Hepatic Gα13 ablation shifts region-specific colonic inflammatory status by modulating the bile acid synthetic pathway in mice

Abstract

Inflammatory bowel disease is defined by inflammation and immune dysregulation. This study investigated the effects of G alpha 13 liver-specific knockout (LKO) on proximal and distal colons of dextran sodium sulfate (DSS)-induced mice in conjunction with a high-fat diet (HFD). HFD improved body weight gain and disease activity index scores. G alpha 13LKO exerted no improvement. In the proximal colon, HFD augmented the DSS effect on Il6, which was not observed in G alpha 13LKO mice. In the distal colon, HFD plus DSS oppositely fortified an increase in Tnfa and Cxcl10 mRNA in G alpha 13LKO but not WT. Il6 levels remained unchanged. Bioinformatic approaches using G alpha 13LKO livers displayed bile acid and cholesterol metabolism-related gene sets. Cholic acid and chenodeoxycholic acid levels were increased in the liver of mice treated with DSS, which was reversed by G alpha 13LKO. Notably, mice treated with DSS showed a reduction in hepatic ABCB11, CYP7B1, CYP7A1, and CYP8B1, which was reversed by G alpha 13LKO. Overall, feeding HFD augments the effect of DSS on Il6 in the proximal colon of WT, but not G alpha 13LKO mice, and enhances DSS effect on Tnfa and Cxcl10 in the distal colon of G alpha 13LKO mice, suggesting site-specific changes in the inflammatory cytokines, potentially resulting from changes in BA synthesis and excretion.