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 1? (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 3 - Evaluate the efficacy of nutrition-based therapeutic interventions in ALD. We expect that the results of our study will provide critical molecular insights and facilitate the development of therapeutic interventions for ALD.
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