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.
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.
|Koyama, Yukinori; Xu, Jun; Liu, Xiao et al. (2016) New Developments on the Treatment of Liver Fibrosis. Dig Dis 34:589-96|
|Wang, Lirui; Fouts, Derrick E; StÃ¤rkel, Peter et al. (2016) Intestinal REG3 Lectins Protect against Alcoholic Steatohepatitis by Reducing Mucosa-Associated Microbiota and Preventing Bacterial Translocation. Cell Host Microbe 19:227-39|
|Wang, Ping; Koyama, Yukinori; Liu, Xiao et al. (2016) Promising Therapy Candidates for Liver Fibrosis. Front Physiol 7:47|
|Hartmann, Phillipp; Seebauer, Caroline T; Mazagova, Magdalena et al. (2016) Deficiency of intestinal mucin-2 protects mice from diet-induced fatty liver disease and obesity. Am J Physiol Gastrointest Liver Physiol 310:G310-22|
|Nakamoto, Nobuhiro; Schnabl, Bernd (2016) Does the Intestinal Microbiota Explain Differences in the Epidemiology of Liver Disease between East and West? Inflamm Intest Dis 1:3-8|
|Inamine, Tatsuo; Yang, An-Ming; Wang, Lirui et al. (2016) Genetic Loss of Immunoglobulin A Does Not Influence Development of Alcoholic Steatohepatitis in Mice. Alcohol Clin Exp Res 40:2604-2613|
|Chen, Peng; Miyamoto, Yukiko; Mazagova, Magdalena et al. (2015) Microbiota Protects Mice Against Acute Alcohol-Induced Liver Injury. Alcohol Clin Exp Res 39:2313-23|
|Mazagova, Magdalena; Wang, Lirui; Anfora, Andrew T et al. (2015) Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice. FASEB J 29:1043-55|
|Lan, Tian; Kisseleva, Tatiana; Brenner, David A (2015) Deficiency of NOX1 or NOX4 Prevents Liver Inflammation and Fibrosis in Mice through Inhibition of Hepatic Stellate Cell Activation. PLoS One 10:e0129743|
|Kim, In Hee; Kisseleva, Tatiana; Brenner, David A (2015) Aging and liver disease. Curr Opin Gastroenterol 31:184-91|
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