Microbiome-derived tryptophan metabolites and their aryl hydrocarbon receptor-dependent agonist and antagonist activities

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

Research output: Contribution to journalArticlepeer-review

150 Scopus citations

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 microbiotaderived 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-pdioxin)- 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.

Original languageEnglish (US)
Pages (from-to)777-788
Number of pages12
JournalMolecular Pharmacology
Volume85
Issue number5
DOIs
StatePublished - May 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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