TY - JOUR T1 - Microbiome-Derived Tryptophan Metabolites and Their Aryl Hydrocarbon Receptor-Dependent Agonist and Antagonist Activities JF - Molecular Pharmacology JO - Mol Pharmacol SP - 777 LP - 788 DO - 10.1124/mol.113.091165 VL - 85 IS - 5 AU - Un-Ho Jin AU - Syng-Ook Lee AU - Gautham Sridharan AU - Kyongbum Lee AU - Laurie A. Davidson AU - Arul Jayaraman AU - Robert S. Chapkin AU - Robert Alaniz AU - Stephen Safe Y1 - 2014/05/01 UR - http://molpharm.aspetjournals.org/content/85/5/777.abstract N2 - The tryptophan metabolites indole, indole-3-acetate, and tryptamine were identified in mouse cecal extracts and fecal pellets by mass spectrometry. The aryl hydrocarbon receptor (AHR) agonist and antagonist activities of these microbiota-derived compounds were investigated in CaCo-2 intestinal cells as a model for understanding their interactions with colonic tissue, which is highly aryl hydrocarbon (Ah)–responsive. Activation of Ah-responsive genes demonstrated that tryptamine and indole 3-acetate were AHR agonists, whereas indole was an AHR antagonist that inhibited TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin)–induced CYP1A1 expression. In contrast, the tryptophan metabolites exhibited minimal anti-inflammatory activities, whereas TCDD decreased phorbol ester-induced CXCR4 [chemokine (C-X-C motif) receptor 4] gene expression, and this response was AHR dependent. These results demonstrate that the tryptophan metabolites indole, tryptamine, and indole-3-acetate modulate AHR-mediated responses in CaCo-2 cells, and concentrations of indole that exhibit AHR antagonist activity (100–250 μM) are detected in the intestinal microbiome. ER -