P-glycoprotein induction by breast milk attenuates intestinal inflammation in experimental necrotizing enterocolitis

Yigit S. Guner, Ashanti L. Franklin, Nikunj K. Chokshi, Shannon L. Castle, Elizabeth Pontarelli, Jin Wang, Larry Wang, Nemani V. Prasadarao, Jeffrey S. Upperman, Anatoly V. Grishin, Henri R. Ford

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

P-glycoprotein (Pgp), a product of the multi-drug resistance gene MDR1a, is a broad specificity efflux ATP cassette transmembrane transporter that is predominantly expressed in epithelial tissues. Because mdr1a / mice tend to develop spontaneous colitis in bacteria-dependent manner, Pgp is believed to have a role in protection of the intestinal epithelium from luminal bacteria. Here we demonstrate that levels of Pgp in the small intestine of newborn rodents dramatically increase during breastfeeding, but not during formula feeding (FF). In rats and mice, levels of intestinal Pgp peak on days 3-7 and 1-5 of breastfeeding, respectively. The mdr1a / neonatal mice subjected to FF, hypoxia, and hypothermia have significantly higher incidence and pathology, as well as significantly earlier onset of necrotizing enterocolitis (NEC) than congenic wild type mice. Breast-fed mdr1a / neonatal mice are also more susceptible to intestinal damage caused by the opportunistic pathogen Cronobacter sakazakii that has been associated with hospital outbreaks of NEC. Breast milk, but not formula, induces Pgp expression in enterocyte cell lines in a dose- and time-dependent manner. High levels of ectopically expressed Pgp protect epithelial cells in vitro from apoptosis induced by C. sakazakii. Taken together, these results show that breast milk-induced expression of Pgp may have a role in the protection of the neonatal intestinal epithelium from injury associated with nascent bacterial colonization.

Original languageEnglish (US)
Pages (from-to)1668-1679
Number of pages12
JournalLaboratory Investigation
Volume91
Issue number11
DOIs
StatePublished - Nov 1 2011
Externally publishedYes

Keywords

  • P-glycoprotein
  • bacteria
  • breast milk
  • intestinal epithelium
  • necrotizing enterocolitis

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Guner, Y. S., Franklin, A. L., Chokshi, N. K., Castle, S. L., Pontarelli, E., Wang, J., Wang, L., Prasadarao, N. V., Upperman, J. S., Grishin, A. V., & Ford, H. R. (2011). P-glycoprotein induction by breast milk attenuates intestinal inflammation in experimental necrotizing enterocolitis. Laboratory Investigation, 91(11), 1668-1679. https://doi.org/10.1038/labinvest.2011.113