Immune-microbiome axis regulates liver inflammation.

Abstract

Abstract Autoimmune hepatitis (AIH) is a liver disease characterized by circulating autoantibodies, persistent liver inflammation, and subsequent hepatocyte damage. Both Th17 cells and the intestinal microbiome have been implicated in AIH. Patients have elevated serum IL-17, an altered microbiota, and increased bacterial translocation. In a murine AIH model, concanavalin A (con A) hepatitis, Il17ra−/− mice are protected, and gentamicin has been reported to ameliorate disease. We sought to better understand the relationship between Th17 cells and the microbiome in hepatitis. To study this, we generated intestinal epithelial-specific IL-17RA deficient mice (Il17rafl/fl × villin cre+ mice). Absence of enteric IL-17R signaling induced commensal dysbiosis, expansion of intestinal Th17 cells, and increased bacterial translocation to the liver at the naïve state. These mice were more susceptible to con A hepatitis, exhibiting increased lethality, serum ALT, and serum and liver IFNγ as compared to controls. This elevated liver IFNγ was susceptible to BET protein inhibition ex vivo, suggesting the Ifng locus is open and susceptible to epigenetic regulation. Cohousing studies eliminated ALT differences between knockouts and controls, suggesting a role of the microbiome. We hypothesize that disrupted enteric IL-17 signaling at the naïve state promotes intestinal dysbiosis and increased bacterial translocation to the liver. This causes epigenetic changes in the liver Ifng locus, poising cells to secrete more IFNγ upon simulation and worsen disease. Understanding the mechanism underlying exacerbated disease in Il17rafl/fl × villin cre+ mice will elucidate the role of enteric Th17 cells and the microbiome in AIH and other liver pathologies.