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

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https://ir.library.oregonstate.edu/concern/articles/8s45qb80k

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  • 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.
  • This is the publisher’s final pdf. The published article is copyrighted by the author(s) and published by Nature Publishing Group. The published article can be found at: http://www.nature.com/articles/srep12689
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  • Hubbard, T. D., Murray, I. A., Bisson, W. H., Lahoti, T. S., Gowda, K., Amin, S. G., ... & Perdew, G. H. (2015). Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles. Scientific reports, 5, 12689. doi:10.1038/srep12689
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  • 5
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  • This work was supported by the National Institutes of Health National Institute of Environmental Health Sciences [Grants ES004869, ES019964]; and National Institutes of Health National Cancer Institute [Grant CA141029].
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