Aryl Hydrocarbon Receptor Deficiency in Intestinal Epithelial Cells Aggravates Alcohol-Related Liver Disease.

Background & aims The ligand-activated transcription factor, aryl hydrocarbon receptor (AHR) can sense xenobiotics, dietary, microbial and metabolic cues. Roles of Ahr in intestinal epithelial cells (IECs) have been much less elucidated compared with those in intestinal innate immune cells. Here we aim to explore whether the intestinal epithelial cells (IECs)-intrinsic Ahr could modulate the development of alcohol-related liver disease (ALD) via gut-liver axis. Methods Mice with IECs-specific Ahr deficiency (AhrΔIEC) were generated and fed with a control or ethanol diet. Alterations of intestinal microbiota and metabolites were investigated by 16S rRNA sequencing, metagenomics and untargeted metabolomics. AHR agonists were used to evaluate the therapeutic potentials of intestinal Ahr activation for ALD treatment. Results AhrΔIEC mice showed more severe liver injury following ethanol feeding than control mice. Ahr deficiency in IECs altered the intestinal metabolite composition, creating an environment that promoted the overgrowth of Helicobacter hepaticus and Helicobacter ganmani in the gut, enhancing their translocation to mesenteric lymph nodes (MLNs) and liver. Among the altered metabolites, isobutyric acid (IBA) was increased in the cecum of ethanol-fed AhrΔIEC mice relative to control mice. Further, both Helicobacter hepaticus and IBA administration aggravated ethanol-induced liver injury in vivo and in vitro. Supplementation with AHR agonists, 6-formylindolo[3,2-b]carbazole (FICZ) and indole-3-carbinol (I3C), protected mice from ALD development by specifically activating intestinal Ahr without affecting liver Ahr function. Alcoholic patients exhibited lower intestinal AHR expression and higher Helicobacter hepaticus levels as compared with healthy individuals. Conclusions Our results indicate that targeted restoration of IECs-intrinsic Ahr function may present as a novel approach for ALD treatment.