Journal
MOLECULAR PHARMACOLOGY
Volume 85, Issue 5, Pages 777-788Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.113.091165
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Funding
- National Institutes of Health National Cancer Institute [R01-CA142697, R21-A1095788]
- National Institutes of Health National Cancer Institute [NSF] [084653]
- Texas AgriLife Research
- Directorate For Engineering
- Div Of Chem, Bioeng, Env, & Transp Sys [0846453, 1264502] Funding Source: National Science Foundation
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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 mu M) are detected in the intestinal microbiome.
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