Effect of delta-8-tetrahydrocannabinol (Δ 8-THC) in modulating immune response and gut microbial dysbiosis in concanavalin-induced acute liver injury

Abstract

Abstract Autoimmune hepatitis (AIH) is a serious health problem characterized by cellular infiltration and progressive destruction of the hepatic parenchyma resulting in cirrhosis, liver failure and death. In the current study, we assessed the ameliorative role of Δ 8-THC in limiting the disease severity by its regulatory role on gut microbiota thereby altering the differentiation of T cell subsets in a murine model of Concanavalin A-induced hepatitis. AIH was induced in C57BL/6 mice by ConA (12.5mg/Kg i.v.) and treated i.p. with vehicle or 20mg/Kg Δ 8-THC. Interestingly, Δ 8-THC treatment after ConA challenge led to significantly decreased liver injury enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels than ConA exposed mice. Flow cytometry analysis of liver infiltrating cells revealed significantly reduced expression of pro-inflammatory cytokines IL-17A and IFNγ and elevated expression of immunosuppressive cytokines TGF-β1 and IL-10 in ConA-treated mice following Δ 8-THC treatment. More importantly, Δ 8-THC induced differentiation of CD4+ helper T cells from RORγt+ Th 17 cells and T-bet+ Th1 cells to Foxp3+ regulatory T cells in the liver of AIH mice. 16S rRNA sequencing of the gut microbiome revealed that ConA+Δ 8-THC and naïve groups had lower abundance of bacteria belonging to families, Ruminococcaceaeand Lachnospiraceaewhile higher abundance of Erysipelotrichaceaecompared with ConA+Vehicle group. In addition, Δ 8-THC treatment caused accumulation of Peptococcaceaefamily in AIH mice which may be responsible for a shift from pro-inflammatory to anti-inflammatory immune responses. Our data demonstrate that Δ 8-THC may be used as a therapeutic drug against immune-mediated liver inflammation Supported in part by NIH grants P01AT003961, P20GM103641, R01ES030144, R01AI129788, R01AI123947 and R01AI160896