Bidirectional communication between the Aryl hydrocarbon Receptor (AhR) and the microbiome tunes host metabolism.

Agata Korecka,Yoshiaki Fujii-Kuriyama,Shawon Lahiri,Jeremy Nicholson,Anthony Dona,Viorica Braniste,Arjan Narbad,Velmurugesan Arulampalam,Sven Pettersson,Afrouz Abbaspour,Maha Al-Asmakh,Adrian James Tett,Nicole Reichardt,Joseph Rafter,Rossana D’Arienzo,Elaine Holmes

doi:10.1038/npjbiofilms.2016.14

Abstract

The ligand-induced transcription factor, aryl hydrocarbon receptor (AhR) is known for its capacity to tune adaptive immunity and xenobiotic metabolism—biological properties subject to regulation by the indigenous microbiome. The objective of this study was to probe the postulated microbiome-AhR crosstalk and whether such an axis could influence metabolic homeostasis of the host. Utilising a systems-biology approach combining in-depth 1H-NMR-based metabonomics (plasma, liver and skeletal muscle) with microbiome profiling (small intestine, colon and faeces) of AhR knockout (AhR−/−) and wild-type (AhR+/+) mice, we assessed AhR function in host metabolism. Microbiome metabolites such as short-chain fatty acids were found to regulate AhR and its target genes in liver and intestine. The AhR signalling pathway, in turn, was able to influence microbiome composition in the small intestine as evident from microbiota profiling of the AhR+/+ and AhR−/− mice fed with diet enriched with a specific AhR ligand or diet depleted of any known AhR ligands. The AhR−/− mice also displayed increased levels of corticosterol and alanine in serum. In addition, activation of gluconeogenic genes in the AhR−/− mice was indicative of on-going metabolic stress. Reduced levels of ketone bodies and reduced expression of genes involved in fatty acid metabolism in the liver further underscored this observation. Interestingly, exposing AhR−/− mice to a high-fat diet showed resilience to glucose intolerance. Our data suggest the existence of a bidirectional AhR-microbiome axis, which influences host metabolic pathways.

Highlights

The mammalian body is a mosaic of different microorganisms and eukaryotic cells which share a set of biological and biochemical needs important for growth, body physiology, survival and reproduction
The gut microbiota, in addition to their ability to process dietary derived material, influences host responses to xenobiotics,[2] adding to the growing consensus that factors involved in xenobiotic metabolism could be in intimate partnership with the microbial world
The aryl hydrocarbon receptor (AhR) is a xenobiotic sensor and, belongs to the basic helix–loop–helix Per–Arnt–Sim family and regulates phase I drug-metabolising enzymes from the cytochrome p450 family: Cyp1a1, Cyp1a2 and Cyp1b1.3 Apart from well-known man-made pollutants (e.g., 2,3,7,8-tetrachlorodibenzo-p-dioxin),[4] a battery of natural AhR ligands have been discovered. These include kynurenine and planar indoles made during metabolism of tryptophan,[5,6] such as indole-3-carbinol, which is present in broccoli and cauliflower.[7,8]

Summary

Introduction

The mammalian body is a mosaic of different microorganisms and eukaryotic cells which share a set of biological and biochemical needs important for growth, body physiology, survival and reproduction (reviewed in reference 1). The aryl hydrocarbon receptor (AhR) is a xenobiotic sensor and, belongs to the basic helix–loop–helix Per–Arnt–Sim family and regulates phase I drug-metabolising enzymes from the cytochrome p450 family: Cyp1a1, Cyp1a2 and Cyp1b1.3 Apart from well-known man-made pollutants (e.g., 2,3,7,8-tetrachlorodibenzo-p-dioxin),[4] a battery of natural AhR ligands have been discovered These include kynurenine and planar indoles made during metabolism of tryptophan,[5,6] such as indole-3-carbinol, which is present in broccoli and cauliflower.[7,8] AhR is known to be an important regulator of metabolic and immune processes, both of which are vital for intestinal homeostasis, as well as for optimal coexistence of the host and its microbiome.

Objectives

Methods

Results