Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles

Sci Rep. 2015 Aug 3;5:12689. doi: 10.1038/srep12689.

Abstract

Ligand activation of the aryl hydrocarbon (AHR) has profound effects upon the immunological status of the gastrointestinal tract, establishing and maintaining signaling networks, which facilitate host-microbe homeostasis at the mucosal interface. However, the identity of the ligand(s) responsible for such AHR-mediated activation within the gut remains to be firmly established. Here, we combine in vitro ligand binding, quantitative gene expression, protein-DNA interaction and ligand structure activity analyses together with in silico modeling of the AHR ligand binding domain to identify indole, a microbial tryptophan metabolite, as a human-AHR selective agonist. Human AHR, acting as a host indole receptor may exhibit a unique bimolecular (2:1) binding stoichiometry not observed with typical AHR ligands. Such bimolecular indole-mediated activation of the human AHR within the gastrointestinal tract may provide a foundation for inter-kingdom signaling between the enteric microflora and the immune system to promote commensalism within the gut.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Gastrointestinal Tract / metabolism*
  • Hep G2 Cells
  • Humans
  • Indoles / metabolism*
  • Mice, Transgenic
  • Microbiota*
  • Receptors, Aryl Hydrocarbon / metabolism*

Substances

  • AHR protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • Indoles
  • Receptors, Aryl Hydrocarbon
  • indole