# Epigenetic regulation of bile acids in health and disease

> **NIH NIH F30** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $50,520

## Abstract

PROJECT SUMMARY
 Despite major advancements in our understanding of the pathophysiology of inflammatory bowel disease,
relatively little is known with respect to epigenetic factors that predispose to development of IBD. Epigenetic
changes, including DNA methylation, have been implicated as risk factors for these debilitating diseases.
Elevated intestinal luminal bile acids are known to exacerbate IBD symptoms, but it is not known whether
changes in DNA methylation alter bile acid regulation and, thus, contribute to the severe intestinal inflammation.
Luminal bile acids can become elevated either as a result of increased hepatic bile acid synthesis or decreased
intestinal bile acid reabsorption. Fibroblast growth factor 19 (FGF19; FGF15 in rodents), which is induced in the
ileum by reabsorbed bile acids, circulates to the liver to inhibit bile acid synthesis. Our preliminary data showed
that in a dietary model of DNA hypermethylation, ileal FGF15 mRNA is repressed and the hepatic bile
acid synthesis gene CYP7A1 is induced. We demonstrated that CpG methylation of the FGF15 gene is
increased in this model, suggesting that methylation represses FGF15 expression. To establish the novel link
between epigenetic changes and bile acid regulation, our proposed studies will test the hypothesis that DNA
hypermethylation leads to dysregulation of bile acid synthesis and absorption, contributing to increased
susceptibility to intestinal inflammation. The studies proposed in Specific Aim 1 will investigate the mechanisms
by which DNA methylation decreases FGF15/19 expression and causes bile acid dysregulation using
sophisticated in vitro and in vivo models. We will also explore the proposed link between elevated luminal bile
acids and susceptibility to inflammation using established models of intestinal inflammation and transgenic mice
with intestine-specific FGF15 overexpression. It is also known that intestinal bile acid absorption via the apical
sodium-dependent bile acid transporter (ASBT) is rapidly modulated via phosphatases and kinases, the
expression of which can be altered by DNA methylation. Thus, studies in Specific Aim 2 will investigate the
effects of DNA methylation on bile acid absorption using a novel luminescence-based method for measuring bile
acid uptake in live animals. Our preliminary data indicate that this method is suitable for measuring ASBT
function in vitro. Our proposed studies will establish an innovative method for noninvasive, real-time
measurement of bile acid absorption in animals. We will use this method to assess bile acid absorption in animal
models of DNA hypermethylation. The methods established in Specific Aim 2 will provide a novel investigative
tool for measuring bile acid transport in vitro and in vivo. Overall, the successful completion of the proposed
studies will illuminate the mechanisms underlying how epigenetic factors such as DNA methylation contribute to
bile acid dysregulation and predisposition to intestinal i...

## Key facts

- **NIH application ID:** 9903114
- **Project number:** 5F30DK117535-03
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Alexander Louis Ticho
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2018-05-22 → 2021-05-07

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9903114

## Citation

> US National Institutes of Health, RePORTER application 9903114, Epigenetic regulation of bile acids in health and disease (5F30DK117535-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9903114. Licensed CC0.

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