title: Microbiome-derived tryptophan metabolites and their aryl hydrocarbon receptor-dependent agonist and antagonist activities.
abstract: 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.
authors.affiliation: Institute of Biosciences and Technology, Texas A&M Health Sciences Center, Houston, Texas (U.-H.J., S.-O.L., S.S.); Department of Microbial and Molecular Pathogenesis, Texas A&M University Health Sciences Center (A.J., R.A.), Department of Veterinary Physiology and Pharmacology (S.S.), Department of Chemical Engineering (A.J.), and Department of Nutrition and Food Science (L.A.D., R.S.C.), Texas A&M University, College Station, Texas; Department of Food Science and Technology, Keimyung University, Daegu, Republic of Korea (S.-O.L.); and Department of Chemical and Biological Engineering, Tufts University, Medford, Massachusetts (G.S., K.L.).
authors.forename: Un-Ho
authors.initials: UH
authors.lastname: Jin
authors.forename: Syng-Ook
authors.initials: SO
authors.lastname: Lee
authors.forename: Gautham
authors.initials: G
authors.lastname: Sridharan
authors.forename: Kyongbum
authors.initials: K
authors.lastname: Lee
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Davidson
authors.forename: Arul
authors.initials: A
authors.lastname: Jayaraman
authors.forename: Robert S
authors.initials: RS
authors.lastname: Chapkin
authors.forename: Robert
authors.initials: R
authors.lastname: Alaniz
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D003106:Colon / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D064307:Microbiota / Q000502:physiology*; D009924:Organ Culture Techniques; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000037:antagonists & inhibitors*; D014364:Tryptophan / Q000378:metabolism*
chemical_list: D018336:Receptors, Aryl Hydrocarbon; D014364:Tryptophan