Reduced Expression of UGT1A1 in Intestines of Humanized UGT1 Mice via Inactivation of NF-κB Leads to Hyperbilirubinemia

BACKGROUND & AIMS: Bilirubin is a natural and potent antioxidant that accumulates in the blood of newborn children and leads to physiological jaundice. Breastfed infants have higher serum levels of bilirubin than formula-fed infants and are at risk for bilirubin-induced neurological dysfunction (BIND). Clearance of bilirubin requires the expression of uridine diphosphate glucuronosyltransferase (UGT) 1A1; we investigated its role in the association between breast feeding with jaundice in mice. METHODS: We studied mice in which the original Ugt1 locus was disrupted and replaced with the human UGT1 locus (hUGT1 mice); these mice spontaneously develop neonatal hyperbilirubinemia and BIND. We fed human breast milk or formula to neonatal hUGT1 mice and examined activation of the intestinal xenobiotic receptors pregnane X receptor and constitutive androstane receptor. We also examined inflammatory signaling pathways in mice with disruptions in I kappa B-kinase-alpha and I kappa B kinase-beta in the intestinal epithelium. RESULTS: hUGT1 mice that were fed breast milk developed severe hyperbilirubinemia because of suppression of UGT1A1 in the gastrointestinal tract. Formula-fed hUGT1 mice had lower serum levels of bilirubin, which resulted from induction of UGT1A1 in the gastrointestinal tract. hUGT1/Pxr-null mice did not develop severe hyperbilirubinemia, whereas hUGT1/Car-null mice were susceptible to BIND when they were fed breast milk. Breast milk appeared to suppress intestinal I kappa B kinase alpha and beta, resulting in inactivation of nuclear factor-kappa B and loss of expression of UGT1A1, leading to hyperbilirubinemia. CONCLUSIONS: Breast milk reduces expression of intestinal UGT1A1, which leads to hyperbilirubinemia and BIND; suppression of this gene appears to involve inactivation of nuclear factor-B. Hyperbilirubinemia can be reduced by activation of pregnane X receptor, constitutive androstane receptor, or nuclear factor-kappa B.