ICA69 deficiency exacerbates the inflammation on liver injury associated with distinct alteration in the gut microbiota

Hepatitis is a major problem around the worlds, which is characterized by hepatic inflammation and intestinal gut microbiome imbalance. Our previous study has been provided that Islet-cell autoantigen 69(Ica69) plays a central role in liver injury and found that both Ica69 mRNA and protein are significantly upregulated in mouse hepatocytes at the early stage of liver regeneration. In this study, we found that Ica69-deficient mice have more severe liver injury than wild-type mice (WT) by intraperitoneal injection of D-galactosamine (D-GalN) combined with lipopolysaccharide (LPS)(DL injection). Analysis of serum biochemical indexes and histology revealed an increment in hepatic inflammation in the Ica69-deficient group. And we also found that Ica69 deficiency exacerbated the gut microbiome imbalance, including the reduction of probiotics, Lactobacilli, Bifidobacteria and Bacteroides, and the increment of conditional pathogens, Proteobacteria,in the intestine.Mechanistically,Ica69 deficiency upregulated the expression of inflammation-related (IL-17 and IL-22) genes expression and toll-like receptor 4(TLR4)/tumor necrosis factor (TNF-a ) pathway. We conclude that Ica69 mediates liver inflammation and the intestinal microbial disorder caused by D-GalN combined with LPS induced acute liver injury, indicating that Ica69 in protection against immune-associated liver injury and providing a theoretical foundation for treating liver disease.