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 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced CYP1A1 expression. In contrast, the tryptophan metabolites exhibited minimal anti-inflammatory activities, whereas TCDD decreased phorbol ester-induced CXCR4 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.
- Receptor binding studies
- Regulation of gene expression
- Nuclear receptors (AHR, PXR, CAR, FXR, etc.)
- Pharmacokinetics, metabolism and activation
- The American Society for Pharmacology and Experimental Therapeutics