# Role of Intestinal Autophagy in the Pathogenesis of Alcohol Associated Liver Disease

> **NIH NIH R01** · AUBURN UNIVERSITY AT AUBURN · 2024 · $483,388

## Abstract

Abstract:
Alcohol-Associated Liver Disease (ALD) continues to be a major cause of morbidity and mortality worldwide.
Currently, there are no FDA-approved therapies that block or reverse ALD progression. Understanding the key
steps that promote ALD progression is essential to identifying new treatment targets and methods that alleviate
ALD. Prominent among the factors that contribute to ALD progression is the alcohol-induced disruption of
intestinal barrier integrity, accompanied by microbial flora imbalance (dysbiosis). Both these promote gut and
liver injury. However, the cellular/molecular mechanisms by which excessive drinking triggers dysbiosis and
compromises intestinal barrier integrity must be clearly established. Here, we present unique, exciting new data,
showing that chronic ethanol (EtOH) feeding disrupts intestinal autophagy, a crucial intracellular catabolic
process that begins with the formation of autophagosomes (AV), which sequester and deliver senescent
macromolecules and organelles to lysosomes for breakdown in this organelle. The degraded species are
replenished by synthesis. This process of rapid and constant turnover preserves the specialized functions of all
cells, but especially intestinal cells and it regulates intestinal microbial composition as well, thereby, maintaining
gut homeostasis. Our understanding of autophagy’s role in preserving intestinal barrier function has progressed
significantly, but we need a better understanding of how EtOH misuse disrupts gut autophagy to impair barrier
function. Our objective is to ascertain the mechanism(s) by which EtOH exposure dysregulates autophagy in
intestinal cells to compromise gut barrier integrity and promotes alcohol-induced liver injury. We propose the
following Specific Aims: Aim 1. Investigate how EtOH-induced lysosome disruption affects epithelial cell barrier
integrity; Aim 2) Clarify the effects of EtOH-induced autophagy disruption on Paneth cell function and Aim 3)
Ascertain how EtOH-induced liver injury is exacerbated by deficient intestinal autophagy but is alleviated by
autophagy reactivation in the gut.

## Key facts

- **NIH application ID:** 10990737
- **Project number:** 7R01AA030571-02
- **Recipient organization:** AUBURN UNIVERSITY AT AUBURN
- **Principal Investigator:** Paul Gideon Thomes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $483,388
- **Award type:** 7
- **Project period:** 2024-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10990737

## Citation

> US National Institutes of Health, RePORTER application 10990737, Role of Intestinal Autophagy in the Pathogenesis of Alcohol Associated Liver Disease (7R01AA030571-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10990737. Licensed CC0.

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