The influence of the intestinal microbiota in humanized mouse models of nonalcoholic fatty liver disease and its role as target using bacteriophage therapy.

• Applicant: Dr. Sonja Lang
• Subject Area: Gastroenterology
• Term: from 2018 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 401846036

Nonalcoholic fatty liver disease (NAFLD) has evolved as the most common chronic liver disease in the world with growing incidence. While simple steatosis (nonalcoholic fatty liver, NAFL) carries a relatively benign prognosis, the risk of disease progression to liver fibrosis, cirrhosis and liver-related events like development of hepatocellular cancer is increased in individuals with nonalcoholic steatohepatitis (NASH). A disruption of the symbiosis between gut microbiota and host, known as dysbiosis, has been identified as an important contributor to NAFLD development and disease progression. However, little is known about how dysbiosis with subsequent metabolic consequences affects NAFLD. In some human studies, the Gram-negative bacteria Escherichia or Escherichia coli has been associated with NASH and NASH-fibrosis. Object of the research program is the development and use of a humanized mouse model of NASH. We will investigate the importance of human gut microbiota in NAFLD disease progression and expect that NAFL and NASH are transmissible diseases via transplantation of human feces in germ-free mice. Further aim is to investigate, which bacterial species causes progression from NAFLD to NASH and in particular, we will focus on the effect of E. coli on liver specific macrophages (Kupffer cells), liver cells (hepatocytes) and stellate cells, which play a crucial role in inflammation and fibrosis in NAFLD. A novel precision microbiome approach with bacteriophages will be used to reduce intestinal E. coli in the humanized mouse model. Bacteriophages are viruses that infect and destroy bacteria and are highly specific for one bacterial strain. Bacteriophage therapy has shown an excellent safety profile in human studies. Since no pharmaceutical NASH therapy has been established so far, this might be a promising approach for precision microbiome NASH therapy.

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