ABSTRACT Severe neonatal hyperbilirubinemia (SNH) and necrotizing enterocolitis (NEC) are the most common causes of morbidity in newborns worldwide, with both symptoms being linked to human breast milk (HBM). Enteral formula feeding is a direct biomarker for the induction of NEC in preterm newborns, while HBM protects against NEC. In newborns, HBM suppresses UDP-glucuronosyltransferase (UGT) 1A1 expression, the only transferase capable of conjugating bilirubin, thus contributing to the development of hyperbilirubinemia. Humanized UGT1 (hUGT1) mice that express the human UGT1A1 gene mimic what is observed in humans with neonatal hUGT1 mice developing SNH. As an animal model to examine the mechanisms that lead to regulation of the UGT1A1 gene, we have documented that the UGT1A1 gene is repressed in liver tissue, which plays a key role in total serum bilirubin (TSB) accumulation. While approximately 10% of the neonatal hUGT1 mice develop Kernicterus Spectrum Disorder (KSD), which is lethal, most of the newborns are healthy, have normal reproductive cycles, and represent an excellent model to study the underlying mechanisms linking UGT1A1 expression to SNH. New findings from our laboratory have demonstrated that the delay in intestinal UGT1A1 expression is controlled specifically by the nuclear receptor transcriptional corepressor protein, NCoR1. When NCoR1 is rendered non-functional through genetic knockout experiments in the intestines, neonatal TSB levels are normal and intestinal UGT1A1 is dramatically induced, resulting from intestinal epithelial cell (IEC) maturation. The delay in intestinal UGT1A1 in neonatal hUGT1 mice is a direct result of breast milk, since formula feeding leads to significant induction of UGT1A1. HBM plays a key role in the development of SNH by blocking bilirubin metabolism while simultaneously protecting newborns against NEC. Thus, we hypothesize that the underlying mechanisms leading to SNH are also linked to the underlying mechanisms that regulate NEC. This may not be a coincidence but crucially important to understand, since bilirubin is a potent antioxidant that could combat oxidative stress induced intestinal inflammation, which leads to NEC. Thus, the focus of our efforts will determine if complimentary cellular mechanisms are tied to the development of both SNH and NEC. The major focus areas, based upon current publications and preliminary findings, will be to tie the role of microflora, TRL4 signaling, HBM oligosaccharides, and neonatal IEC maturation, with the control and regulation of SNH and NEC. The experiments outlined are anticipated to lead to a greater understanding of these syndromes, made available using novel mouse models and advanced technology that will allow us to connect the early biological events after birth leading to the developmental control of SNH with those same processes that will be tied to the onset of NEC. Because there does not exist effective therapeutic interventions for the treatment...