# Immune-Metabolic Regulation of Biliary Atresia

> **NIH NIH R03** · UNIVERSITY OF COLORADO DENVER · 2023 · $116,625

## Abstract

Biliary atresia (BA) is a cholestatic liver disease of infancy and is the leading cause of pediatric
liver transplantation. Current evidence supports the principle that BA arises from an aberrant
immune response to an environmental trigger. However, the exact mechanism of disease remains
unknown. While macrophages (M) have been implicated in both human and murine BA, M are
heterogeneous by nature and the metabolic networks responsible for pro-restorative vs pro-
inflammatory M polarization have not been defined. Our central premise is that identifying
macrophage-specific immune-metabolic signatures associated with patient outcome will lead to
novel prognostic biomarkers and cell-subset specific therapies to prolong transplant-free survival.
We have been the first to identify a prognostic metabolite signature in BA infants at the time of
diagnosis. We have shown that distinct changes in serum arginine metabolites, particularly
increased polyamines, in BA infants at the time of diagnosis was associated with increased
survival with native liver (SNL) at the age of 2 years despite no baseline differences in clinical
characteristics. Polyamines are known to reprogram M to an anti-inflammatory phenotype, in
part through efferocytosis (i.e. apoptotic cell uptake). Our preliminary data found that BA patients
with a polyamine-high metabolic signature had increased hepatic numbers of previously
characterized monocyte-like M (MLM, increased expression for genes associated with
monocytes) and serum GM-CSF. We thereby hypothesize that recruited MLM promote hepatic
adaptation to biliary obstruction; thus, metabolic and epigenetic reprogramming of MLM towards
and anti-inflammatory phenotype will be associated with SNL at 2 years of age. To investigate
this hypothesis, we will: 1) define the prognostic role for serum arginine metabolites, and 2)
identify cell subset specific transcriptional phenotypes associated with SNL.

## Key facts

- **NIH application ID:** 10645435
- **Project number:** 1R03DK135784-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Sarah Ann Taylor
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $116,625
- **Award type:** 1
- **Project period:** 2023-04-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10645435

## Citation

> US National Institutes of Health, RePORTER application 10645435, Immune-Metabolic Regulation of Biliary Atresia (1R03DK135784-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10645435. Licensed CC0.

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