The role of microbiota-driven T-cell immunity for intestinal inflammation in alcohol-associated liver disease

• Applicant: Dr. Aenne Harberts
• Subject Area: Gastroenterology ; Immunology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 531907998

Alcohol-associated liver disease (ALD) accounts for 50% of the ~1 million deaths per year associated with chronic liver disease. Patients with ALD have an altered microbiome, termed dysbiosis. Dysbiosis contributes to impaired intestinal barrier function and leads to the translocation of bacterial products (BT) from the intestine into circulation. BT triggers systemic inflammation and contributes to the progression of chronic liver disease. Microbiome-targeted therapeutic approaches to improve barrier function are increasingly coming into focus. Th17 cells play an important role in maintaining intestinal integrity. Th17 cells can attain an anti- or pro-inflammatory phenotype in line with their different functions: They provide protection against pathogens but are also necessary for the recognition of the beneficial commensal microbiota. Under healthy conditions, the microbiome induces T-cell homeostasis. Intestinal T-cell dysregulation, characterized by a predominant pro-inflammatory or ‘pathogenic’ Th17-cell phenotype, is thought to be responsible for different immune pathologies, but little is known about intestinal T-cell function in ALD. In this project, we want to investigate the role of dysbiosis-driven Th17-cell dysregulation in intestinal barrier dysfunction. Akkermansia muciniphila belong to the commensal microbiota and influence intestinal T-cell regulation. In ALD patients A. muciniphila abundance is diminished and administration of A. muciniphila was shown to ameliorate disease severity in experimental ALD. We consider A. muciniphila as a promising target to investigate in the context of ALD-associated T cell-driven barrier dysfunction. We hypothesize that a low abundance of A. muciniphila in ALD patients leads to a decreased frequency of Th17 cells with a predominantly pathogenic Th17 phenotype causing intestinal inflammation and consequently barrier dysfunction. To investigate the hypothesis, we want to thoroughly characterize intestinal T cells in experimental ALD. Therefore, mice will be subjected to chronic plus binge ethanol feeding and intestinal T cell phenotype and function will be analysed. Intestinal T-cell phenotype will be correlated with intestinal inflammation and permeability, systemic inflammation, and liver disease severity. Further, we will test whether colonization of mice with A. muciniphila ameliorates intestinal inflammation and thereby improves barrier function. Additionally, we will investigate the influences of faecal microbiota transplantation from ALD patients to germ-free mice on intestinal T-cell and barrier function. Lastly, to test whether the effect of A. muciniphila on intestinal inflammation is directly Th17-dependent, we will perform an adoptive T-cell transfer of A. muciniphila-primed Th17 cells into RAG1 KO mice and analyse intestinal T-cell phenotype and barrier function.

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