Aryl hydrocarbon receptor utilises cellular zinc signals to maintain the gut epithelial barrier

Xiuchuan (Lucas) Hu, Wenfeng Xiao, Yuxian Lei, Adam Green, Xinyi Lee, Muralidhara Rao Maradana, Yajing Gao, Xueru Xie, Rui Wang, George Chennell, M. Albert Basson, Pete Kille, Wolfgang Maret, Gavin A. Bewick, Yufeng Zhou () and Christer Hogstrand ()
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Xiuchuan (Lucas) Hu: Fudan University
Wenfeng Xiao: Fudan University
Yuxian Lei: King’s College London
Adam Green: King’s College London
Xinyi Lee: King’s College London
Muralidhara Rao Maradana: The Francis Crick Institute
Yajing Gao: Fudan University
Xueru Xie: Fudan University
Rui Wang: King’s College London
George Chennell: King’s College London
M. Albert Basson: King’s College London
Pete Kille: Cardiff University
Wolfgang Maret: King’s College London
Gavin A. Bewick: King’s College London
Yufeng Zhou: Fudan University
Christer Hogstrand: King’s College London

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Zinc and plant-derived ligands of the aryl hydrocarbon receptor (AHR) are dietary components affecting intestinal epithelial barrier function. Here, we explore whether zinc and the AHR pathway are linked. We show that dietary supplementation with an AHR pre-ligand offers protection against inflammatory bowel disease in a mouse model while protection fails in mice lacking AHR in the intestinal epithelium. AHR agonist treatment is also ineffective in mice fed zinc depleted diet. In human ileum organoids and Caco-2 cells, AHR activation increases total cellular zinc and cytosolic free Zn2+ concentrations through transcription of genes for zinc importers. Tight junction proteins are upregulated through zinc inhibition of nuclear factor kappa-light-chain-enhancer and calpain activity. Our data show that AHR activation by plant-derived dietary ligands improves gut barrier function at least partly via zinc-dependent cellular pathways, suggesting that combined dietary supplementation with AHR ligands and zinc might be effective in preventing inflammatory gut disorders.

Date: 2023
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DOI: 10.1038/s41467-023-41168-y

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