Work

Aryl hydrocarbon receptor regulates kynurenine pathway enzymes in dendritic cells to modulate quinolinic acid and reduce depressive-like behavior during colitis 3333

Year: 2025

Type: article

Abstract: Description Inflammatory bowel disease (IBD) is linked with increased incidence of major depressive disorder. Although mechanisms attributed to this gut-brain axis (GBA) observation remain unclear, destabilization of the gut-derived metabolome and extraintestinal trafficking due to increased intestinal permeability have been indicated. In the current study, we assessed the impact of aryl hydrocarbon receptor (AhR) via supplementation with AhR ligand indole-3-carbinol (I3C) on colitis-associated metabolomic destabilization and depressive-like behavior in murine models of colitis. Untargeted fecal metabolomics studies revealed quinolinic acid (QA), a neurotoxic metabolite of the kynurenine pathway (KP) linked to depression, was significantly altered in disease and treated states. Single cell RNA sequencing of colonocytes showed I3C treatment during colitis decreased expression of KP enzymes directly involved in QA production specifically in dendritic cells (DCs), and in silico analysis identified AhR binding sites present in the promoters of these enzymes. Treatment with I3C was also found to reduce local gut and peripheral levels of QA, and decreasing neural biomarkers related to depression. Lastly, behavioral tests showed I3C treatment or select inhibition of KP enzymes involved in QA production reduced colitis-induced depressive-like symptoms. Collectively, these studies provide evidence AhR could be a potential therapeutic target for both colitis and colitis-associated depression. Funding Sources These studies were supported by NIH and NIGMS grant P20GM103641, and the University of South Carolina School of Medicine Resource Core Facility RRID: SCR_023955 Topic Categories Neuroimmunology (NEUR)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkaf283.1149