Gut Microbiota as a Target in T cell- mediated hepatic Injury

Introduction: The microbiota contributes to various auto-immune and liver diseases. It remains unclear whether the immunological response is modulated by the microbiota directly, or indirectly by its metabolites like short chain fatty acids (SCFAs) or bile salts. These are important signaling molecules in gut and liver. Currently, little is known about the influence of microbiota in immune-mediated liver injury. We investigated the role of gut microbiota in the model of Concanavalin A (ConA), which is a well-established mouse model of T-cell mediated hepatitis.

Methods: Germ free C57BL/6 or antibiotic-treated FIRxtiger mice were challenged with ConA and analyzed during initial, peak and recovery phase of the disease. The influence of SCFAs on immune-cell composition was analyzed via flow-cytometry after in vitro co-culture experiments w/o liver sinusoidal endothelial cells (LSECs).

Results: Germ free and antibiotic-treated mice were protected from ConA-induced hepatitis. Antibiotic-treatment reduces CD4+T-cells and IL-10+ regulatory T-cells (Tregs) frequencies following ConA. Hepatic expression of the butyrate receptor GPR-43 and CYP7A1, an enzyme in the bile acid pathway, were up-regulated in response to antibiotic-treatment and down-regulated after ConA-challenge. The opposite effects were shown for the bile acid membrane receptor TGR5. In vitro butyrate reduces interferon-γ and IL-10 production by CD4+T-cells in co-culture with LSECs.

Conclusion: ConA-damage was ameliorated by reduction or absence of the gut microbiota. Reduced IL-10+Tregs in the liver are in line with less severe hepatitis. Our results indicate that further analysis of SCFAs and bile salt metabolism is needed to determine its specific function during pathogenesis of liver disease.