Breast feeding is known to protect the recipient infant against common infectious diseases of the intestinal and respiratory tracts. To explain this observation, we suggest as an overall working hypothesis for this proposal that breast milk, particularly colostrum, contains trophic factors that can directly stimulate the development of normal intestinal mucosal barrier function in the newborn. During the previous 17 years of funding on this grant, we have reported, in many primary publications and reviews, pathophysiologic evidence to support this hypothesis in animal models and more recently at the cellular level in human enterocyte cancer cell lines. We now plan to further define the observations in the human intestine at the cellular/molecular levels using a newly established human fetal small intestinal epithelial cell line and at the organ level using human organ cultures/small intestinal transplant models. Specifically we will: a) further define the function of the epithelial cell line including receptor expression and signal transduction, determine microenvironmental influences (mesenchyme and luminal, including breast milk) and immortalize the cell line with a SV40 T antigen/villin promotor construct; b) use the data from these studies to determine the effect of amniotic fluid/breast milk from preterm and term mothers and combinations of trophic factors in milk to measure proliferation, differentiation, and effects on epithelium immune function (chemokine, class II MHC, IgAR, and integrin expression); c) also study the immaturities of bacterial colonization and exotoxin responses in the fetal and neonatal human intestine and determine if breast milk trophic factors can cause maturation of these processes towards normal. Finally having described an IgG Fc receptor in human fetal upper small intestine and cloned that receptor, we will now d) determine at the cellular level the effect of breast milk on the developmental regulation and function of this receptor as a possible shuttle for maternal IgG from amniotic fluid preterm colostrum to the fetal circulation. Information from these studies will help us as we begin to fully understand the immaturities of enterocyte function in newborns and will allow us to plan strategies for managing the consequences of these immaturities, i.e. an increased incidence of specific diseases of the intestine. At the very least by carefully documenting the active stimulatory effect of breast milk on gut maturation we can hopefully encourage a higher percentage of mothers to breast feed their newborn infants and to continue nursing for a longer period of time.
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