Microbiome-derived tryptophan metabolites and their aryl hydrocarbon receptor-dependent agonist and antagonist activities. Academic Article uri icon

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 M) are detected in the intestinal microbiome.

published proceedings

  • Mol Pharmacol

altmetric score

  • 14

author list (cited authors)

  • Jin, U., Lee, S., Sridharan, G., Lee, K., Davidson, L. A., Jayaraman, A., ... Safe, S.

citation count

  • 189

complete list of authors

  • Jin, Un-Ho||Lee, Syng-Ook||Sridharan, Gautham||Lee, Kyongbum||Davidson, Laurie A||Jayaraman, Arul||Chapkin, Robert S||Alaniz, Robert||Safe, Stephen

publication date

  • May 2014