Alcohol abuse and alcohol-related diseases are a major medical burden in industrialized countries. Chronic alcoholism is associated with changes in the intestinal microbiome, increases in intestinal permeability, and elevated systemic levels of bacterial products. We have demonstrated quantitative (overgrowth) and qualitative dysbiotic changes in the intestinal microbiota in mouse models of chronic alcohol administration. A strong association exists between gut-derived bacterial products and progression of alcoholic liver diseases in several animal models, yet factors facilitating the onset of intestinal dysbiosis are unknown. Furthermore, how dysbiosis contributes to alcoholic liver disease beyond increasing intestinal permeability is also not known. Results from our laboratory suggest that suppression of gastric acid secretion and inhibition of the intestinal antimicrobial proteins regenerating-islet derived (Reg)-3b and Reg3g contribute to dysbiosis and liver disease following chronic ethanol feeding in mice. Furthermore, dysbiosis leads to deconjugation of intestinal bile acids in the proximal small intestine. Deconjugated bile acids are rapidly absorbed by nonionic diffusion in the jejunum, and a smaller amount of conjugated bile acids reaches the terminal ileum, which disrupts the enterohepatic circulation and results in increased hepatic bile acid synthesis. A larger bile acid pool contributes to more hepatocyte damage and alcoholic liver disease. The focus of this application is to characterize factors contributing to changes in the microbiota and to investigate how dysbiosis affects liver disease after chronic alcohol administration. We hypothesize that gastric acid suppression and alcohol-mediated inhibition of the antimicrobial Reg3 lectins modulate the intestinal microbiota. Dysbiosis in turn disrupts enterohepatic circulation of bile acids and increases the total bile acid pool, which enhances alcohol-induced liver damage. Our experimental approach is to use mouse models of chronic alcohol feeding to investigate the role of gastric acid in inducing intestinal dysbiosis and liver disease (Aim 1). We will also assess the functional contribution of the antimicrobial proteins Reg3b and Reg3g to changes in the microbiota composition, bacterial translocation and alcoholic liver disease (Aim 2). We will then determine the consequences of dysbiotic microbiome changes by focusing on bile acid metabolism (Aim 3). We believe these studies will provide novel insights into the contribution of the microbiota and its metabolites to alcoholic liver disease. New strategies will evolve to prevent or ameliorate alcoholic liver disease in patients.

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. Chronic alcohol consumption is associated with changes in the composition of intestinal bacteria, but the exact mechanisms of intestinal bacterial overgrowth and dysbiosis are poorly understood. Understanding the mechanisms by which alcohol results in microbiome changes and understanding how these changes contribute to liver disease, 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 #
5R01AA020703-07
Application #
9322606
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Wang, Joe
Project Start
2011-09-25
Project End
2021-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
7
Fiscal Year
2017
Total Cost
Indirect Cost
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
Hartmann, Phillipp; Schnabl, Bernd (2018) Risk factors for progression of and treatment options for NAFLD in children. Clin Liver Dis (Hoboken) 11:11-15
Boule, Lisbeth A; Ju, Cynthia; Agudelo, Marisela et al. (2018) Summary of the 2016 Alcohol and Immunology Research Interest Group (AIRIG) meeting. Alcohol 66:35-43
Brandl, Katharina; Hartmann, Phillipp; Jih, Lily J et al. (2018) Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis. J Hepatol 69:396-405
Chu, Huikuan; Williams, Brandon; Schnabl, Bernd (2018) Gut microbiota, fatty liver disease, and hepatocellular carcinoma. Liver Res 2:43-51
Hendrikx, Tim; Schnabl, Bernd (2018) Antimicrobial proteins: intestinal guards to protect against liver disease. J Gastroenterol :
Inamine, Tatsuo; Schnabl, Bernd (2018) Immunoglobulin A and liver diseases. J Gastroenterol 53:691-700
Khanova, Elena; Wu, Raymond; Wang, Wen et al. (2018) Pyroptosis by caspase11/4-gasdermin-D pathway in alcoholic hepatitis in mice and patients. Hepatology 67:1737-1753
Hartmann, Phillipp; Hochrath, Katrin; Horvath, Angela et al. (2018) Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice. Hepatology 67:2150-2166
Llorente, Cristina; Jepsen, Peter; Inamine, Tatsuo et al. (2017) Gastric acid suppression promotes alcoholic liver disease by inducing overgrowth of intestinal Enterococcus. Nat Commun 8:837
Yue, Feng; Zeng, Sien; Tang, Rongping et al. (2017) MPTP Induces Systemic Parkinsonism in Middle-Aged Cynomolgus Monkeys: Clinical Evolution and Outcomes. Neurosci Bull 33:17-27

Showing the most recent 10 out of 48 publications