# HDAC Mediated Epigenetic Mechanisms in Alcohol-Induced Abnormal Gut-Liver Axis

> **NIH NIH P50** · UNIVERSITY OF LOUISVILLE · 2020 · $157,211

## Abstract

There is increasing evidence that demonstrates a critical pathogenic role for the “gut-liver axis” in the 
development of alcoholic liver disease (ALD). The major goal of this proposal is to conduct studies that 
determine the mechanisms underlying chronic alcohol induced pathogenic changes in the gut-liver axis leading 
to ALD. Chronic alcohol consumption-mediated enteric microbiota (dysbiosis) and impairment of the gut barrier 
function, leads to increased intestinal permeability and exposes the liver to gut-derived microbial products 
including endotoxin. The consequent hepatic steatosis and inflammation can in turn promote gut dysfunction. 
Our recent work has begun to identify specific alcohol-induced alterations in enteric microbiome, and shows 
that chronic alcohol consumption leads to a significant expansion of pathogenic gram-negative bacteria that 
may lead to the development of systemic endotoxemia. Significantly, the alcohol-induced intestinal and hepatic 
pathogenic changes were markedly attenuated by supplementation with the probiotic Lactobacillus rhamnosus 
Gorbach-Goldin (LGG). 
 There is gathering evidence and increasing interest regarding the contributory role of epigenetic 
mechanisms in the development of ALD. In this regard, it has been observed that histone associated 
epigenetic modifications play a significant role in the development of hepatic pathology induced by chronic as 
well as binge alcohol exposure. Our recent work showed that binge alcohol treatment decreases hepatic class 
I, II, and IV HDACs with a sole increase in HDAC3, and a correspondent increase in the global hepatic histone 
H3 acetylation (H3Ac) status. Subsequently, we demonstrated that increased HDAC3 plays a critical role in the 
binge alcohol-induced suppression of the carnitine palmitoyltransferase 1α (Cpt1a) gene expression and 
development of hepatic steatosis. Besides altered hepatic HDAC expression, our recent preliminary data also 
show that chronic ethanol feeding leads to a significant increase in the intestinal HDAC1 expression. 
Accordingly, the current proposal examines the unifying hypothesis that chronic alcohol induced 
alterations in the intestinal as well as hepatic HDACs and histone modifications constitute critical 
epigenetic mechanisms driving the abnormal gut-liver axis and liver disease. Importantly, the proposal 
also pursues translational studies that examine the efficacy of nutrition based therapeutic interventions 
targeted at intestinal dysbiosis and HDAC inhibition in mitigating alcohol-induced gut-liver axis changes and 
liver disease. The specific aims of the proposal are: Aim 1 - Determine the effect of chronic alcohol on 
intestinal and hepatic HDAC expression and global histone modifications underlying gut-liver axis changes in 
ALD; Aim 2 - Determine the impact of alcohol-induced HDAC alterations on gene-specific histone modifications 
and consequent pathogenic expression affecting the gut-liver axis in ALD and; Aim...

## Key facts

- **NIH application ID:** 9917670
- **Project number:** 5P50AA024337-05
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** SHIRISH S BARVE
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $157,211
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9917670

## Citation

> US National Institutes of Health, RePORTER application 9917670, HDAC Mediated Epigenetic Mechanisms in Alcohol-Induced Abnormal Gut-Liver Axis (5P50AA024337-05). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/9917670. Licensed CC0.

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