Multi-Omics analysis reveals the protection of Gasdermin D in concanavalin A-induced autoimmune hepatitis

Autoimmune hepatitis (AIH) is a progressive inflammation-associated liver injury. Pyroptosis is a novel inflammatory programmed cell death wherein gasdermin D (GSDMD) served as the executioner. Our work challenged Gsdmd-/- mice with ConA and try to unveil the actual role of GSDMD in AIH. After concanavalin A (ConA) injection, Gsdmd-/- mice exhibited more severe liver damage characterized by a lower survival rate, more extensive hepatocyte necrosis and apoptosis, and higher serum transaminase levels, indicating the protection of GSDMD on ConA-induced AIH. Furthermore, the Gsdmd-/- mice exhibited higher hepatic expression and serum levels of inflammatory cytokines (IFN-g, TNF-a, IL-17A) and more infiltration of macrophages and neutrophils after ConA treatment compared to WT mice. Gsdmd-/- mice with AIH showed increased hepatic L-glutamine levels whereas decreased glycerophospholipid metabolites levels. L-glutamine levels showed positive correlations while glycerophospholipid metabolites showed negative associations with liver injury indexes and inflammation markers. We further observed a destroyed intestinal barrier in Gsdmd-/- mice after ConA injection as indicated by decreased transcriptional expressions of Tjp1, Ocln, Reg3g, and Muc2. ConA-treated Gsdmd-/- mice also exhibited higher serum LBP concentrations and hepatic Tlr4 and Cd14 mRNA levels. Further fecal 16S rRNA gene sequencing demonstrated decreased abundances of Lactobacillus, and Roseburia, whereas increased abundances of Allobaculum and Dubosiella. Lactobacillus was negatively correlated with liver injury and inflammation indexes and positively associated with Ocln, Muc2, and Reg3g levels. Allobaculum was positively related to liver injury and inflammatory cytokines and negatively correlated with gut barrier indexes.