The role of the fungal microbiota in alcoholic liver disease

• Applicant: Dr. Katrin Hochrath
• Subject Area: Gastroenterology
• Term: from 2015 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 280800749

Alcohol-induced liver damage is the most important cause of cirrhosis in the industrialized world. Although the progression of alcoholic fatty liver disease to cirrhosis is dose-dependent, it is also influenced by genetic and environmental factors. Alterations to the intestinal microbiome, such as bacterial overgrowth, dysbiosis and bacterial translocation into the systemic circulation, is one factor that is known to be involved in the progression of alcoholic liver disease. Our preliminary data show for the first time that chronic alcohol abuse also results in changes of the intestinal mycobiome, which are characterized by increased fungal colonization and differences in the phylogenetic composition. To date, the relevance of changes in the mycobiome in chronic liver disease is unknown; therefore, the aim of this project is to assess the role of the intestinal mycobiome on the progression of alcoholic liver disease. Due to the presence of a preexisting leaky gut in chronic liver diseases, we hypothesize that fungal products such as beta-glucan translocate from the intestinal lumen and reach the liver via the portal circulation. Beta-glucan binds to its receptor on hepatic cells to induce an inflammatory cascade and to promote alcoholic liver injury and fibrosis. Preliminary results already show the expression of dectin-1 on liver macrophages (Kupffer cells) and hepatic stellate cells, which are known to be key players in alcoholic liver disease and fibrosis. Therefore, to investigate the role of fungi and fungal products in the pathogenesis of chronic alcoholic liver disease, we propose the following three aims: (1) Characterization of the intestinal mycobiome after chronic alcohol administration in mice. (2) In vivo interventions with fungi and antimycotic agents during chronic alcohol feeding in mice. (3) Hepatic and intestinal phenotyping of dectin-1 deficient mice after chronic alcohol administration, and quantification of the dectin-1 dependent secretion of inflammatory and fibrotic mediators in vitro.This will be the first study, analyzing quantitative and qualitative changes in the intestinal mycobiome during chronic alcohol liver diseases. Our results will expand the knowledge and understanding for the role of the mycobiome for the progression of chronic liver diseases.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Bernd Schnabl