# Goblet cells and intestinal immune response in alcohol-associated liver disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $458,665

## Abstract

Project Summary/Abstract
Excessive alcohol drinking modulates the innate and adaptive immune systems. It is associated with gut
dysbiosis and bacterial overgrowth. Consequently, it induces intestinal permeability and microbial translocation
to the liver which triggers inflammation aggravating alcohol-associated liver disease. The immune system
interacts, tolerates, and shapes the intestinal microbiota while monitoring for pathogens. The balance between
gut tolerance and immunity is critical in the regulation of intestinal homeostasis. A balanced intestinal
homeostasis is essential to prevent intestinal permeability and microbial translocation to the liver. Goblet cells
regulate the intestinal immune response by secreting mucin and presenting luminal antigens to lamina propria
dendritic cells (LP-DCs) through goblet-cell associated antigen passages (GAPs). LP-DCs adjacent to GAPs
have preferential tolerogenic properties. Chronic alcohol overuse decreases the pool of myeloid DCs and
modifies its properties. However, the effect of chronic ethanol overuse on the LP-immune response is not well
characterized.
The hypothesis is that chronic ethanol exposure alters goblet cell biology resulting in the dysfunction of
LP-DCs with tolerogenic properties adjacent to GAPs. Hence, a lack of antigen presentation to
tolerogenic LP-DCs would induce an imbalance of the intestinal homeostasis. Therefore, goblet cells
might have a central role in the onset of alcohol-related liver diseases.
To explore the proposed hypothesis, aim 1 will investigate the impact of chronic alcohol abuse on goblet cell
biology. It will assess goblet cell numbers, GAP formation, mucin secretion, and the consequent alterations in
the LP-immune system in mice and humans. Aim 2 will define the impact of GAPs and mucin from goblet cells
on ethanol-induced liver disease in ethanol-fed mice with both, loss and gain of function approaches. Finally,
aim 3 will explore a pharmacological approach to manipulate goblet cells to prevent ethanol-induced liver
disease in mice subjected to chronic ethanol feeding. This pharmacological intervention will induce LP-DCs
with tolerogenic properties by stimulating GAP formation to regulate the mucosal immune system.
The proposed study will characterize the role of goblet cells in preclinical models of ethanol-induced liver
disease and patients with alcohol use disorder using cutting edge microbiomics and state-of-the-art
technology. The proposed intervention will find innovative strategies to prevent alcohol-associated liver disease
in patients.

## Key facts

- **NIH application ID:** 10834264
- **Project number:** 5R01AA029106-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Ana Cristina Llorente Izquierdo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $458,665
- **Award type:** 5
- **Project period:** 2022-08-10 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10834264

## Citation

> US National Institutes of Health, RePORTER application 10834264, Goblet cells and intestinal immune response in alcohol-associated liver disease (5R01AA029106-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10834264. Licensed CC0.

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