A hepatocyte-specific transcriptional program driven by Rela and Stat3 exacerbates experimental colitis in mice by modulating bile synthesis

Abstract

AbstractHepatic factors secreted by the liver promote homeostasis and are pivotal to maintain liver-gut axis. Dysfunctional interactions between the liver and the intestine stimulate varied pathological outcomes through its bidirectional portal communication for example an aberrant bile acid metabolism has been reported in inflammatory bowel disease (IBD). However, the molecular mechanisms underlying these crosstalks that perpetuate intestinal permeability and inflammation remains obscure. Here, we identify a novel hepatic gene program regulated by Rela and Stat3 that accentuates the inflammation in an acute experimental colitis model. Hepatocyte specific ablation of Rela and Stat3 reduces the levels of primary bile acids in both liver and gut and shows restricted colitogenic phenotype. On supplementation of chenodeoxycholic acid (CDCA), knock-out mice show enhanced colitis-induced alterations. This study provides persuasive evidence for the development of multi-organ strategies for treating IBD and identifies a hepatocyte-specificrela-stat3network as a promising therapeutic target.