Circadian tryptophan metabolism contributes to systemic aryl hydrocarbon receptor activity

Diet-phytochemical derived activation, host and microbial tryptophan metabolism represent the dominant route to endogenously mediated stimulation of physiological Ah receptor (AHR) activity. Whether host tryptophan metabolism provides a phytochemical independent circadian AHR tone has not been established. Using mice maintained on a nocturnally restricted feeding schedule with a nutritionally defined diet, we utilized quantitative gene/protein expression analyses in conjunction with targeted metabolomics to examine the temporal relationship between host tryptophan metabolism and circadian AHR activity. Time-resolved, targeted LCMS metabolomic, gene, and protein expression analyses reveal circadian cycling of hepatic tryptophan metabolizing enzymes (TDO2, TAT, GOT1, GOT2, KAT1, KAT2, and IL4I1) and serum tryptophan metabolites (indole-3-acetate, indole-3-lactate, indole-3-propionate, indole aldehyde, kynurenine, kynurenic acid) previously established as AHR ligands. We observed cyclical hepatic AHR activity directed by circadian feeding. These data suggest that a circadian rhythm of tryptophan metabolism orchestrates a daily tone in AHR activity that likely modulates AHR dependent physiology.