# Microbiome and Intestinal Innate Immune Response in Alcoholic Liver Disease

> **NIH NIH R37** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $422,582

## 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 microbiota, increases in intestinal permeability, and
elevated systemic levels of bacterial products. We demonstrated that Enterococcus faecalis (E. faecalis) is
sufficient to cause mild steatotic liver disease and to exacerbate ethanol-induced liver disease in mice. We
identified cytolysin, a two-subunit exotoxin secreted by E. faecalis, to cause hepatocyte death and liver injury.
Compared with controls, patients with alcohol use disorder or alcoholic hepatitis have increased fecal numbers
of E. faecalis. The presence of cytolysin-positive (cytolytic) E. faecalis correlated with liver disease severity and
mortality in patients with alcoholic hepatitis. How chronic alcohol use results in increased intestinal and hepatic
numbers of cytolysin-positive E. faecalis is not known. Results from our laboratory suggest that increased
intestinal numbers of E. faecalis are facilitated by changes in the intestinal glycocalyx and in particular by
reduced (1,2)-fucosylation of glycoproteins on the apical membrane of intestinal epithelial cells. Alcohol-
mediated suppression of Fucosyltransferase 2 (Fut2) allows intestinal colonization and bacterial translocation
of E. faecalis. Furthermore, translocated E. faecalis is phagocytosed and eliminated by the complement
receptor of the immunoglobulin superfamily (CRIg) on Kupffer cells. Patients with chronic alcoholic hepatitis
have lower hepatic CRIg expression, which reduces E. faecalis elimination, prolongs exposure to E. faecalis
and increases liver damage. Thus, ethanol associated changes in intestinal colonization and hepatic
elimination of E. faecalis promotes alcohol-related liver disease. Our experimental approach is to use mouse
models of ethanol feeding to investigate the role of Fut2 in limiting intestinal colonization of E. faecalis and
reducing liver disease (Aim 1). We will also assess the functional contribution of the phagocytic protein CRIg to
E. faecalis elimination and to liver disease (Aim 2). New strategies will be tested to prevent and ameliorate
ethanol-induced liver disease in preclinical models. We believe these studies will provide novel insights into the
contribution of the microbiota to alcohol-related liver disease.

## Key facts

- **NIH application ID:** 10454768
- **Project number:** 5R37AA020703-12
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Bernd G. Schnabl
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $422,582
- **Award type:** 5
- **Project period:** 2011-09-25 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10454768

## Citation

> US National Institutes of Health, RePORTER application 10454768, Microbiome and Intestinal Innate Immune Response in Alcoholic Liver Disease (5R37AA020703-12). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10454768. Licensed CC0.

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