Influence of endogenous retroviral elements on alcohol associated liver disease

• Applicant: Dr. Henriette Kreimeyer
• Subject Area: Gastroenterology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 516418925

Alcohol associated liver disease (ALD) is a major cause of morbidity and mortality in western countries. Chronic alcohol use can lead to intestinal bacterial overgrowth, changes in the microbiota composition, and elevated systemic levels of bacteria related products and alcohol-associated liver disease can be transmitted by fecal microbiota. The microbiome consists of bacteria, fungi, viruses and bacteriophages. However, current approaches in the field of alcohol-related diseases mostly highlight interaction between host and bacteria and to a lesser extent host and fungi. The part of the gut microbiota containing virus and bacteriophages is called virome.In alcohol-associated liver disease metagenomic sequencing of viruses and viral-like particles showed that fecal samples of patients with ALD contained three times more mammalian viruses than healthy controls including retroviruses from the family of retroviridae. This seems to be exclusive in patients with ALD as this could not be observed in fecal samples of patients with non-alcoholic fatty liver disease (NAFLD).Retroviruses integrated into the host during evolution and became part of the human genome as endogenous retroviral elements (ERVs). They are generally harmless, as evolutionary mutations have made them unable to produce infectious viral agents, and ERVs are mostly epigenetically silenced by DNA methylation. ERVs can contribute to cell homeostasis and host immune response as regulatory RNA in healthy state. Enhanced expression of ERVs is observed in the context of certain environmental stressors, and recent evidences have shown links between ERVs and major inflammatory diseases and cancers. Under certain circumstances, e.g. stress or application of DNA methyltransferase inhibitors, ERVs can be induced and double stranded RNA (dsRNA) is transcribed. Preliminary data of Prof. Schnabl’s Laboratory reveal show that ethanol leads to chromatin remodeling and ERV transcription in the intestine of mice and in intestinal organoids.In this study we want to analyze the contribution of endogenous retroviral elements to alcohol-associated liver disease. Human ERVs will be characterized in intestinal biopsies of patients with alcohol use disorder, mild and progressive alcohol-associated liver disease. Ethanol-mediated chromatin remodeling and induction of ERV transcription will be studied in intestinal organoids. We will colonize germ-free mice with retrovirus positive and negative stool from patients with alcohol-associated liver disease, and subject them to ethanol-induced liver disease models. A pharmacological intervention with anti-retrovirals will be studied in gnotobiotic mice.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Bernd Schnabl