Alcohol associated health problems are a major medical burden in industrialized countries. Alcoholic liver disease comprises steatosis, steatohepatitis, alcoholic hepatitis, fibrosis, and cirrhosis. Alcoholic hepatitis is a distinct acte on chronic disease with significant morbidity and mortality. Patients with alcoholic hepatitis show intestinal bacterial overgrowth and increased intestinal permeability. Disease severity correlates with systemic levels of bacterial products or pathogen-associated molecular patterns (PAMPs), and many patients succumb to bacterial infections. Results from our laboratory suggest that quantitative changes in the intestinal microbiome occur early in a mouse model of alcoholic liver disease, while qualitative changes are characterized by a profound suppression of commensal probiotic bacteria including Lactobacillus. Pathway analysis revealed that genes involved in fatty acid biosynthesis are underrepresented in the intestinal metagenome following chronic alcohol feeding. Our central hypothesis is that chronic hepatic and systemic inflammation is an important etiological factor in alcoholic hepatitis resulting from disturbances in the gut microbia flora induced by alcohol. The focus of our application is to further characterize the host gut microbiome, metagenome, metatranscriptome and metabolome in patients and in a mouse model of alcoholic hepatitis. We speculate that intestinal bacterial overgrowth and suppression of commensal probiotic bacteria contribute to a dysfunction of the gut-liver axis in alcoholic hepatitis. Using massively parallel 454 pyrosequencing, our focus will be on the analysis of the microbiome associated with alcoholic hepatitis (Aim 1). We further hypothesize that dysbiosis-induced changes in bacterial metabolites affect the mucosal barrier function and induce liver injury. We therefore will analyze the enteric metagenome, metatranscriptome and metabolome in alcoholic hepatitis (Aim 2). We will then test potential therapeutic interventions that manipulate alcoholic hepatitis-induced dysbiosis by reducing bacterial overgrowth using non-absorbable antibiotics, by restoring eubiosis using probiotics, or by altering the enteric metabolome using fatty acid supplementation. We propose that a reversal of qualitative and/or quantitative changes in the enteric microbiome associated with alcoholic hepatitis is sufficient to improve liver disease and systemic inflammation (Aim 3). We believe these studies will provide important insights into alcohol-mediated changes of the intestinal microbiome that result in quantitative and qualitative changes in the intestinal microflora and bacterial translocation. Eventually this approach might lead to new therapeutic targets for patients with alcoholic hepatitis.

Public Health Relevance

Alcoholic liver disease affects several million people in the United States, and alcoholic hepatitis has a high mortality despite optimal medical management. Gut-derived bacterial products are necessary for progression of alcoholic hepatitis, but changes in the intestinal microbiome are poorly understood. Understanding the mechanisms by which alcohol results in intestinal bacterial overgrowth and promotes bacterial translocation by increasing intestinal permeability would greatly enhance our ability to design preventive and therapeutic interventions for patients with alcoholic hepatitis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AA021856-02
Application #
8669778
Study Section
Special Emphasis Panel (ZAA1-JJ (07))
Program Officer
Wang, Joe
Project Start
2013-06-01
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$414,673
Indirect Cost
$85,188
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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