Exploration Into the Relationship Between Colitis and Depression: A Potential Role for the Aryl Hydrocarbon Receptor

Inflammatory Bowel Disease (IBD) is a group of chronic gastrointestinal disorders with unclear etiology comprised of two defined disorders – Crohn’s Disease (CD) and Ulcerative Colitis (UC). IBD leads to chronic pain, socially isolating symptoms, and an overall reduction in patient quality of life. There is currently no cure for IBD. Due to decreased mucous production and weakening of the colonic epithelial lining, gut-microbiota and their metabolites can invade the intestinal lamina propria and circulate systemically, a term known as “leaky gut”. Recent studies show a relationship exists between peripheral inflammation, such as IBD, and depression. The gut-brain axis (GBA) acts as a bidirectional communication pathway between the enteric nervous system (ENS) and central nervous system (CNS), and colitis patients have an increased incidence of depression. In the current study, we investigate the relationship of UC and its impact on depressive-like symptoms in mice. Colitis was chemically induced in mice and treated with indole-3-carbinol (I3C), a naturally-occurring aryl hydrocarbon receptor (AhR) ligand our lab previously showed reduced colitis severity. Untargeted metabolomic profiles of over 200 metabolites revealed that during disease induction a potentially neurotoxic and tryptophan-kynurenine (TRP-KYN) pathway metabolite, quinolinic acid (QA), was upregulated in colitis models, but reduced after I3C treatment. As high QA levels are linked to depression, we performed tail suspension tests (TST) over the course of disease and treatment to assess depressive-like behavior in experimental mice. Our results show that colitis- induced mice had altered immobility times, with results depending on the testing time of day, when compared to healthy controls. These altered immobility times, which are a measure of depressive-like behavior in mice, were reversed upon treatment with I3C. These results suggest that colonic inflammation can lead to altered behavior and increased depressive-like symptoms through dysregulation of the gut metabolome but may be restored after treatment with an AhR ligand like I3C. Collectively, this suggests that activation of AhR can improve colitis-induced symptoms, which include colitis-associated depressive-like behavior