# Severe neonatal hyperbilirubinemia (SNH) and the expression of UDP-glucuronosyltransferase 1A1 (UGT1A1) play key roles in the development of necrotizing enterocolitis (NEC)

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $614,400

## Abstract

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...

## Key facts

- **NIH application ID:** 10874535
- **Project number:** 5R01DK136599-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Robert H Tukey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $614,400
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10874535

## Citation

> US National Institutes of Health, RePORTER application 10874535, Severe neonatal hyperbilirubinemia (SNH) and the expression of UDP-glucuronosyltransferase 1A1 (UGT1A1) play key roles in the development of necrotizing enterocolitis (NEC) (5R01DK136599-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10874535. Licensed CC0.

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