Alcohol associated health problems are a major medical burden in industrialized countries. Alcoholic liver disease is characterized by steatosis and may progress to alcoholic hepatitis, fibrosis, or cirrhosis. Patients with alcoholic liver disease show intestinal bacterial overgrowth and dysbiosis. They also demonstrate increased intestinal permeability, and disease severity correlates with systemic levels of bacterial products. Although experimental alcoholic liver disease is dependent on gut derived bacterial products, yet it is unknown how alcohol disrupts the mucosal barrier and mediates changes in the enteric microbiome. Results from our laboratory suggest that qualitative and quantitative changes in the intestinal microbiome are facilitated by suppression of the mucosal innate immune system and in particular of antimicrobial molecules such as regenerating-islet derived 3-gamma (Reg3g). Reduced expression of antimicrobial molecules opens up a spatial niche that enables the growth of certain bacterial strains with pathogenic activity enhancing bacterial translocation. The focus of this application is to further characterize the relationship between alcohol, the intestinal innate immune system and changes in the intestinal microflora. Our experimental approach is to use a mouse model of intragastric alcohol feeding to investigate the contribution of antimicrobial proteins to intestinal dysbiosis and bacterial overgrowth associated with liver disease (Aim 1). We will then assess the consequences of microbiome changes and their contribution to bacterial translocation. The focus will be on the bacterial species Akkermansia muciniphila that is induced following alcohol feeding. We will test the new concept that Akkermansia muciniphila facilitates bacterial translocation by degrading the intestinal mucus layer (Aim 2). We will then manipulate alcohol-induced dysbiosis by altering enteral nutrient availability using prebiotics. A system biology approach with new and powerful methods for pyrosequencing will be used for monitoring changes in the host transcriptome and the enteric microbiome, following administration of prebiotics (Aim 3). We believe these studies will provide important insights into alcohol-mediated changes of the intestinal innate immune system that result in changes in the intestinal microbiome and bacterial translocation. Eventually this approach might lead to new therapeutic targets for patients with alcoholic liver disease.

Public Health Relevance

Alcoholic liver disease affects several million people in the United States, and alcohol abuse is the most important cause of liver cirrhosis in industrialized countries. Gut-derived bacterial products are necessary for progression of alcoholic liver disease, but the exact mechanisms of intestinal bacterial overgrowth and translocation 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 chronic alcohol abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA020703-03
Application #
8499172
Study Section
Special Emphasis Panel (ZAA1-JJ (01))
Program Officer
Murray, Gary
Project Start
2011-09-25
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$360,375
Indirect Cost
$127,875
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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