Title: Role of Butyrate in the Gut-Liver Interaction of Ethanol Induced Liver Injury Key words: alcohol, acetate, intestine, liver, butyrate A gut-liver interaction has recently been linked with the progression of alcoholic liver disease (ALD). Evidence supports that alcohol exposure impairs gut integrity allowing for bacterial and/or endotoxin translocation to the liver and activation of toll-like receptor 4, the receptor for endotoxin which is associated with progression of steatohepatitis and liver fibrosis. Ethanol is metabolized to acetaldehyde and then to acetate. Following ethanol feeding, blood acetate levels are higher than acetaldehyde. Monocarboxylate transporters expressed in the basolateral membrane of the distal gut can transport systemic acetate into the colon. Research has focused primarily on acetaldehyde as the primary culprit in increasing gut permeability to endotoxin and progression of ALD leaving the role of acetate understudied. Short-chain fatty acids (acetate, propionate, and butyrate) are produced in the distal gut through the fermentation of undigested dietary fiber and starch by the commensal gut microbiota. Butyrate plays an important role in maintaining gut health by serving as the primary energy source for the colonocyte, increasing normal colonic epithelium proliferation but decreasing neoplastic colonocyte proliferation, and regulating gene expression through its role as an inhibitor of histone deacetylase. Higher acetate to butyrate ratios are associated with increased colonic pathology. Absence of luminal butyrate is associated with mucosal atrophy, as well as apoptosis and inflammation, which is reversible by butyrate instillation. Given the important role of butyrate in maintaining gut health and integrity, we hypothesize chronic ethanol consumption decreases butyrate ratios in the gut secondary to non-physiologic elevations in acetate ratios and that maintaining physiologic ratios of SCFA will prevent and/or restore impaired gut integrity and the progression of early stages of ALD. To test our hypothesis we will use a chronic heavy ethanol feeding protocol which induces steatohepatitis, and a chronic low-dose ethanol with carbon-tetrachloride feeding protocol in which liver fibrosis is enhanced with ethanol feeding. We will test the prediction that SCFA ratios are altered in these models leading to increased gut permeability and progression of ALD and that tributyrin supplementation will prevent and/or treat these effects. The proposed work will provide preclinical data to help determine new therapeutic management of alcoholic liver disease (ALD).

Public Health Relevance

Excessive alcohol consumption leads to liver damage. There is no straightforward treatment available to date. Liver transplantation is the only possible option for the patient suffering from alcohol-induced liver damage. Our proposed work will help us to better understand the cause of alcoholic liver damage as well as identify new therapeutic targets for prevention and/or treatment of alcoholic liver damage.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AA021044-03
Application #
8531795
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Murray, Gary
Project Start
2011-09-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
3
Fiscal Year
2013
Total Cost
$53,942
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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Cresci, Gail A; Bush, Katelyn; Nagy, Laura E (2014) Tributyrin supplementation protects mice from acute ethanol-induced gut injury. Alcohol Clin Exp Res 38:1489-501
DeSantis, David A; Lee, Peter; Doerner, Stephanie K et al. (2013) Genetic resistance to liver fibrosis on A/J mouse chromosome 17. Alcohol Clin Exp Res 37:1668-79
Cresci, Gail; Nagy, Laura E; Ganapathy, Vadivel (2013) Lactobacillus GG and tributyrin supplementation reduce antibiotic-induced intestinal injury. JPEN J Parenter Enteral Nutr 37:763-74