Gut and immune effects of bioactive milk factors in preterm pigs exposed to prenatal inflammation

Am J Physiol Gastrointest Liver Physiol. 2019 Jul 1;317(1):G67-G77. doi: 10.1152/ajpgi.00042.2019. Epub 2019 May 15.


Prenatal inflammation may predispose to preterm birth and postnatal inflammatory disorders such as necrotizing enterocolitis (NEC). Bioactive milk ingredients may help to support gut maturation in such neonates, but mother's milk is often insufficient after preterm birth. We hypothesized that supplementation with bioactive ingredients from bovine milk [osteopontin (OPN), caseinoglycomacropeptide (CGMP), colostrum (COL)] supports gut, immunity, and NEC resistance in neonates born preterm after gram-negative infection before birth. Using preterm pigs as a model for preterm infants, fetal pigs were given intraamniotic injections of lipopolysaccharide (LPS; 1 mg/fetus) and delivered 3 days later (90% gestation). For 5 days, groups of LPS-exposed pigs were fed formula (FOR), bovine colostrum (COL), or formula enriched with OPN or CGMP. LPS induced intraamniotic inflammation and postnatal systemic inflammation but limited effects on postnatal gut parameters and NEC. Relative to FOR, COL feeding to LPS-exposed pigs showed less diarrhea, NEC severity, reduced gut IL-1β and IL-8 levels, greater gut goblet cell density and digestive enzyme activities, and blood helper T-cell fraction. CGMP improved neonatal arousal and gut lactase activities and reduced LPS-induced IL-8 secretion in intestinal epithelial cells (IECs) in vitro. Finally, OPN tended to reduce diarrhea and stimulated IEC proliferation in vitro. No effects on villus morphology, circulating cytokines, or colonic microbiota were observed among groups. In conclusion, bioactive milk ingredients exerted only modest effects on gut and systemic immune parameters in preterm pigs exposed to prenatal inflammation. Short-term, prenatal exposure to inflammation may render the gut less sensitive to immune-modulatory milk effects. NEW & NOTEWORTHY Prenatal inflammation is a risk factor for preterm birth and postnatal complications including infections. However, from clinical studies, it is difficult to separate the effects of only prenatal inflammation from preterm birth. Using cesarean-delivered preterm pigs with prenatal inflammation, we documented some beneficial gut effects of bioactive milk diets relative to formula, but prenatal inflammation appeared to decrease the sensitivity of enteral feeding. Special treatments and diets may be required for this neonatal population.

Keywords: bovine colostrum; caseinoglycomacropeptide; lipopolysaccharide; osteopontin; prenatal inflammation; preterm pigs.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Caseins / administration & dosage*
  • Caseins / immunology
  • Cell Line
  • Chorioamnionitis / chemically induced
  • Chorioamnionitis / diet therapy*
  • Chorioamnionitis / immunology
  • Chorioamnionitis / metabolism
  • Colostrum / immunology
  • Disease Models, Animal
  • Enterocolitis, Necrotizing / etiology
  • Enterocolitis, Necrotizing / immunology
  • Enterocolitis, Necrotizing / metabolism
  • Enterocolitis, Necrotizing / prevention & control*
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism
  • Female
  • Food, Fortified*
  • Gastrointestinal Microbiome
  • Gestational Age
  • Humans
  • Immunity, Mucosal*
  • Infant Formula*
  • Infant, Newborn
  • Intestinal Absorption
  • Intestines / immunology*
  • Intestines / microbiology
  • Intestines / pathology
  • Lipopolysaccharides
  • Nutritive Value
  • Osteopontin / administration & dosage*
  • Osteopontin / immunology
  • Peptide Fragments / administration & dosage*
  • Peptide Fragments / immunology
  • Permeability
  • Pregnancy
  • Premature Birth*
  • Sus scrofa


  • Caseins
  • Lipopolysaccharides
  • Peptide Fragments
  • caseinomacropeptide
  • lipopolysaccharide, E coli O55-B5
  • Osteopontin