# Southern California Research Center for ALPD and Cirrhosis

> **NIH NIH P50** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2024 · $186,890

## Abstract

RP1: The role of endogenous retroviral elements in alcohol-associated liver disease
Project Summary
Alcohol associated health problems are a major medical burden in industrialized countries. Patients with
alcohol-associated liver disease show intestinal bacterial dysbiosis and increased intestinal permeability.
Although there is considerable progress in understanding the interaction between the host and intestinal
bacteria, the role of the intestinal virome in alcohol-associated liver disease has not been investigated.
Preliminary data from our laboratories demonstrate that ethanol leads to chromatin remodeling and
transcription of endogenous retroviral elements (ERVs) in intestinal organoids and in the intestine of
ethanol-fed mice. Colonization of germ-free mice with feces from patients with alcohol-associated hepatitis
positive for fecal retroviruses increases ethanol-induced liver disease. This is supported by data
demonstrating that anti-retroviral treatment reduces intestinal ERVs and improves ethanol-induced liver
disease in gnotobiotic mice. Importantly, we demonstrate that ethanol-induced ERVs activate Z-nucleic acid
binding protein 1 (Zbp1) in intestinal epithelial cells. Mice with an intestinal epithelial cell specific deletion of
Zbp1 developed less severe ethanol-induced liver disease as compared with Zbp1-floxed littermates. The
testable central hypothesis of this proposed collaborative and multidisciplinary research application
implicates disturbances in the gut virome as an important etiological factor in the modulation of alcohol-
associated liver disease. Through the proposed study, we will characterize ERVs in a human cohort. We will
mechanistically test our hypothesis in a mouse model of ethanol-induced liver disease. Towards this goal,
we will use pharmacological interventions, microbiota humanized and genetically modified mice. We predict
that ethanol-mediated chromatin remodeling results in induction of ERV transcription in intestinal epithelial
cells (Aim 1). We further hypothesize that ethanol-induced ERVs activate Z-nucleic acid binding protein 1
(Zbp1) in intestinal epithelial cells contributing to cell death, increased intestinal permeability and ethanol-
induced liver disease (Aim 2). We believe these studies will provide important insights into alcohol-mediated
changes of the intestinal virome that result in gut barrier dysfunction and promote alcohol-associated liver
disease. Eventually this approach might lead to new therapeutic targets for patients with alcohol-associated
liver disease.

## Key facts

- **NIH application ID:** 10739248
- **Project number:** 2P50AA011999-26
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Bernd G. Schnabl
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $186,890
- **Award type:** 2
- **Project period:** 1998-12-31 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10739248

## Citation

> US National Institutes of Health, RePORTER application 10739248, Southern California Research Center for ALPD and Cirrhosis (2P50AA011999-26). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10739248. Licensed CC0.

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