# Microbiome and intestinal innate immune response in alcoholic liver disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $348,750

## Abstract

Project Summary
Alcohol abuse and alcohol-related diseases are a major medical burden in industrialized countries. Chronic
alcoholism is associated with changes in the intestinal microbiome, increases in intestinal permeability, and
elevated systemic levels of bacterial products. We have demonstrated quantitative (overgrowth) and qualitative
dysbiotic changes in the intestinal microbiota in mouse models of chronic alcohol administration. A strong
association exists between gut-derived bacterial products and progression of alcoholic liver diseases in several
animal models, yet factors facilitating the onset of intestinal dysbiosis are unknown. Furthermore, how
dysbiosis contributes to alcoholic liver disease beyond increasing intestinal permeability is also not known.
Results from our laboratory suggest that suppression of gastric acid secretion and inhibition of the intestinal
antimicrobial proteins regenerating-islet derived (Reg)-3b and Reg3g contribute to dysbiosis and liver disease
following chronic ethanol feeding in mice. Furthermore, dysbiosis leads to deconjugation of intestinal bile acids
in the proximal small intestine. Deconjugated bile acids are rapidly absorbed by nonionic diffusion in the
jejunum, and a smaller amount of conjugated bile acids reaches the terminal ileum, which disrupts the
enterohepatic circulation and results in increased hepatic bile acid synthesis. A larger bile acid pool contributes
to more hepatocyte damage and alcoholic liver disease. The focus of this application is to characterize factors
contributing to changes in the microbiota and to investigate how dysbiosis affects liver disease after chronic
alcohol administration. We hypothesize that gastric acid suppression and alcohol-mediated inhibition of the
antimicrobial Reg3 lectins modulate the intestinal microbiota. Dysbiosis in turn disrupts enterohepatic
circulation of bile acids and increases the total bile acid pool, which enhances alcohol-induced liver damage.
Our experimental approach is to use mouse models of chronic alcohol feeding to investigate the role of gastric
acid in inducing intestinal dysbiosis and liver disease (Aim 1). We will also assess the functional contribution of
the antimicrobial proteins Reg3b and Reg3g to changes in the microbiota composition, bacterial translocation
and alcoholic liver disease (Aim 2). We will then determine the consequences of dysbiotic microbiome changes
by focusing on bile acid metabolism (Aim 3). We believe these studies will provide novel insights into the
contribution of the microbiota and its metabolites to alcoholic liver disease. New strategies will evolve to
prevent or ameliorate alcoholic liver disease in patients.

## Key facts

- **NIH application ID:** 9961339
- **Project number:** 5R01AA020703-10
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Bernd G. Schnabl
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $348,750
- **Award type:** 5
- **Project period:** 2011-09-25 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9961339

## Citation

> US National Institutes of Health, RePORTER application 9961339, Microbiome and intestinal innate immune response in alcoholic liver disease (5R01AA020703-10). Retrieved via AI Analytics 2026-07-25 from https://api.ai-analytics.org/grant/nih/9961339. Licensed CC0.

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