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  • Review Article
  • Published:

AHR in the intestinal microenvironment: safeguarding barrier function

Nature Reviews Gastroenterology & Hepatology volume 18, pages 559–570 (2021)Cite this article

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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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References

  1. Burbach, K. M., Poland, A. & Bradfield, C. A. Cloning of the Ah-receptor cDNA reveals a distinctive ligand-activated transcription factor. Proc. Natl Acad. Sci. USA 89, 8185–8189 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Schmidt, J. V. & Bradfield, C. A. Ah receptor signaling pathways. Annu. Rev. Cell Dev. Biol. 12, 55–89 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Veldhoen, M. et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453, 106–109 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Quintana, F. J. et al. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature 453, 65–71 (2008).

    Article  CAS  PubMed  Google Scholar 

  5. Stockinger, B., Di Meglio, P., Gialitakis, M. & Duarte, J. H. The aryl hydrocarbon receptor: multitasking in the immune system. Annu. Rev. Immunol. 32, 403–432 (2014).

    Article  CAS  PubMed  Google Scholar 

  6. Hubbard, T. D., Murray, I. A. & Perdew, G. H. Indole and tryptophan metabolism: endogenous and dietary routes to Ah receptor activation. Drug Metab. Dispos. 43, 1522–1535 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  7. McMillan, B. J. & Bradfield, C. A. The aryl hydrocarbon receptor sans xenobiotics: endogenous function in genetic model systems. Mol. Pharmacol. 72, 487–498 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Chiaro, C. R., Patel, R. D., Marcus, C. B. & Perdew, G. H. Evidence for an aryl hydrocarbon receptor-mediated cytochrome P450 autoregulatory pathway. Mol. Pharmacol. 72, 1369–1379 (2007).

    Article  CAS  PubMed  Google Scholar 

  9. Wincent, E. et al. Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZ as a mechanism for activation of the aryl hydrocarbon receptor. Proc. Natl Acad. Sci. USA 109, 4479–4484 (2012). This article shows that AHR activation can be indirect via inhibition of CYP1-mediated ligand metabolism that allows response to endogenous ligands.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bock, K. W. From TCDD-mediated toxicity to searches of physiologic AHR functions. Biochem. Pharmacol. 155, 419–424 (2018).

    Article  CAS  PubMed  Google Scholar 

  11. Giani Tagliabue, S., Faber, S. C., Motta, S., Denison, M. S. & Bonati, L. Modeling the binding of diverse ligands within the Ah receptor ligand binding domain. Sci. Rep. 9, 10693 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Agus, A., Planchais, J. & Sokol, H. Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe 23, 716–724 (2018).

    Article  CAS  PubMed  Google Scholar 

  13. Hu, W., Sorrentino, C., Denison, M. S., Kolaja, K. & Fielden, M. R. Induction of Cyp1a1 is a nonspecific biomarker of aryl hydrocarbon receptor activation: results of large scale screening of pharmaceuticals and toxicants in vivo and in vitro. Mol. Pharmacol. 71, 1475–1486 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Avilla, M. N., Malecki, K. M. C., Hahn, M. E., Wilson, R. H. & Bradfield, C. A. The Ah receptor: adaptive metabolism, ligand diversity, and the xenokine model. Chem. Res. Toxicol. 33, 860–879 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lamas, B., Natividad, J. M. & Sokol, H. Aryl hydrocarbon receptor and intestinal immunity. Mucosal Immunol. 11, 1024–1038 (2018).

    Article  CAS  PubMed  Google Scholar 

  16. Costantini, C. et al. Tryptophan Co-metabolism at the host-pathogen interface. Front. Immunol. 11, 67 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hestermann, E. V., Stegeman, J. J. & Hahn, M. E. Relative contributions of affinity and intrinsic efficacy to aryl hydrocarbon receptor ligand potency. Toxicol. Appl. Pharmacol. 168, 160–172 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Schiering, C., Vonk, A., Das, S., Stockinger, B. & Wincent, E. Cytochrome P4501-inhibiting chemicals amplify aryl hydrocarbon receptor activation and IL-22 production in T helper 17 cells. Biochem. Pharmacol. 151, 47–58 (2018).

    Article  CAS  PubMed  Google Scholar 

  19. Schiering, C. et al. Feedback control of AHR signalling regulates intestinal immunity. Nature 542, 242–245 (2017). This study demonstrates a key role for the intestinal epithelial barrier in regulating both local and systemic distribution of luminal-derived AHR ligands. Constitutive expression of Cyp1a1 in IECs leads to systemic AHR ligand deficiency in mice, recapitulating hallmarks of AHR deficiency.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Seok, S. H. et al. Trace derivatives of kynurenine potently activate the aryl hydrocarbon receptor (AHR). J. Biol. Chem. 293, 1994–2005 (2018). This study provides evidence that kynurenine is not an AHR ligand per se but acts as an AHR proligand, which requires novel chemical conversions for it to act as a receptor agonist.

    Article  CAS  PubMed  Google Scholar 

  21. Rannug, A. How the AHR became important in intestinal homeostasis — a diurnal FICZ/AHR/CYP1A1 feedback controls both immunity and immunopathology. Int. J. Mol. Sci. 21, 5681 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  22. Bjeldanes, L. F., Kim, J. Y., Grose, K. R., Bartholomew, J. C. & Bradfield, C. A. Aromatic hydrocarbon responsiveness-receptor agonists generated from indole-3-carbinol in vitro and in vivo: comparisons with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Proc. Natl Acad. Sci. USA 88, 9543–9547 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hubbard, T. D. et al. Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles. Sci. Rep. 5, 12689 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Murray, I. A. & Perdew, G. H. Ligand activation of the Ah receptor contributes to gastrointestinal homeostasis. Curr. Opin. Toxicol. 2, 15–23 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Scott, S. A., Fu, J. & Chang, P. V. Microbial tryptophan metabolites regulate gut barrier function via the aryl hydrocarbon receptor. Proc. Natl Acad. Sci. USA 117, 19376–19387 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zelante, T. et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39, 372–385 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. Rannug, A. & Rannug, U. The tryptophan derivative 6-formylindolo[3,2-b]carbazole, FICZ, a dynamic mediator of endogenous aryl hydrocarbon receptor signaling, balances cell growth and differentiation. Crit. Rev. Toxicol. 48, 555–574 (2018).

    Article  CAS  PubMed  Google Scholar 

  28. Flaveny, C. A., Murray, I. A., Chiaro, C. R. & Perdew, G. H. Ligand selectivity and gene regulation by the human aryl hydrocarbon receptor in transgenic mice. Mol. Pharmacol. 75, 1412–1420 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Naganuma, M. et al. Efficacy of indigo naturalis in a multicenter randomized controlled trial of patients with ulcerative colitis. Gastroenterology 154, 935–947 (2018).

    Article  PubMed  Google Scholar 

  30. Marafini, I. et al. NPD-0414-2 and NPD-0414-24, two chemical entities designed as aryl hydrocarbon receptor (AhR) ligands, inhibit gut inflammatory signals. Front. Pharmacol. 10, 380 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chen, J. et al. Modulation of lymphocyte-mediated tissue repair by rational design of heterocyclic aryl hydrocarbon receptor agonists. Sci. Adv. 6, eaay8230 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Suzuki, T., Hidaka, T., Kumagai, Y. & Yamamoto, M. Environmental pollutants and the immune response. Nat. Immunol. 21, 1486–1495 (2020).

    Article  PubMed  CAS  Google Scholar 

  33. Murray, I. A., Patterson, A. D. & Perdew, G. H. Aryl hydrocarbon receptor ligands in cancer: friend and foe. Nat. Rev. Cancer 14, 801–814 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Safe, S., Han, H., Goldsby, J., Mohankumar, K. & Chapkin, R. S. Aryl hydrocarbon receptor (AhR) ligands as selective AhR modulators: genomic studies. Curr. Opin. Toxicol. 11-12, 10–20 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Vogel, C. F. A. & Haarmann-Stemmann, T. The aryl hydrocarbon receptor repressor - More than a simple feedback inhibitor of AhR signaling: clues for its role in inflammation and cancer. Curr. Opin. Toxicol. 2, 109–119 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Davarinos, N. A. & Pollenz, R. S. Aryl hydrocarbon receptor imported into the nucleus following ligand binding is rapidly degraded via the cytosplasmic proteasome following nuclear export. J. Biol. Chem. 274, 28708–28715 (1999).

    Article  CAS  PubMed  Google Scholar 

  37. MacPherson, L. et al. 2,3,7,8-Tetrachlorodibenzo-p-dioxin poly(ADP-ribose) polymerase (TiPARP, ARTD14) is a mono-ADP-ribosyltransferase and repressor of aryl hydrocarbon receptor transactivation. Nucleic Acids Res. 41, 1604–1621 (2013).

    Article  CAS  PubMed  Google Scholar 

  38. Inouye, K., Shinkyo, R., Takita, T., Ohta, M. & Sakaki, T. Metabolism of polychlorinated dibenzo-p-dioxins (PCDDs) by human cytochrome P450-dependent monooxygenase systems. J. Agric. Food Chem. 50, 5496–5502 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Wincent, E. et al. The suggested physiologic aryl hydrocarbon receptor activator and cytochrome P4501 substrate 6-formylindolo[3,2-b]carbazole is present in humans. J. Biol. Chem. 284, 2690–2696 (2009).

    Article  CAS  PubMed  Google Scholar 

  40. Ehrlich, A. K. & Kerkvliet, N. I. Is chronic AhR activation by rapidly metabolized ligands safe for the treatment of immune-mediated diseases? Curr. Opin. Toxicol. 2, 72–78 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Uno, S. et al. Oral exposure to benzo[a]pyrene in the mouse: detoxication by inducible cytochrome P450 is more important than metabolic activation. Mol. Pharmacol. 65, 1225–1237 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Nebert, D. W., Dalton, T. P., Okey, A. B. & Gonzalez, F. J. Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer. J. Biol. Chem. 279, 23847–23850 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Metidji, A. et al. The environmental sensor AHR protects from inflammatory damage by maintaining intestinal stem cell homeostasis and barrier integrity. Immunity 49, 353–362.e5 (2018). This study elucidates the mechanisms underlying AHR-mediated CRC protection, demonstrating an epithelial-intrinsic role for AHR in restraining dysregulated stem cell activity through transcriptional activation of the E3 ubiquitin ligases RNF43 and ZNRF3, which inhibit WNT–β-catenin.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Evans, B. R. et al. Repression of aryl hydrocarbon receptor (AHR) signaling by AHR repressor: role of DNA binding and competition for AHR nuclear translocator. Mol. Pharmacol. 73, 387–398 (2008).

    Article  CAS  PubMed  Google Scholar 

  45. Mimura, J., Ema, M., Sogawa, K. & Fujii-Kuriyama, Y. Identification of a novel mechanism of regulation of Ah (dioxin) receptor function. Genes Dev. 13, 20–25 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Brandstatter, O. et al. Balancing intestinal and systemic inflammation through cell type-specific expression of the aryl hydrocarbon receptor repressor. Sci. Rep. 6, 26091 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Dey, A., Jones, J. E. & Nebert, D. W. Tissue- and cell type-specific expression of cytochrome P450 1A1 and cytochrome P450 1A2 mRNA in the mouse localized in situ hybridization. Biochem. Pharmacol. 58, 525–537 (1999).

    Article  CAS  PubMed  Google Scholar 

  48. Uno, S. et al. Basal and inducible CYP1 mRNA quantitation and protein localization throughout the mouse gastrointestinal tract. Free Radic. Biol. Med. 44, 570–583 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Schanz, O. et al. Dietary AhR ligands regulate ahrr expression in intestinal immune cells and intestinal microbiota composition. Int. J. Mol. Sci. 21, 3189 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  50. Bernshausen, T., Jux, B., Esser, C., Abel, J. & Fritsche, E. Tissue distribution and function of the aryl hydrocarbon receptor repressor (AhRR) in C57BL/6 and aryl hydrocarbon receptor deficient mice. Arch. Toxicol. 80, 206–211 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Hosoya, T. et al. Inducibility of cytochrome P450 1A1 and chemical carcinogenesis by benzo[a]pyrene in AhR repressor-deficient mice. Biochem. Biophys. Res. Commun. 365, 562–567 (2008).

    Article  CAS  PubMed  Google Scholar 

  52. Tigges, J. et al. Aryl hydrocarbon receptor repressor (AhRR) function revisited: repression of CYP1 activity in human skin fibroblasts is not related to AhRR expression. J. Invest. Dermatol. 133, 87–96 (2013).

    Article  CAS  PubMed  Google Scholar 

  53. Ahmed, S. et al. Loss of the mono-ADP-ribosyltransferase, Tiparp, increases sensitivity to dioxin-induced steatohepatitis and lethality. J. Biol. Chem. 290, 16824–16840 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Hutin, D. et al. Hepatocyte-specific deletion of TIPARP, a negative regulator of the aryl hydrocarbon receptor, is sufficient to increase sensitivity to dioxin-induced wasting syndrome. Toxicol. Sci. 165, 347–360 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yamada, T. et al. Constitutive aryl hydrocarbon receptor signaling constrains type I interferon-mediated antiviral innate defense. Nat. Immunol. 17, 687–694 (2016).

    Article  CAS  PubMed  Google Scholar 

  56. Mowat, A. M. Anatomical basis of tolerance and immunity to intestinal antigens. Nat. Rev. Immunol. 3, 331–341 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Li, Y. et al. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 147, 629–640 (2011).

    Article  CAS  PubMed  Google Scholar 

  58. Cervantes-Barragan, L. et al. Lactobacillus reuteri induces gut intraepithelial CD4+CD8alphaalpha+ T cells. Science 357, 806–810 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Aoki, R., Aoki-Yoshida, A., Suzuki, C. & Takayama, Y. Indole-3-pyruvic acid, an aryl hydrocarbon receptor activator, suppresses experimental colitis in mice. J. Immunol. 201, 3683–3693 (2018).

    Article  CAS  PubMed  Google Scholar 

  60. Li, S., Bostick, J. W. & Zhou, L. Regulation of innate lymphoid cells by aryl hydrocarbon receptor. Front. Immunol. 8, 1909 (2017).

    Article  PubMed  CAS  Google Scholar 

  61. Seillet, C. & Jacquelot, N. Sensing of physiological regulators by innate lymphoid cells. Cell Mol. Immunol. 16, 442–451 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Gomez de Aguero, M. et al. The maternal microbiota drives early postnatal innate immune development. Science 351, 1296–1302 (2016).

    Article  PubMed  CAS  Google Scholar 

  63. Lamas, B. et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat. Med. 22, 598–605 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Li, J., Doty, A. & Glover, S. C. Aryl hydrocarbon receptor signaling involves in the human intestinal ILC3/ILC1 conversion in the inflamed terminal ileum of Crohn’s disease patients. Inflamm. Cell Signal. 3, e1404 (2016).

    PubMed  PubMed Central  Google Scholar 

  65. Cella, M. et al. Subsets of ILC3-ILC1-like cells generate a diversity spectrum of innate lymphoid cells in human mucosal tissues. Nat. Immunol. 20, 980–991 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Zhao, Y. et al. MicroRNA-124 promotes intestinal inflammation by targeting aryl hydrocarbon receptor in Crohn’s disease. J. Crohns Colitis 10, 703–712 (2016).

    Article  PubMed  Google Scholar 

  67. Li, S. et al. Aryl hydrocarbon receptor signaling cell intrinsically inhibits intestinal group 2 innate lymphoid cell function. Immunity 49, 915–928.e5 (2018). This article reveals a cell-intrinsic role for AHR in balancing intestinal ILC3 and ILC2 populations through repression of the IL-33–ST2 axis, thereby limiting TH2 cell-mediated immunity in favour of ILC3 effector function.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Liang, S. C. et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med. 203, 2271–2279 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Basu, R. et al. Th22 cells are an important source of IL-22 for host protection against enteropathogenic bacteria. Immunity 37, 1061–1075 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Gagliani, N. et al. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 523, 221–225 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Coombes, J. L., Robinson, N. J., Maloy, K. J., Uhlig, H. H. & Powrie, F. Regulatory T cells and intestinal homeostasis. Immunol. Rev. 204, 184–194 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Russler-Germain, E. V., Rengarajan, S. & Hsieh, C. S. Antigen-specific regulatory T-cell responses to intestinal microbiota. Mucosal Immunol. 10, 1375–1386 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Kim, K. S. et al. Dietary antigens limit mucosal immunity by inducing regulatory T cells in the small intestine. Science 351, 858–863 (2016).

    Article  CAS  PubMed  Google Scholar 

  74. Duarte, J. H., Di Meglio, P., Hirota, K., Ahlfors, H. & Stockinger, B. Differential influences of the aryl hydrocarbon receptor on Th17 mediated responses in vitro and in vivo. PLoS ONE 8, e79819 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Ye, J. et al. The aryl hydrocarbon receptor preferentially marks and promotes gut regulatory T cells. Cell Rep. 21, 2277–2290 (2017). This article probes a cell-intrinsic role for AHR in Treg cells, demonstrating the importance of Treg cell AHR signalling in regulating intestinal homing, and its requirement for immunosuppressive function in colitis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Xiong, L. et al. Ahr-Foxp3-RORgammat axis controls gut homing of CD4+ T cells by regulating GPR15. Sci. Immunol. 5, eaaz7277 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Goudot, C. et al. Aryl hydrocarbon receptor controls monocyte differentiation into dendritic cells versus macrophages. Immunity 47, 582–596.e6 (2017).

    Article  CAS  PubMed  Google Scholar 

  78. Chen, F. et al. mTOR mediates IL-23 induction of neutrophil IL-17 and IL-22 production. J. Immunol. 196, 4390–4399 (2016).

    Article  CAS  PubMed  Google Scholar 

  79. Ireland, H. et al. Inducible Cre-mediated control of gene expression in the murine gastrointestinal tract: effect of loss of beta-catenin. Gastroenterology 126, 1236–1246 (2004).

    Article  CAS  PubMed  Google Scholar 

  80. Ito, S., Chen, C., Satoh, J., Yim, S. & Gonzalez, F. J. Dietary phytochemicals regulate whole-body CYP1A1 expression through an arylhydrocarbon receptor nuclear translocator-dependent system in gut. J. Clin. Invest. 117, 1940–1950 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).

    Article  CAS  PubMed  Google Scholar 

  82. Clevers, H. The intestinal crypt, a prototype stem cell compartment. Cell 154, 274–284 (2013).

    Article  CAS  PubMed  Google Scholar 

  83. Novellasdemunt, L., Antas, P. & Li, V. S. Targeting Wnt signaling in colorectal cancer. a review in the theme: cell signaling: proteins, pathways and mechanisms. Am. J. Physiol. Cell Physiol 309, C511–C521 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Boitano, A. E. et al. Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science 329, 1345–1348 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Gialitakis, M. et al. Activation of the aryl hydrocarbon receptor interferes with early embryonic development. Stem Cell Rep. 9, 1377–1386 (2017).

    Article  CAS  Google Scholar 

  86. Villa, M. et al. The aryl hydrocarbon receptor controls cyclin O to promote epithelial multiciliogenesis. Nat. Commun. 7, 12652 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Ly, M. et al. Diminished AHR signaling drives human acute myeloid leukemia stem cell maintenance. Cancer Res. 79, 5799–5811 (2019).

    Article  CAS  PubMed  Google Scholar 

  88. Schneider, A. J., Branam, A. M. & Peterson, R. E. Intersection of AHR and Wnt signaling in development, health, and disease. Int. J. Mol. Sci. 15, 17852–17885 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Luecke-Johansson, S. et al. A molecular mechanism to switch the aryl hydrocarbon receptor from a transcription factor to an E3 ubiquitin ligase. Mol. Cell Biol. 37, e00630-16 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Koo, B. K. et al. Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature 488, 665–669 (2012).

    Article  CAS  PubMed  Google Scholar 

  91. Alvarado, D. M. et al. Epithelial indoleamine 2,3-dioxygenase 1 modulates aryl hydrocarbon receptor and Notch signaling to increase differentiation of secretory cells and alter mucus-associated microbiota. Gastroenterology 157, 1093–1108.e11 (2019).

    Article  CAS  PubMed  Google Scholar 

  92. Yu, M. et al. Aryl hydrocarbon receptor activation modulates intestinal epithelial barrier function by maintaining tight junction integrity. Int. J. Biol. Sci. 14, 69–77 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Singh, R. et al. Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway. Nat. Commun. 10, 1–18 (2019).

    Article  CAS  Google Scholar 

  94. Lahvis, G. P. et al. Portosystemic shunting and persistent fetal vascular structures in aryl hydrocarbon receptor-deficient mice. Proc. Natl Acad. Sci. USA 97, 10442–10447 (2000). This study characterizes physiological and morphological abnormalities in AHR-deficient mice, providing early evidence for a critical function of AHR in the regulation of vascular development and patterning.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Walisser, J. A., Glover, E., Pande, K., Liss, A. L. & Bradfield, C. A. Aryl hydrocarbon receptor-dependent liver development and hepatotoxicity are mediated by different cell types. Proc. Natl Acad. Sci. USA 102, 17858–17863 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Agbor, L. N., Elased, K. M. & Walker, M. K. Endothelial cell-specific aryl hydrocarbon receptor knockout mice exhibit hypotension mediated, in part, by an attenuated angiotensin II responsiveness. Biochem. Pharmacol. 82, 514–523 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Fandriks, L. The angiotensin II type 2 receptor and the gastrointestinal tract. J. Renin Angiotensin Aldosterone Syst. 11, 43–48 (2010).

    Article  PubMed  Google Scholar 

  98. Nakajima, H. & Mochizuki, N. Flow pattern-dependent endothelial cell responses through transcriptional regulation. Cell Cycle 16, 1893–1901 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Lin, K. et al. Molecular mechanism of endothelial growth arrest by laminar shear stress. Proc. Natl Acad. Sci. USA 97, 9385–9389 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. McMillan, B. J. & Bradfield, C. A. The aryl hydrocarbon receptor is activated by modified low-density lipoprotein. Proc. Natl Acad. Sci. USA 104, 1412–1417 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Han, Z. et al. Aryl hydrocarbon receptor mediates laminar fluid shear stress-induced CYP1A1 activation and cell cycle arrest in vascular endothelial cells. Cardiovasc. Res. 77, 809–818 (2008).

    Article  CAS  PubMed  Google Scholar 

  102. Conway, D. E. et al. Expression of CYP1A1 and CYP1B1 in human endothelial cells: regulation by fluid shear stress. Cardiovasc. Res. 81, 669–677 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Hanahan, D. & Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353–364 (1996).

    Article  CAS  PubMed  Google Scholar 

  104. Lee, J. H. et al. Lung stem cell differentiation in mice directed by endothelial cells via a BMP4-NFATc1-thrombospondin-1 axis. Cell 156, 440–455 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Hsu, T., Nguyen-Tran, H. H. & Trojanowska, M. Active roles of dysfunctional vascular endothelium in fibrosis and cancer. J. Biomed. Sci. 26, 86 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Deban, L., Correale, C., Vetrano, S., Malesci, A. & Danese, S. Multiple pathogenic roles of microvasculature in inflammatory bowel disease: a jack of all trades. Am. J. Pathol. 172, 1457–1466 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Pousa, I. D., Mate, J. & Gisbert, J. P. Angiogenesis in inflammatory bowel disease. Eur. J. Clin. Invest. 38, 73–81 (2008).

    Article  CAS  PubMed  Google Scholar 

  108. Zhu, Z. et al. Aryl hydrocarbon receptor in cutaneous vascular endothelial cells restricts psoriasis development by negatively regulating neutrophil recruitment. J. Invest. Dermatol. 140, 1233–1243.e9 (2019).

    Article  PubMed  CAS  Google Scholar 

  109. Cardoso, V. et al. Neuronal regulation of type 2 innate lymphoid cells via neuromedin U. Nature 549, 277–281 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Ibiza, S. et al. Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence. Nature 535, 440–443 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Juricek, L. & Coumoul, X. The aryl hydrocarbon receptor and the nervous system. Int. J. Mol. Sci. 19, 2504 (2018).

    Article  PubMed Central  CAS  Google Scholar 

  112. Memic, F. et al. Transcription and signaling regulators in developing neuronal subtypes of mouse and human enteric nervous system. Gastroenterology 154, 624–636 (2018).

    Article  CAS  PubMed  Google Scholar 

  113. Obata, Y. et al. Neuronal programming by microbiota regulates intestinal physiology. Nature 578, 284–289 (2020). This study identifies that enteric neurons in the colon express AHR in a manner dependent on the microbiota. Cell-intrinsic AHR activation is required for the integration of environmental cues from the microbiota in order to regulate peristalsis.

    Article  CAS  PubMed  Google Scholar 

  114. De Vadder, F. et al. Gut microbiota regulates maturation of the adult enteric nervous system via enteric serotonin networks. Proc. Natl Acad. Sci. USA 115, 6458–6463 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Kabouridis, P. S. et al. Microbiota controls the homeostasis of glial cells in the gut lamina propria. Neuron 85, 289–295 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Bielefeldt, K., Tuteja, A. & Nusrat, S. Disorders of gastrointestinal hypomotility. F1000Res 5, 1897 (2016).

    Article  CAS  Google Scholar 

  117. Yano, J. M. et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161, 264–276 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Manzella, C. R. et al. Serotonin modulates AhR activation by interfering with CYP1A1-mediated clearance of AhR ligands. Cell. Physiol. Biochem. 54, 126–141 (2020).

    CAS  PubMed  Google Scholar 

  119. Yuan, H. X. et al. Whole exome sequencing identifies a KCNJ12 mutation as a cause of familial dilated cardiomyopathy. Medicine 96, e7727 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Silver, J., Schwab, M. E. & Popovich, P. G. Central nervous system regenerative failure: role of oligodendrocytes, astrocytes, and microglia. Cold Spring Harb. Perspect. Biol. 7, a020602 (2014).

    Article  PubMed  Google Scholar 

  121. Kruger, G. M. et al. Neural crest stem cells persist in the adult gut but undergo changes in self-renewal, neuronal subtype potential, and factor responsiveness. Neuron 35, 657–669 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Heanue, T. A. & Pachnis, V. Enteric nervous system development and Hirschsprung’s disease: advances in genetic and stem cell studies. Nat. Rev. Neurosci. 8, 466–479 (2007).

    Article  CAS  PubMed  Google Scholar 

  123. Di Giaimo, R. et al. The aryl hydrocarbon receptor pathway defines the time frame for restorative neurogenesis. Cell Rep. 25, 3241–3251.e5 (2018).

    Article  PubMed  CAS  Google Scholar 

  124. Bersten, D. C., Sullivan, A. E., Peet, D. J. & Whitelaw, M. L. bHLH-PAS proteins in cancer. Nat. Rev. Cancer 13, 827–841 (2013).

    Article  CAS  PubMed  Google Scholar 

  125. Denissenko, M. F., Pao, A., Tang, M. & Pfeifer, G. P. Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53. Science 274, 430–432 (1996).

    Article  CAS  PubMed  Google Scholar 

  126. McGuire, J., Okamoto, K., Whitelaw, M. L., Tanaka, H. & Poellinger, L. Definition of a dioxin receptor mutant that is a constitutive activator of transcription: delineation of overlapping repression and ligand binding functions within the PAS domain. J. Biol. Chem. 276, 41841–41849 (2001).

    Article  CAS  PubMed  Google Scholar 

  127. Andersson, P. et al. A constitutively active dioxin/aryl hydrocarbon receptor induces stomach tumors. Proc. Natl Acad. Sci. USA 99, 9990–9995 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Moennikes, O. et al. A constitutively active dioxin/aryl hydrocarbon receptor promotes hepatocarcinogenesis in mice. Cancer Res. 64, 4707–4710 (2004).

    Article  CAS  PubMed  Google Scholar 

  129. Diaz-Diaz, C. J. et al. The aryl hydrocarbon receptor is a repressor of inflammation-associated colorectal tumorigenesis in mouse. Ann. Surg. 264, 429–436 (2016).

    Article  PubMed  Google Scholar 

  130. Dinallo, V. et al. Protective effects of aryl hydrocarbon receptor signaling in celiac disease mucosa and in poly I:C-induced small intestinal atrophy mouse model. Front. Immunol. 10, 91 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Ikuta, T., Kurosumi, M., Yatsuoka, T. & Nishimura, Y. Tissue distribution of aryl hydrocarbon receptor in the intestine: implication of putative roles in tumor suppression. Exp. Cell Res. 343, 126–134 (2016).

    Article  CAS  PubMed  Google Scholar 

  132. Beyaz, S. et al. High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature 531, 53–58 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Mayne, S. T., Playdon, M. C. & Rock, C. L. Diet, nutrition, and cancer: past, present and future. Nat. Rev. Clin. Oncol. 13, 504–515 (2016).

    Article  PubMed  Google Scholar 

  134. Terry, P. et al. Fruit, vegetables, dietary fiber, and risk of colorectal cancer. J. Natl Cancer Inst. 93, 525–533 (2001).

    Article  CAS  PubMed  Google Scholar 

  135. Cunningham, D. et al. Colorectal cancer. Lancet 375, 1030–1047 (2010).

    Article  PubMed  Google Scholar 

  136. Zitvogel, L., Pietrocola, F. & Kroemer, G. Nutrition, inflammation and cancer. Nat. Immunol. 18, 843–850 (2017).

    Article  CAS  PubMed  Google Scholar 

  137. Fernandez-Salguero, P. M., Ward, J. M., Sundberg, J. P. & Gonzalez, F. J. Lesions of aryl-hydrocarbon receptor-deficient mice. Vet. Pathol. 34, 605–614 (1997).

    Article  CAS  PubMed  Google Scholar 

  138. Monteleone, I. et al. Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract. Gastroenterology 141, 237–248.e1 (2011).

    Article  CAS  PubMed  Google Scholar 

  139. Lanis, J. M. et al. Tryptophan metabolite activation of the aryl hydrocarbon receptor regulates IL-10 receptor expression on intestinal epithelia. Mucosal Immunol. 10, 1133–1144 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Hernandez, P., Gronke, K. & Diefenbach, A. A catch-22: interleukin-22 and cancer. Eur. J. Immunol. 48, 15–31 (2018).

    Article  CAS  PubMed  Google Scholar 

  141. Gronke, K. et al. Interleukin-22 protects intestinal stem cells against genotoxic stress. Nature 566, 249–253 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Kirchberger, S. et al. Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model. J. Exp. Med. 210, 917–931 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Thompson, C. L., Plummer, S. J., Tucker, T. C., Casey, G. & Li, L. Interleukin-22 genetic polymorphisms and risk of colon cancer. Cancer Causes Control. 21, 1165–1170 (2010).

    Article  PubMed  Google Scholar 

  144. Rothhammer, V. et al. Microglial control of astrocytes in response to microbial metabolites. Nature 557, 724–728 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Shinde, R. & McGaha, T. L. The aryl hydrocarbon receptor: connecting immunity to the microenvironment. Trends Immunol. 39, 1005–1020 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Fatkhullina, A. R. et al. An interleukin-23-interleukin-22 axis regulates intestinal microbial homeostasis to protect from diet-induced atherosclerosis. Immunity 49, 943–957.e9 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Rosser, E. C. et al. Microbiota-Derived metabolites suppress arthritis by amplifying aryl-hydrocarbon receptor activation in regulatory B cells. Cell Metab. 31, 837–851.e10 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Natividad, J. M. et al. Impaired aryl hydrocarbon receptor ligand production by the gut microbiota is a key factor in metabolic syndrome. Cell Metab. 28, 737–749.e4 (2018). This article links metabolic syndrome with reduced capacity for generation of AHR ligands via microbiota metabolism of tryptophan.

    Article  CAS  PubMed  Google Scholar 

  149. Lavelle, A. & Sokol, H. Gut microbiota-derived metabolites as key actors in inflammatory bowel disease. Nat. Rev. Gastroenterol. Hepatol. 17, 223–237 (2020).

    Article  PubMed  Google Scholar 

  150. Busbee, P. B. et al. Indole-3-carbinol prevents colitis and associated microbial dysbiosis in an IL-22-dependent manner. JCI Insight 5, e127551 (2020).

    Article  PubMed Central  Google Scholar 

  151. Kim, Y. S. & Milner, J. A. Targets for indole-3-carbinol in cancer prevention. J. Nutr. Biochem. 16, 65–73 (2005).

    Article  CAS  PubMed  Google Scholar 

  152. Weng, J. R., Tsai, C. H., Kulp, S. K. & Chen, C. S. Indole-3-carbinol as a chemopreventive and anti-cancer agent. Cancer Lett. 262, 153–163 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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  1. The Francis Crick Institute, London, UK

    Brigitta Stockinger & Kathleen Shah

  2. Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden

    Emma Wincent

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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 18, 559–570 (2021). https://doi.org/10.1038/s41575-021-00430-8

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