title: Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles.
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.
authors.affiliation: 1] Graduate Program in Biochemistry, Microbiology, and Molecular Biology [2] Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802.
authors.forename: Troy D
authors.initials: TD
authors.lastname: Hubbard
authors.affiliation: Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802.
authors.forename: Iain A
authors.initials: IA
authors.lastname: Murray
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331.
authors.forename: William H
authors.initials: WH
authors.lastname: Bisson
authors.affiliation: Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802.
authors.forename: Tejas S
authors.initials: TS
authors.lastname: Lahoti
authors.affiliation: Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17033, USA.
authors.forename: Krishne
authors.initials: K
authors.lastname: Gowda
authors.affiliation: Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17033, USA.
authors.forename: Shantu G
authors.initials: SG
authors.lastname: Amin
authors.affiliation: Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Patterson
authors.affiliation: Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802.
authors.forename: Gary H
authors.initials: GH
authors.lastname: Perdew
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D041981:Gastrointestinal Tract / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D007211:Indoles / Q000378:metabolism*; D008822:Mice, Transgenic; D064307:Microbiota; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D007211:Indoles; D018336:Receptors, Aryl Hydrocarbon; C111235:AHR protein, human; C030374:indole