Microbiome-derived tryptophan metabolites and their aryl hydrocarbon receptor-dependent agonist and antagonist
Un-Ho Jin1, Syng-Ook Lee, Gautham Sridharan
1Institute 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.).
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.
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