Liver-gut axis controls the colonic mucus barrier via hepatic FXR

Background and aimsThe inter-organ cross-talk between liver and intestine has been focus of intense research. Key in this cross-talk are bile acids, which are secreted from the liver into the intestine, interact with the microbiome, and upon absorption reach back to the liver. The bile acid-activated Farnesoid X receptor (Fxr) mediates in the gut-to-liver axis. However, liver-to-gut communication and the roles of bile acids and Fxr herein remain elusive. Here, we aim to get a better understanding of Fxr-mediated liver-to-gut communication, particularly in colon functioning.MethodsFxr floxed/floxed mice were crossed with cre-expressing mice to yield Fxr ablation in intestine (Fxr-intKO), liver (Fxr-livKO), or total body (Fxr-totKO). The effects on colonic gene expression (RNA sequencing), the microbiome (16S Sequencing) and mucus barrier function by ex vivo imaging, were analyzed.ResultsDespite relatively small changes in biliary bile acid concentration and composition, more genes were differentially expressed in colons of Fxr-livKO mice compared to Fxr-intKO and Fxr-totKO mice (3272, 731 and 1824, respectively). Colons of Fxr-livKO showed increased expression of anti-microbial genes, Toll-like receptors, inflammasome related genes and genes belonging to the Mucin-type O-glycan biosynthesis pathway. Fxr-livKO mice have a microbiome profile favorable for the protective capacity of the mucus barrier. The thickness of the inner sterile mucus layer was increased and colitis symptoms reduced in Fxr-livKO.ConclusionsTargeting of FXR is at the forefront in the battle against metabolic diseases. We show that ablation of Fxr in the liver greatly impacts colonic gene expression and increased the colonic mucus barrier. Increasing the mucus barrier is of utmost importance to battle intestinal diseases like IBD and we show that this might be done by antagonizing FXR in the liver.