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

Troy D Hubbard,Krishne Gowda,Andrew D Patterson,Tejas S Lahoti,Iain A Murray,Gary H Perdew,Shantu G Amin,William H Bisson

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.

Highlights

Bacterial phyla, and protection from pathogenic insults[18,19,20,21,22,23]
This finding is contrary to prevailing evidence which suggests that for many aryl hydrocarbon receptor (AHR) ligands, the mouse AHR exhibits higher affinity than human AHR29
The low molecular weight of indole, compared to typical high affinity AHR ligands, combined with the relatively large ligand binding pocket of AHR, which is mostly conserved across species suggested that accommodation of indole would likely be conserved across mouse and human AHR

Summary

Introduction

The protective action of the AHR is dependent upon ligand-mediated activation with the diet, providing a source of presumptive ligands[18]. In silico modeling data suggests that such species specificity may be a consequence of a bimolecular (2:1) stoichiometry between indole and the ligand-binding domain of human AHR. These data suggest that activation by indole may establish the AHR as a host sensor of the enteric bacterial population through their TnaA-dependent metabolism of tryptophan and provide an additional link between the diet, gut microbiota, AHR, and gastrointestinal homeostasis

Methods

Results

Conclusion