Depressive-like behavior associated with colitis is altered after treatment with aryl hydrocarbon receptor ligand

Abstract Colitis is a chronic inflammatory disease with no cure and an overall reduction in patient quality of life. 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 and depression. The gut-brain axis (GBA) acts as a bidirectional communication pathway between the enteric and central nervous system (CNS), and colitis patients are known to have increased incidence of depression. In the current study, we aimed to investigate the relationship between colitis, 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) our lab previously showed reduced colitis severity. Untargeted metabolomic profiles of over 200 metabolites revealed that during disease induction a potential neurotoxic and kynurenine 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 a higher immobility time as compared to healthy controls, but this was 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 restored after treatment with AhR ligand, I3C. NIH P20GM103641