Dietary L-tryptophan determines the number of colonic regulatory T-cells and susceptibility to colitis via GPR15

Abstract Environmental factors play a prominent role in the onset of immunological disorders such as ulcerative colitis, but mechanisms are unclear. Diet is major environmental factor, mostly known to influence gut microbiota, which turn affects host immune system. Here, we demonstrated microbiota-independent effect ubiquitous dietary component, L-tryptophan (L-Trp) on mucosal responses. We discovered that amount ingested L-Trp determines number colonic CD4 +T-cells through aryl hydrocarbon receptor (AhR), triggers direct transcriptional activation colon T-cell homing receptor, GPR15. However, default pathway connecting L-Trp, AhR, GPR15, and T-cells involves IDO1 IDO2 enzymes, selectively increasing GPR15 +Tregs. Consequently, two weeks supplementation nearly doubled +Tregs significantly decreased future risk colitis. Our extensive, vitro screening AhR ligands suggests ligand-specific variations target gene expression may account for Treg-selective response L-Trp. also identified benzo[a]pyrene, compound enriched cigarette smoke grilled meat, an AHR agonist strongly promotes GPR15+FOXP3+ Treg generation. Thus, our findings uncover by routine behavioral practices have significant impact responses, suggesting potential non- invasive therapeutic approach Supported grant from NIH (R01AI141787, R21AI142318, T32 AI134646, 5P30CA056036-22) CCFA (Career Development Award 329388)