.

    Article  PubMed  CAS  Google Scholar 

  3. Penttila I. Effects of transforming growth factor-beta and formula feeding on systemic immune responses to dietary beta-lactoglobulin in allergy-prone rats. Pediatr Res. 2006;59:650–655. doi:10.1203/01.pdr.0000203149.75465.74.

    Article  PubMed  CAS  Google Scholar 

  4. Edwards LJ, Coulter CL, Symonds ME, McMillen IC. Prenatal undernutrition, glucocorticoids and the programming of adult hypertension. Clin Exp Pharm Phys. 2001;28:938–941. doi:10.1046/j.1440-1681.2001.03553.x.

    Article  CAS  Google Scholar 

  5. McMillen IC, Adams MB, Ross JT, et al. Fetal growth restriction: adaptations and consequences. Reproduction. 2001;122:195–204. doi:10.1530/rep.0.1220195.

    Article  PubMed  CAS  Google Scholar 

  6. Liem JJ, Kozyrskyj AL, Huq SI, Becker AB. The risk of developing food allergy in premature or low-birth-weight children. J Allergy Clin Immunol. 2007;119(5):1203–1209.

    Article  PubMed  Google Scholar 

  7. Shulman RJ, Wong WW, Smith EO. Influence of changes in lactase activity and small-intestinal mucosal growth on lactose digestion and absorption in preterm infants. Am J Clin Nutr. 2005;81:472–479.

    PubMed  CAS  Google Scholar 

  8. Wales PW, de Silva N, Kim JH, Lecce L, Sandhu A, Moore AM. Neonatal short bowel syndrome: a cohort study. J Pediatr Surg. 2005;40:755–762. doi:10.1016/j.jpedsurg.2005.01.037.

    Article  PubMed  Google Scholar 

  9. Ziegler AG, Schmid S, Huber D, Hummel M, Bonifacio E. Early infant feeding and risk of developing type 1 diabetes-associated autoantibodies. JAMA. 2003;290:1721–1728. doi:10.1001/jama.290.13.1721.

    Article  PubMed  CAS  Google Scholar 

  10. Chehade M. Ige and non-IGE-mediated food allergy: treatment in 2007. Curr Opin Allergy Clin Immunol. 2007;7:264–268. doi:10.1097/ACI.0b013e32814a5607.

    Article  PubMed  CAS  Google Scholar 

  11. Cummins AG, Thompson FM. Effect of breast milk and weaning on epithelial growth of the small intestine in humans. Gut. 2002;51:748–754. doi:10.1136/gut.51.5.748.

    Article  PubMed  CAS  Google Scholar 

  12. Hawkes JS, Bryan DL, James MJ, Gibson RA. Cytokines (il-1beta, il-6, TNF-alpha, TGF-beta1, and TGF-beta2) and prostaglandin E2 in human milk during the first three months postpartum. Pediatr Res. 1999;46:194–199. doi:10.1203/00006450-199908000-00012.

    Article  PubMed  CAS  Google Scholar 

  13. Penttila IA, Flesch IE, McCue AL, et al. Maternal milk regulation of cell infiltration and interleukin 18 in the intestine of suckling rat pups. Gut. 2003;52:1579–1586. doi:10.1136/gut.52.11.1579.

    Article  PubMed  CAS  Google Scholar 

  14. Zhang M, Zola H, Read L, Penttila I. Identification of soluble transforming growth factor-beta receptor III ((sTbetaIII)) in rat milk. Immunol Cell Biol. 2001;79:291–297. doi:10.1046/j.1440-1711.2001.01013.x.

    Article  PubMed  CAS  Google Scholar 

  15. Penttila IA, van Spriel AB, Zhang MF, et al. Transforming growth factor-beta levels in maternal milk and expression in postnatal rat duodenum and ileum. Pediatr Res. 1998;44:524–531. doi:10.1203/00006450-199810000-00010.

    Article  PubMed  CAS  Google Scholar 

  16. Hawkes JS, Neumann MA, Gibson RA. The effect of breast feeding on lymphocyte subpopulations in healthy term infants at 6 months of age. Pediatr Res. 1999;45:648–651. doi:10.1203/00006450-199905010-00006.

    Article  PubMed  CAS  Google Scholar 

  17. Dvorak B, McWilliam DL, Williams CS, et al. Artificial formula induces precocious maturation of the small intestine of artificially reared suckling rats. J Pediatr Gastroenterol Nutr. 2000;31:162–169. doi:10.1097/00005176-200008000-00013.

    Article  PubMed  CAS  Google Scholar 

  18. Patel MS, Vadlamudi SP, Johanning GL. Overview of pup in a cup model: hepatic lipogenesis in rats artificially reared on a high-carbohydrate formula. J Nutr. 1993;123:373–377.

    PubMed  CAS  Google Scholar 

  19. Singh RR, Hahn BH, Sercarz EE. Neonatal peptide exposure can prime t cells and, upon subsequent immunization, induce their immune deviation: implications for antibody vs. T cell-mediated autoimmunity. J Exp Med. 1996;183:1613–1621. doi:10.1084/jem.183.4.1613.

    Article  PubMed  CAS  Google Scholar 

  20. Tooley KL, Howarth GS, Lymn KA, Lawrence A, Butler RN. Oral ingestion of streptococcus thermophilus diminishes severity of small-intestinal mucositis in methotrexate treated rats. Cancer Biol Ther. 2006;5:593–600. doi:10.1158/1535-7163.MCT-05-0457.

    Article  PubMed  CAS  Google Scholar 

  21. Dahlqvist A. Assay of intestinal disaccharidases. Anal Biochem. 1968;22:99–107. doi:10.1016/0003-2697(68)90263-7.

    Article  PubMed  CAS  Google Scholar 

  22. Symonds EL, Butler RN, Omari TI. Assessment of gastric emptying in the mouse using the 13c-octanoic acid breath test. Clin Exp Pharm Phys. 2000;27:671–675. doi:10.1046/j.1440-1681.2000.03318.x.

    Article  CAS  Google Scholar 

  23. Funaba M, Ikeda T, Murakami M, et al. Involvement of p38 MAP kinase and smad3 in TGF-beta-mediated mast cell functions. Cell Signal. 2006;18:2154–2161. doi:10.1016/j.cellsig.2006.04.005.

    Article  PubMed  CAS  Google Scholar 

  24. Rosbottom A, Scudamore CL, von der Mark H, Thornton EM, Wright SH, Miller HR. TGF-beta 1 regulates adhesion of mucosal mast cell homologues to laminin-1 through expression of integrin alpha 7. J Immunol. 2002;169:5689–5695.

    PubMed  CAS  Google Scholar 

  25. Di Sabatino A, Pickard KM, Rampton D, et al. Blockade of transforming growth factor beta upregulates t-box transcription factor t-bet, and increases t helper cell type 1 cytokine and matrix metalloproteinase-3 production in the human gut mucosa. Gut. 2008;57:605–612. doi:10.1136/gut.2007.130922.

    Article  PubMed  CAS  Google Scholar 

  26. Maheshwari A, Lu W, Lacson A, et al. Effects of interleukin-8 on the developing human intestine. Cytokine. 2002;20:256–267. doi:10.1006/cyto.2002.1996.

    Article  PubMed  CAS  Google Scholar 

  27. Zemann B, Schwaerzler C, Griot-Wenk M, et al. Oral administration of specific antigens to allergy-prone infant dogs induces IL-10 and TGF-beta expression and prevents allergy in adult life. J Allergy Clin Immunol. 2003;111:1069–1075.

    Article  PubMed  CAS  Google Scholar 

  28. Buccigrossi V, de Marco G, Bruzzese E, et al. Lactoferrin induces concentration-dependent functional modulation of intestinal proliferation and differentiation. Pediatr Res. 2007;61:410–414. doi:10.1203/pdr.0b013e3180332c8d.

    Article  PubMed  CAS  Google Scholar 

  29. Edde L, Hipolito RB, Hwang FF, Headon DR, Shalwitz RA, Sherman MP. Lactoferrin protects neonatal rats from gut-related systemic infection. Am J Physiol Gastrointest Liver Physiol. 2001;281:G1140–G1150.

    PubMed  CAS  Google Scholar 

  30. Philipps AF, Anderson GG, Dvorak B, et al. Growth of artificially fed infant rats: effect of supplementation with insulin-like growth factor i. Am J Physiol. 1997;272:R1532–R1539.

    PubMed  CAS  Google Scholar 

  31. Dvorak B, Fituch CC, Williams CS, Hurst NM, Schanler RJ. Increased epidermal growth factor levels in human milk of mothers with extremely premature infants. Pediatr Res. 2003;54:15–19. doi:10.1203/01.PDR.0000065729.74325.71.

    Article  PubMed  CAS  Google Scholar 

  32. Dvorak B, Halpern MD, Holubec H, et al. Maternal milk reduces severity of necrotizing enterocolitis and increases intestinal IL-10 in a neonatal rat model. Pediatr Res. 2003;53:426–433. doi:10.1203/01.PDR.0000050657.56817.E0.

    Article  PubMed  CAS  Google Scholar 

  33. Aggett PJ, Agostoni C, Axelsson I, et al. Feeding preterm infants after hospital discharge: a commentary by the ESPGHAN committee on nutrition. J Pediatr Gastroenterol Nutr. 2006;42:596–603. doi:10.1097/01.mpg.0000221915.73264.c7.

    Article  PubMed  Google Scholar 

  34. Niklasson A, Engstrom E, Hard AL, Wikland KA, Hellstrom A. Growth in very preterm children: a longitudinal study. Pediatr Res. 2003;54:899–905. doi:10.1203/01.PDR.0000091287.38691.EF.

    Article  PubMed  Google Scholar 

  35. Schanler RJ, Lau C, Hurst NM, Smith EO. Randomized trial of donor human milk versus preterm formula as substitutes for mothers’ own milk in the feeding of extremely premature infants. Pediatrics. 2005;116:400–406. doi:10.1542/peds.2004-1974.

    Article  PubMed  Google Scholar 

  36. Schanler RJ, Shulman RJ, Lau C, Smith EO, Heitkemper MM. Feeding strategies for premature infants: randomized trial of gastrointestinal priming and tube-feeding method. Pediatrics. 1999;103:434–439. doi:10.1542/peds.103.2.434.

    Article  PubMed  CAS  Google Scholar 

  37. Xu D, Trajkovic V, Hunter D, et al. IL-18 induces the differentiation of Th1 or Th2 cells depending upon cytokine milieu and genetic background. Eur J Immunol. 2000;30:3147–3156. doi :10.1002/1521-4141(200011)30:11<3147::AID-IMMU3147>3.0.CO;2-J.

  38. Jang I, Jung K, Cho J. Influence of age on duodenal brush border membrane and specific activities of brush border membrane enzymes in Wistar rats. Exp Anim. 2000;49:281–287. doi:10.1538/expanim.49.281.

    Article  PubMed  CAS  Google Scholar 

  39. Ewer AK, Yu VY. Gastric emptying in pre-term infants: the effect of breast milk fortifier. Acta Paediatr. 1996;85:1112–1115. doi:10.1111/j.1651-2227.1996.tb14227.x.

    Article  PubMed  CAS  Google Scholar 

  40. Symonds EL, Butler R, Omari TI. A mouse model for assessing the impact of ingested nutrients on gastric emptying rate. Clin Exp Pharmacol Physiol. 2007;34:132–133. doi:10.1111/j.1440-1681.2007.04546.x.

    Article  PubMed  CAS  Google Scholar 

  41. Billeaud C, Guillet J, Sandler B. Gastric emptying in infants with or without gastro-oesophageal reflux according to the type of milk. Eur J Clin Nutr. 1990;44:577–583.

    PubMed  CAS  Google Scholar 

  42. Tomomasa T, Hyman PE, Itoh K, et al. Gastroduodenal motility in neonates: response to human milk compared with cow’s milk formula. Pediatrics. 1987;80:434–438.

    PubMed  CAS  Google Scholar 

  43. Van Den Driessche M, Peeters K, Marien P, Ghoos Y, Devlieger H, Veereman-Wauters G. Gastric emptying in formula-fed and breast-fed infants measured with the 13c-octanoic acid breath test. J Pediatr Gastroenterol Nutr. 1999;29:46–51. doi:10.1097/00005176-199907000-00013.

    Article  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Helen Bougesis, Jade Duncan, Nicole Pelton, Katy Ramsden, Leana Coleman, and Julie Clarke for assistance with experimentation and analyses.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to K. L. Tooley.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tooley, K.L., Howarth, G.S., Butler, R.N. et al. The Effects of Formula Feeding on Physiological and Immunological Parameters in the Gut of Neonatal Rats. Dig Dis Sci 54, 1432–1439 (2009). https://doi.org/10.1007/s10620-008-0513-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-008-0513-6

Keywords

Navigation