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AHR in the intestinal microenvironment: safeguarding barrier function

Abstract

Mammalian aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that belongs to the basic helix–loop–helix (bHLH)–PAS family of transcription factors, which are evolutionarily conserved environmental sensors. In the absence of ligands, AHR resides in the cytoplasm in a complex with molecular chaperones such as HSP90, XAP2 and p23. Upon ligand binding, AHR translocates into the nuclear compartment, where it dimerizes with its partner protein, AHR nuclear translocator (ARNT), an obligatory partner for the DNA-binding and functional activity. Historically, AHR had mostly been considered as a key intermediary for the detrimental effects of environmental pollutants on the body. However, following the discovery of AHR-mediated functions in various immune cells, as well as the emergence of non-toxic ‘natural’ AHR ligands, this view slowly began to change, and the study of AHR-deficient mice revealed a plethora of important beneficial functions linked to AHR activation. This Review focuses on regulation of the AHR pathway and the barrier-protective roles AHR has in haematopoietic, as well as non-haematopoietic, cells within the intestinal microenvironment. It covers the nature of AHR ligands and feedback regulation of the AHR pathway, outlining the currently known physiological functions in immune, epithelial, endothelial and neuronal cells of the intestine.

Key points

  • Aryl hydrocarbon receptor (AHR) is widely expressed in the intestinal microenvironment, and its activation by natural ligands results in barrier-protective effects.

  • In addition to well-documented functions in intestinal immune cells, AHR has important and less well-studied functions in epithelial and endothelial cells as well as in neurons of the enteric nervous system.

  • AHR involvement can appear subtle under homeostatic conditions but becomes prominent in regeneration following tissue injury.

  • AHR acts as a tumour suppressor for development of colonic malignancy.

  • New models and tools enabling the dissection of cell type-specific and tissue type-specific AHR functions in vivo are needed to understand the effect of environmental signals on inflammation and tissue repair in the gastrointestinal barrier.

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Fig. 1: Mechanisms for negative-feedback regulation of AHR activity.
Fig. 2: AHR in the intestinal microenvironment.
Fig. 3: AHR function in intestinal epithelial cells.
Fig. 4: From the gut and beyond: systemic implications of AHR signalling in the intestine.

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Acknowledgements

B.S. and K.S. are supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK, the UK Medical Research Council and the Wellcome Trust (FC001159). E.W. is supported by the Swedish research councils FORMAS (216-2013-1966) and VR (2020-03418).

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Nature Reviews Gastroenterology & Hepatology thanks C. Bradfield, who co-reviewed with R. Wilson and P. Carney, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Ligands

Molecules or compounds exhibiting specific binding to a receptor.

‘Natural’ AHR ligands

Ligands derived from the diet or the gut microbiota or formed endogenously.

Efficacy

Biological effectiveness of the ligand; that is, its ability to induce an active form of the receptor and the degree to which it produces a biological response.

Potency

The concentration or amount of the ligand needed to produce a specific biological effect; that is, the sum of a ligand’s affinity and efficacy.

Affinity

The strength with which a ligand binds to its receptor; that is, how well it fits into the ligand-binding pocket.

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Stockinger, B., Shah, K. & Wincent, E. AHR in the intestinal microenvironment: safeguarding barrier function. Nat Rev Gastroenterol Hepatol (2021). https://doi.org/10.1038/s41575-021-00430-8

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