# The role of pathobionts in alcoholic liver disease

> **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2024 · —

## Abstract

Alcohol use disorder and alcohol-related liver disease are a major cause of morbidity and mortality among
Veterans. Chronic alcoholism is associated with changes in the intestinal microbiota, increased intestinal
permeability, and elevated systemic levels of bacterial products. Results from our laboratory indicate that
intestinal pathobionts contribute to alcohol-related liver disease. Using an unbiased approach by metagenomic
sequencing we found significantly more virulence factors in fecal metagenomes from patients with alcoholic
hepatitis than patients with alcohol use disorder or non-alcoholic controls. The presence of the virulence factor
kpsM encoded in the genome of Escherichia coli (E. coli), is independently associated with mortality in patients
with alcoholic hepatitis. E. coli kpsM is involved in the synthesis and expression of the polysialic acid capsule.
Our preliminary data further shows that E. coli kpsM escapes phagocytosis by Kupffer cells. A subsequent
increase in hepatic inflammation contributes to the development of ethanol-induced liver disease. This is
supported by additional data demonstrating that colonization of gnotobiotic mice with feces from a patient with
alcoholic hepatitis positive for E. coli kpsM exacerbates ethanol-induced liver disease. We hypothesize that
pathobiontic kpsM-positive E. coli are an important etiological factor in the modulation of hepatic inflammation
and the development of alcohol-related liver disease. Our experimental approach is to correlate specific
virulence-related genes in the gut metagenomes with clinical outcomes of Veterans with alcohol-related liver
disease (Aim 1). We will investigate the molecular mechanism of how kpsM-positive E. coli contribute to
alcohol-related liver disease in vivo and in cultured liver cells (Aim 2). Using a precision-microbiome approach,
we will test the hypothesis that targeted manipulation of alcohol-associated dysbiosis can ameliorate ethanol-
induced liver disease (Aim 3). We believe these studies will provide novel insights into the contribution of the
microbiota to alcohol-related liver disease. Innovative and novel strategies will be developed to prevent or
ameliorate alcohol-related liver disease in Veterans.

## Key facts

- **NIH application ID:** 10721829
- **Project number:** 5I01BX004594-06
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** Bernd G. Schnabl
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-10-01 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10721829

## Citation

> US National Institutes of Health, RePORTER application 10721829, The role of pathobionts in alcoholic liver disease (5I01BX004594-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10721829. Licensed CC0.

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