Enterally Administered Bovine Colostral Extract Modulates Intestinal Barrier Function & Immune Gene Expression in Parentally-fed Neonatal Piglets

Total parenteral nutrition (TPN) is a standard clinical treatment for preterm infants who are unable to tolerate enteral nutrition (TEN).  However, TPN induces small intestinal atrophy, impairs digestive and absorptive function and alters intestinal adaptive and innate immunity. Partial enteral nutrition (PEN) is often used to stimulate intestinal function and to ease the transition from TPN to TEN, however, PEN alone does not fully prevent the structural and functional impairments associated with TPN.  Thus, our goal was to determine whether PEN supplemented with a bovine colostral extract would be more efficacious than PEN alone in maintaining intestinal function in neonates on TPN.  Two-day-old piglets (n=6/group) were maintained on TEN, TPN, PEN (20% of calories enterally as formula; PEN A) or PEN+colostrum (PEN B) for 7 days.  TPN reduced (p<0.001) duodenal mucosal weight, villus height, enterocyte proliferation and migration, and transmucosal resistance, a marker of barrier function.  Provision of PEN partially ameliorated (p<0.001) TPN-induced reductions in mucosal growth and lactase activity.  Supplementation of the bovine colostral extract to PEN further improved villus height, epithelial cell proliferation and migration, transmucosal resistance and ion transport over PEN alone, achieving levels similar to TEN.  A 13,000-gene porcine-specific oligonucleotide microarray was used to examine gene expression profiles in duodenal epithelial cells isolated by laser capture microdissection.  Following amplification, mRNA was labeled with Cy3 and Cy5 fluorescent dyes and competitively hybridized to microarrays.  Data were analyzed using the limma package in R.  Compared to PEN A, 418 genes (218 up-regulated and 200 down-regulated genes) were differentially expressed by PEN B at a FDR-adjusted p<0.05.  Genes related to cell cycle (MT-1A, MPP8), immune response (B2M, LILRB2, LILRB3, IFITM3, SLA, MAPKK3), oxidative stress (GSTM14, EPHX1), transport (TAP1, RBP2) and structure (TMSL3, ACTG2) displayed >1.5-fold differences in expression.  Ingenuity Pathway Analysis was used to identify biological mechanisms, pathways and functions most relevant to our genes of interest.  Genes were clustered into 22 molecular networks.  Three networks regulating cell death, cellular growth and proliferation, DNA replication, gene expression and immunological and inflammatory disease processes had scores of 51, with 35 genes each.  Compared to PEN alone, colostrum supplementation up-regulated a network of genes related to antigen presentation and immune function, which coupled with improved barrier function suggests a potential enhancement of innate immunity.  Funded by Wyeth Nutrition.