Natural killer T cells play a necessary role in modulating of immune-mediated liver injury by gut microbiota

Gut microbiota are implicated in many liver diseases. Concanavalin A (ConA)-induced hepatitis is a well-characterized murine model of fulminant immunological hepatic injury. Oral administration of pathogenic bacteria or gentamycin to the mice before ConA injection, liver injury and lymphocyte distribution in liver and intestine were assessed. Our data show that administration of pathogenic bacteria exacerbated the liver damage. There was more downregulation of activation-induced natural killer T (NKT) cells in the liver of pathogenic bacteria-treated ConA groups. Also, there was a negative correlation between the numbers of hepatic NKT cells and liver injury in our experiments. Moreover, intestinal dendritic cells (DCs) were increased in pathogenic bacteria-treated ConA groups. The activation of DCs in Peyer's patches and the liver was similar to the intestine. However, depletion of gut gram-negative bacteria alleviated ConA-induced liver injury, through suppressed hepatic NKT cells activation and DCs homing in liver and intestine. In vitro experiments revealed that DCs promoted NKT cell cytotoxicity against hepatocyte following stimulation with pathogenic bacteria. Our study suggests that increased intestinal pathogenic bacteria facilitate immune-mediated liver injury, which may be due to the activation of NKT cells that mediated by intestinal bacterial antigens activated DCs.