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 explored whether the IEC intrinsic Ahr could modulate the development of alcohol-related liver disease (ALD) via the gut-liver axis. METHODS: ) were generated and fed with a control or ethanol diet. Alterations of intestinal microbiota and metabolites were investigated by 16S ribosomal RNA sequencing, metagenomics, and untargeted metabolomics. AHR agonists were used to evaluate the therapeutic potentials of intestinal Ahr activation for ALD treatment. RESULTS: mice relative to control mice. Furthermore, both H.hepaticus and isobutyric acid administration aggravated ethanol-induced liver injury in vivo and in vitro. Supplementation with AHR agonists, 6-formylindolo[3,2-b]carbazole and indole-3-carbinol, protected mice from ALD development by specifically activating intestinal Ahr without affecting liver Ahr function. Alcoholic patients showed lower intestinal AHR expression and higher H.hepaticus levels compared with healthy individuals. CONCLUSIONS: Our results indicate that targeted restoration of IEC intrinsic Ahr function may present as a novel approach for ALD treatment.