1932

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-activated basic-helix-loop-helix transcription factor that binds structurally diverse ligands and senses cues from environmental toxicants and physiologically relevant dietary/microbiota-derived ligands. The AhR is an ancient conserved protein and is widely expressed across different tissues in vertebrates and invertebrates. AhR signaling mediates a wide range of cellular functions in a ligand-, cell type–, species-, and context-specific manner. Dysregulation of AhR signaling is linked to many developmental defects and chronic diseases. In this review, we discuss the emerging role of AhR signaling in mediating bidirectional host–microbiome interactions. We also consider evidence showing the potential for the dietary/microbial enhancement ofhealth-promoting AhR ligands to improve clinical pathway management in the context of inflammatory bowel diseases and colon tumorigenesis.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-nutr-043020-090050
2021-10-11
2024-06-21
Loading full text...

Full text loading...

/deliver/fulltext/nutr/41/1/annurev-nutr-043020-090050.html?itemId=/content/journals/10.1146/annurev-nutr-043020-090050&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Agus A, Planchais J, Sokol H. 2018. Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe 23:716–24
    [Google Scholar]
  2. 2. 
    Ahmad A, Ali S, Wang Z, Ali AS, Sethi S et al. 2011. 3,3′-Diindolylmethane enhances taxotere-induced growth inhibition of breast cancer cells through downregulation of FoxM1. Int. J. Cancer 129:1781–91 Erratum. 2014. Int. J. Cancer 135:E10
    [Google Scholar]
  3. 3. 
    Alexeev EE, Lanis JM, Kao DJ, Campbell EL, Kelly CJ et al. 2018. Microbiota-derived indole metabolites promote human and murine intestinal homeostasis through regulation of interleukin-10 receptor. Am. J. Pathol. 188:1183–94
    [Google Scholar]
  4. 4. 
    Am. Cancer Soc 2021. Key statistics for colorectal cancer. American Cancer Society https://www.cancer.org/cancer/colon-rectal-cancer/about/key-statistics.html
    [Google Scholar]
  5. 5. 
    Andrews C, McLean MH, Durum SK. 2018. Cytokine tuning of intestinal epithelial function. Front. Immunol. 9:1270
    [Google Scholar]
  6. 6. 
    Apetoh L, Quintana FJ, Pot C, Joller N, Xiao S et al. 2010. The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Nat. Immunol. 11:854–61
    [Google Scholar]
  7. 7. 
    Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y et al. 2013. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500:232–36
    [Google Scholar]
  8. 8. 
    Avilla MN, Malecki KMC, Hahn ME, Wilson RH, Bradfield CA. 2020. The Ah receptor: adaptive metabolism, ligand diversity, and the xenokine model. Chem. Res. Toxicol. 33:860–79
    [Google Scholar]
  9. 9. 
    Baan R, Grosse Y, Straif K, Secretan B, El Ghissassi F et al. 2009. A review of human carcinogens—Part F: chemical agents and related occupations. Lancet Oncol 10:1143–44
    [Google Scholar]
  10. 10. 
    Banoglu E, Jha GG, King RS. 2001. Hepatic microsomal metabolism of indole to indoxyl, a precursor of indoxyl sulfate. Eur. J. Drug Metab. Pharmacokinet. 26:235–40
    [Google Scholar]
  11. 11. 
    Banoglu E, King RS. 2002. Sulfation of indoxyl by human and rat aryl (phenol) sulfotransferases to form indoxyl sulfate. Eur. J. Drug Metab. Pharmacokinet. 27:135–40
    [Google Scholar]
  12. 12. 
    Barba FJ, Nikmaram N, Roohinejad S, Khelfa A, Zhu Z, Koubaa M. 2016. Bioavailability of glucosinolates and their breakdown products: impact of processing. Front. Nutr. 3:24
    [Google Scholar]
  13. 13. 
    Biton M, Haber AL, Rogel N, Burgin G, Beyaz S et al. 2018. T helper cell cytokines modulate intestinal stem cell renewal and differentiation. Cell 175:1307–20.e22
    [Google Scholar]
  14. 14. 
    Bradfield CA, Poland A. 1988. A competitive binding assay for 2,3,7,8-tetrachlorodibenzo-p-dioxin and related ligands of the Ah receptor. Mol. Pharmacol. 34:682–88
    [Google Scholar]
  15. 15. 
    Brawner KM, Yeramilli VA, Duck LW, Van Der Pol W, Smythies LE et al. 2019. Depletion of dietary aryl hydrocarbon receptor ligands alters microbiota composition and function. Sci. Rep. 9:14724
    [Google Scholar]
  16. 16. 
    Busbee PB, Menzel L, Alrafas HR, Dopkins N, Becker W et al. 2020. Indole-3-carbinol prevents colitis and associated microbial dysbiosis in an IL-22–dependent manner. JCI Insight 5:e127551
    [Google Scholar]
  17. 17. 
    Busbee PB, Nagarkatti M, Nagarkatti P. 2017. Indole-3-carbinol ameliorates murine colitis symptoms through alterations in gut microbial composition and metabolomic pathways, particularly through decreasing disease-associated Bacteroides acidifaciens species. J. Immunol. 198:Suppl.218.18
    [Google Scholar]
  18. 18. 
    Busbee PB, Rouse M, Nagarkatti M, Nagarkatti PS. 2013. Use of natural AhR ligands as potential therapeutic modalities against inflammatory disorders. Nutr. Rev. 71:353–69
    [Google Scholar]
  19. 19. 
    Butler R, Inzunza J, Suzuki H, Fujii-Kuriyama Y, Warner M, Gustafsson J-Å 2012. Uric acid stones in the urinary bladder of aryl hydrocarbon receptor (AhR) knockout mice. PNAS 109:1122–26
    [Google Scholar]
  20. 20. 
    Butler RA, Kelley ML, Powell WH, Hahn ME, Van Beneden RJ. 2001. An aryl hydrocarbon receptor (AHR) homologue from the soft-shell clam, Mya arenaria: evidence that invertebrate AHR homologues lack 2,3,7,8-tetrachlorodibenzo-p-dioxin and beta-naphthoflavone binding. Gene 278:223–34
    [Google Scholar]
  21. 21. 
    Celiberto LS, Graef FA, Healey GR, Bosman ES, Jacobson K et al. 2018. Inflammatory bowel disease and immunonutrition: novel therapeutic approaches through modulation of diet and the gut microbiome. Immunology 155:36–52
    [Google Scholar]
  22. 22. 
    Chevallier A, Mialot A, Petit J-M, Fernandez-Salguero P, Barouki R et al. 2013. Oculomotor deficits in aryl hydrocarbon receptor null mouse. PLOS ONE 8:e53520
    [Google Scholar]
  23. 23. 
    Chevolleau S, Gasc N, Rollin P, Tulliez J 1997. Enzymatic, chemical, and thermal breakdown of 3H-labeled glucobrassicin, the parent indole glucosinolate. J. Agric. Food Chem. 45:4290–96
    [Google Scholar]
  24. 24. 
    Cox JH, Kljavin NM, Ota N, Leonard J, Roose-Girma M et al. 2012. Opposing consequences of IL-23 signaling mediated by innate and adaptive cells in chemically induced colitis in mice. Mucosal Immunol 5:99–109
    [Google Scholar]
  25. 25. 
    Davarinos NA, Pollenz RS. 1999. Aryl hydrocarbon receptor imported into the nucleus following ligand binding is rapidly degraded via the cytosplasmic proteasome following nuclear export. J. Biol. Chem. 274:28708–15
    [Google Scholar]
  26. 26. 
    Denison MS, Nagy SR. 2003. Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu. Rev. Pharmacol. Toxicol. 43:309–34
    [Google Scholar]
  27. 27. 
    Denison MS, Soshilov AA, He G, DeGroot DE, Zhao B. 2011. Exactly the same but different: promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon (dioxin) receptor. Toxicol. Sci. 124:1–22
    [Google Scholar]
  28. 28. 
    Diaz-Diaz CJ, Ronnekleiv-Kelly SM, Nukaya M, Geiger PG, Balbo S et al. 2016. The aryl hydrocarbon receptor is a repressor of inflammation-associated colorectal tumorigenesis in mouse. Ann. Surg. 264:429–36
    [Google Scholar]
  29. 29. 
    Dodd D, Spitzer MH, Van Treuren W, Merrill BD, Hryckowian AJ et al. 2017. A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. Nature 551:648–52
    [Google Scholar]
  30. 30. 
    Fan Y, Pedersen O. 2021. Gut microbiota in human metabolic health and disease. Nat. Rev. Microbiol. 19:55–71
    [Google Scholar]
  31. 31. 
    Flaveny CA, Murray IA, Perdew GH. 2010. Differential gene regulation by the human and mouse aryl hydrocarbon receptor. Toxicol. Sci. 114:217–25
    [Google Scholar]
  32. 32. 
    Flaveny CA, Reen RK, Kusnadi A, Perdew GH. 2008. The mouse and human Ah receptor differ in recognition of LXXLL motifs. Arch. Biochem. Biophys. 471:215–23
    [Google Scholar]
  33. 33. 
    Fritsche E, Schäfer C, Calles C, Bernsmann T, Bernshausen T et al. 2007. Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation. PNAS 104:8851–56
    [Google Scholar]
  34. 34. 
    Furumatsu K, Nishiumi S, Kawano Y, Ooi M, Yoshie T et al. 2011. A role of the aryl hydrocarbon receptor in attenuation of colitis. Dig. Dis. Sci. 56:2532–44
    [Google Scholar]
  35. 35. 
    Gandhi R, Kumar D, Burns EJ, Nadeau M, Dake B et al. 2010. Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3+ regulatory T cells. Nat. Immunol. 11:846–53
    [Google Scholar]
  36. 36. 
    Garcia-Villatoro EL, DeLuca JAA, Callaway ES, Allred KF, Davidson LA et al. 2020. Effects of high-fat diet and intestinal aryl hydrocarbon receptor deletion on colon carcinogenesis. Am. J. Physiol. Gastrointest. Liver Physiol. 318:G451–451
    [Google Scholar]
  37. 37. 
    Gasiewicz TA, Singh KP, Bennett JA. 2014. The Ah receptor in stem cell cycling, regulation, and quiescence. Ann. N. Y. Acad. Sci. 1310:44–50
    [Google Scholar]
  38. 38. 
    Gaweska HM, Taylor AB, Hart PJ, Fitzpatrick PF. 2013. Structure of the flavoprotein tryptophan 2-monooxygenase, a key enzyme in the formation of galls in plants. Biochemistry 52:2620–26
    [Google Scholar]
  39. 39. 
    Geisler S, Mayersbach P, Becker K, Schennach H, Fuchs D, Gostner JM. 2015. Serum tryptophan, kynurenine, phenylalanine, tyrosine and neopterin concentrations in 100 healthy blood donors. Pteridines 26:31–36
    [Google Scholar]
  40. 40. 
    Giani Tagliabue S, Faber SC, Motta S, Denison MS, Bonati L. 2019. Modeling the binding of diverse ligands within the Ah receptor ligand binding domain. Sci. Rep. 9:10693
    [Google Scholar]
  41. 41. 
    Goettel JA, Gandhi R, Kenison JE, Yeste A, Murugaiyan G et al. 2016. AHR activation is protective against colitis driven by T cells in humanized mice. Cell Rep 17:1318–29
    [Google Scholar]
  42. 42. 
    Gronke K, Hernandez PP, Zimmermann J, Klose CSN, Kofoed-Branzk M et al. 2019. Interleukin-22 protects intestinal stem cells against genotoxic stress. Nature 566:249–53
    [Google Scholar]
  43. 43. 
    Gu A, Ji G, Long Y, Zhou Y, Shi X et al. 2011. Assessment of an association between an aryl hydrocarbon receptor gene (AHR) polymorphism and risk of male infertility. Toxicol. Sci. 122:415–21
    [Google Scholar]
  44. 44. 
    Gutierrez-Vazquez C, Quintana FJ. 2018. Regulation of the immune response by the aryl hydrocarbon receptor. Immunity 48:19–33
    [Google Scholar]
  45. 45. 
    Haggar FA, Boushey RP. 2009. Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clin. Colon Rectal Surg. 22:191–97
    [Google Scholar]
  46. 46. 
    Hahn ME, Karchner SI, Merson RR. 2017. Diversity as opportunity: insights from 600 million years of AHR evolution. Curr. Opin. Toxicol. 2:58–71
    [Google Scholar]
  47. 47. 
    Han H, Davidson LA, Fan Y-Y, Goldsby JS, Yoon G et al. 2020. Loss of aryl hydrocarbon receptor potentiates FoxM1 signaling to enhance self-renewal of colonic stem and progenitor cells. EMBO J 39:e104319
    [Google Scholar]
  48. 48. 
    Heller F, Fuss IJ, Nieuwenhuis EE, Blumberg RS, Strober W. 2002. Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. Immunity 17:629–38
    [Google Scholar]
  49. 49. 
    Huang G, Elferink CJ. 2012. A novel nonconsensus xenobiotic response element capable of mediating aryl hydrocarbon receptor-dependent gene expression. Mol. Pharmacol. 81:338–47
    [Google Scholar]
  50. 50. 
    Huang S, Shui X, He Y, Xue Y, Li J et al. 2015. AhR expression and polymorphisms are associated with risk of coronary arterial disease in Chinese population. Sci. Rep. 5:8022
    [Google Scholar]
  51. 51. 
    Hubbard TD, Murray IA, Bisson WH, Lahoti TS, Gowda K et al. 2015. Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles. Sci. Rep. 5:12689
    [Google Scholar]
  52. 52. 
    Hubbard TD, Murray IA, Perdew GH. 2015. Indole and tryptophan metabolism: endogenous and dietary routes to Ah receptor activation. Drug Metab. Dispos. 43:1522–35
    [Google Scholar]
  53. 53. 
    Ikuta T, Kobayashi Y, Kitazawa M, Shiizaki K, Itano N et al. 2013. ASC-associated inflammation promotes cecal tumorigenesis in aryl hydrocarbon receptor-deficient mice. Carcinogenesis 34:1620–27
    [Google Scholar]
  54. 54. 
    Ikuta T, Kurosumi M, Yatsuoka T, Nishimura Y. 2016. Tissue distribution of aryl hydrocarbon receptor in the intestine: implication of putative roles in tumor suppression. Exp. Cell Res. 343:126–34
    [Google Scholar]
  55. 55. 
    Iyer SS, Gensollen T, Gandhi A, Oh SF, Neves JF et al. 2018. Dietary and microbial oxazoles induce intestinal inflammation by modulating aryl hydrocarbon receptor responses. Cell 173:1123–34.e11
    [Google Scholar]
  56. 56. 
    Jaeger C, Tischkau SA. 2016. Role of aryl hydrocarbon receptor in circadian clock disruption and metabolic dysfunction. Environ. Health Insights 10:133–41
    [Google Scholar]
  57. 57. 
    Janney A, Powrie F, Mann EH. 2020. Host–microbiota maladaptation in colorectal cancer. Nature 585:509–17
    [Google Scholar]
  58. 58. 
    Jellinck PH, Forkert PG, Riddick DS, Okey AB, Michnovicz JJ, Bradlow HL. 1993. Ah receptor binding properties of indole carbinols and induction of hepatic estradiol hydroxylation. Biochem. Pharmacol. 45:1129–36
    [Google Scholar]
  59. 59. 
    Jin UH, Park H, Li X, Davidson LA, Allred C et al. 2018. Structure-dependent modulation of aryl hydrocarbon receptor-mediated activities by flavonoids. Toxicol. Sci. 164:205–17
    [Google Scholar]
  60. 60. 
    Johnson AJ, Vangay P, Al-Ghalith GA, Hillmann BM, Ward TL et al. 2019. Daily sampling reveals personalized diet-microbiome associations in humans. Cell Host Microbe 25:789–802.e5
    [Google Scholar]
  61. 61. 
    Kabel AM, Omar MS, Alotaibi SN, Baali MH. 2017. Effect of indole-3-carbinol and/or metformin on female patients with ulcerative colitis (premalignant condition): role of oxidative stress, apoptosis and proinflammatory cytokines. J. Cancer Res. Treat. 5:1–8
    [Google Scholar]
  62. 62. 
    Karlin DA, Mastromarino AJ, Jones RD, Stroehlein JR, Lorentz O. 1985. Fecal skatole and indole and breath methane and hydrogen in patients with large bowel polyps or cancer. J. Cancer Res. Clin. Oncol. 109:135–41
    [Google Scholar]
  63. 63. 
    Kawai S, Iijima H, Shinzaki S, Hiyama S, Yamaguchi T et al. 2017. Indigo Naturalis ameliorates murine dextran sodium sulfate-induced colitis via aryl hydrocarbon receptor activation. J. Gastroenterol. 52:904–19
    [Google Scholar]
  64. 64. 
    Kawajiri K, Kobayashi Y, Ohtake F, Ikuta T, Matsushima Y et al. 2009. Aryl hydrocarbon receptor suppresses intestinal carcinogenesis in ApcMin/+ mice with natural ligands. PNAS 106:13481–86
    [Google Scholar]
  65. 65. 
    Kimura A, Naka T, Nakahama T, Chinen I, Masuda K et al. 2009. Aryl hydrocarbon receptor in combination with Stat1 regulates LPS-induced inflammatory responses. J. Exp. Med. 206:2027–35
    [Google Scholar]
  66. 66. 
    Knerr S, Schrenk D. 2006. Carcinogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in experimental models. Mol. Nutr. Food Res. 50:897–907
    [Google Scholar]
  67. 67. 
    Kolluri SK, Jin UH, Safe S. 2017. Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target. Arch. Toxicol. 91:2497–513
    [Google Scholar]
  68. 68. 
    Korecka A, Dona A, Lahiri S, Tett AJ, Al-Asmakh M et al. 2016. Bidirectional communication between the Aryl hydrocarbon Receptor (AhR) and the microbiome tunes host metabolism. NPJ Biofilms Microbiomes 2:16014
    [Google Scholar]
  69. 69. 
    Kovalova N, Manzan M, Crawford R, Kaminski N 2016. Role of aryl hydrocarbon receptor polymorphisms on TCDD-mediated CYP1B1 induction and IgM suppression by human B cells. Toxicol. Appl. Pharmacol. 309:15–23
    [Google Scholar]
  70. 70. 
    Lamas B, Richard ML, Leducq V, Pham HP, Michel ML et al. 2016. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat. Med. 22:598–605
    [Google Scholar]
  71. 71. 
    Lanis JM, Alexeev EE, Curtis VF, Kitzenberg DA, Kao DJ et al. 2017. Tryptophan metabolite activation of the aryl hydrocarbon receptor regulates IL-10 receptor expression on intestinal epithelia. Mucosal Immunol 10:1133–44
    [Google Scholar]
  72. 72. 
    Larigot L, Juricek L, Dairou J, Coumoul X. 2018. AhR signaling pathways and regulatory functions. Biochim. Open 7:1–9
    [Google Scholar]
  73. 73. 
    Lee JH, Lee J. 2010. Indole as an intercellular signal in microbial communities. FEMS Microbiol. Rev. 34:426–44
    [Google Scholar]
  74. 74. 
    Lee JH, Wood TK, Lee J. 2015. Roles of indole as an interspecies and interkingdom signaling molecule. Trends Microbiol 23:707–18
    [Google Scholar]
  75. 75. 
    Li S, Bostick JW, Ye J, Qiu J, Zhang B et al. 2018. Aryl hydrocarbon receptor signaling cell intrinsically inhibits intestinal group 2 innate lymphoid cell function. Immunity 49:915–28.e5
    [Google Scholar]
  76. 76. 
    Li S, Pei X, Zhang W, Xie HQ, Zhao B. 2014. Functional analysis of the dioxin response elements (DREs) of the murine CYP1A1 gene promoter: beyond the core DRE sequence. Int. J. Mol. Sci. 15:6475–87
    [Google Scholar]
  77. 77. 
    Lindemans CA, Calafiore M, Mertelsmann AM, O'Connor MH, Dudakov JA et al. 2015. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature 528:560–64
    [Google Scholar]
  78. 78. 
    Liu JZ, van Sommeren S, Huang H, Ng SC, Alberts R et al. 2015. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat. Genet. 47:979–86
    [Google Scholar]
  79. 79. 
    Liu Y, Hou Y, Wang G, Zheng X, Hao H. 2020. Gut microbial metabolites of aromatic amino acids as signals in host–microbe interplay. Trends Endocrinol. Metab. 31:P818–818
    [Google Scholar]
  80. 80. 
    Lloyd-Price J, Arze C, Ananthakrishnan AN, Schirmer M, Avila-Pacheco J et al. 2019. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. Nature 569:655–62
    [Google Scholar]
  81. 81. 
    Lowe MM, Mold JE, Kanwar B, Huang Y, Louie A et al. 2014. Identification of cinnabarinic acid as a novel endogenous aryl hydrocarbon receptor ligand that drives IL-22 production. PLOS ONE 9:e87877
    [Google Scholar]
  82. 82. 
    Lucier GW, McDaniel OS, Hook GE, Fowler BA, Sonawane BR, Faeder E. 1973. TCDD-induced changes in rat liver microsomal enzymes. Environ. Health Perspect. 5:199–209
    [Google Scholar]
  83. 83. 
    Lv Q, Shi C, Qiao S, Cao N, Guan C et al. 2018. Alpinetin exerts anti-colitis efficacy by activating AhR, regulating miR-302/DNMT-1/CREB signals, and therefore promoting Treg differentiation. Cell Death Disease 9:890
    [Google Scholar]
  84. 84. 
    Martinez KB, Leone V, Chang EB. 2017. Microbial metabolites in health and disease: navigating the unknown in search of function. J. Biol. Chem. 292:8553–59
    [Google Scholar]
  85. 85. 
    Mayer AK, Mahajnah M, Thomas MG, Cohen Y, Habib A et al. 2019. Homozygous stop mutation in AHR causes autosomal recessive foveal hypoplasia and infantile nystagmus. Brain 142:1528–34
    [Google Scholar]
  86. 86. 
    McDougal A, Wormke M, Calvin J, Safe S 2001. Tamoxifen-induced antitumorigenic/antiestrogenic action synergized by a selective aryl hydrocarbon receptor modulator. Cancer Res 61:3902–7
    [Google Scholar]
  87. 87. 
    Megna BW, Carney PR, Depke MG, Nukaya M, McNally J et al. 2017. The aryl hydrocarbon receptor as an antitumor target of synthetic curcuminoids in colorectal cancer. J. Surg. Res. 213:16–24
    [Google Scholar]
  88. 88. 
    Metidji A, Omenetti S, Crotta S, Li Y, Nye E et al. 2018. The environmental sensor AHR protects from inflammatory damage by maintaining intestinal stem cell homeostasis and barrier integrity. Immunity 49:353–62.e5 Erratum. 2019. Immunity 50:1542
    [Google Scholar]
  89. 89. 
    Mimura J, Ema M, Sogawa K, Fujii-Kuriyama Y. 1999. Identification of a novel mechanism of regulation of Ah (dioxin) receptor function. Genes Dev 13:20–25
    [Google Scholar]
  90. 90. 
    Miyoshi H, VanDussen KL, Malvin NP, Ryu SH, Wang Y et al. 2017. Prostaglandin E2 promotes intestinal repair through an adaptive cellular response of the epithelium. EMBO J 36:5–24
    [Google Scholar]
  91. 91. 
    Mizoguchi A, Yano A, Himuro H, Ezaki Y, Sadanaga T, Mizoguchi E. 2018. Clinical importance of IL-22 cascade in IBD. J. Gastroenterol. 53:465–74
    [Google Scholar]
  92. 92. 
    Monteleone I, Rizzo A, Sarra M, Sica G, Sileri P et al. 2011. Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract. Gastroenterology 141:237–48.e1
    [Google Scholar]
  93. 93. 
    Murray IA, Nichols RG, Zhang L, Patterson AD, Perdew GH. 2016. Expression of the aryl hydrocarbon receptor contributes to the establishment of intestinal microbial community structure in mice. Sci. Rep. 6:33969
    [Google Scholar]
  94. 94. 
    Naganuma M. 2019. Treatment with indigo naturalis for inflammatory bowel disease and other immune diseases. Immunol. Med. 42:16–21
    [Google Scholar]
  95. 95. 
    Natividad JM, Agus A, Planchais J, Lamas B, Jarry AC et al. 2018. Impaired aryl hydrocarbon receptor ligand production by the gut microbiota is a key factor in metabolic syndrome. Cell Metab 28:737–49.e4
    [Google Scholar]
  96. 96. 
    Nikolaus S, Schulte B, Al-Massad N, Thieme F, Schulte DM et al. 2017. Increased tryptophan metabolism is associated with activity of inflammatory bowel diseases. Gastroenterology 153:1504–16.e2
    [Google Scholar]
  97. 97. 
    Novikov O, Wang Z, Stanford EA, Parks AJ, Ramirez-Cardenas A et al. 2016. An aryl hydrocarbon receptor-mediated amplification loop that enforces cell migration in ER/PR/Her2 human breast cancer cells. Mol. Pharmacol. 90:674–88
    [Google Scholar]
  98. 98. 
    Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I et al. 2011. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478:197–203
    [Google Scholar]
  99. 99. 
    Paliy O, Kenche H, Abernathy F, Michail S 2009. High-throughput quantitative analysis of the human intestinal microbiota with a phylogenetic microarray. Appl. Environ. Microbiol. 75:3572–79
    [Google Scholar]
  100. 100. 
    Pandiyan P, Bhaskaran N, Zou M, Schneider E, Jayaraman S, Huehn J. 2019. Microbiome dependent regulation of Tregs and Th17 cells in mucosa. Front. Immunol. 10:426
    [Google Scholar]
  101. 101. 
    Parks OB, Pociask DA, Hodzic Z, Kolls JK, Good M. 2016. Interleukin-22 signaling in the regulation of intestinal health and disease. Front. . Cell Dev. Biol. 3:85
    [Google Scholar]
  102. 102. 
    Petriello MC, Hoffman JB, Vsevolozhskaya O, Morris AJ, Hennig B. 2018. Dioxin-like PCB 126 increases intestinal inflammation and disrupts gut microbiota and metabolic homeostasis. Environ. Pollut. 242:1022–32
    [Google Scholar]
  103. 103. 
    Petrulis JR, Kusnadi A, Ramadoss P, Hollingshead B, Perdew GH. 2003. The hsp90 co-chaperone XAP2 alters importin β recognition of the bipartite nuclear localization signal of the Ah receptor and represses transcriptional activity. J. Biol. Chem. 278:2677–85
    [Google Scholar]
  104. 104. 
    Poland A, Glover E. 1976. Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin by hepatic cytosol. Evidence that the binding species is receptor for induction of aryl hydrocarbon hydroxylase. J. Biol. Chem. 251:4936–46
    [Google Scholar]
  105. 105. 
    Pollet M, Krutmann J, Haarmann-Stemmann T. 2018. Commentary: usage of mitogen-activated protein kinase small molecule inhibitors: more than just inhibition!. Front. Pharmacol. 9:935
    [Google Scholar]
  106. 106. 
    Powell N, Pantazi E, Pavlidis P, Tsakmaki A, Li K et al. 2020. Interleukin-22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells. Gut 69:578–90
    [Google Scholar]
  107. 107. 
    Qiu J, Guo X, Chen ZM, He L, Sonnenberg GF et al. 2013. Group 3 innate lymphoid cells inhibit T-cell-mediated intestinal inflammation through aryl hydrocarbon receptor signaling and regulation of microflora. Immunity 39:386–99
    [Google Scholar]
  108. 108. 
    Qiu J, Heller JJ, Guo X, Chen ZM, Fish K et al. 2012. The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity 36:92–104
    [Google Scholar]
  109. 109. 
    Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF et al. 2008. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature 453:65–71
    [Google Scholar]
  110. 110. 
    Roager HM, Licht TR. 2018. Microbial tryptophan catabolites in health and disease. Nat. Commun. 9:3294
    [Google Scholar]
  111. 111. 
    Rodgers GP, Collins FS. 2020. Precision nutritionthe answer to “what to eat to stay healthy.”. JAMA 324:735–36
    [Google Scholar]
  112. 112. 
    Round JL, Mazmanian SK 2010. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. PNAS 107:12204–9
    [Google Scholar]
  113. 113. 
    Rui L, Reardon KF, Wood TK. 2005. Protein engineering of toluene ortho-monooxygenase of Burkholderia cepacia G4 for regiospecific hydroxylation of indole to form various indigoid compounds. Appl. Microbiol. Biotechnol. 66:422–29
    [Google Scholar]
  114. 114. 
    Safe S. 1990. Polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and related compounds: environmental and mechanistic considerations which support the development of toxic equivalency factors (TEFs). Crit. Rev. Toxicol. 21:51–88
    [Google Scholar]
  115. 115. 
    Safe S, Han H, Goldsby J, Mohankumar K, Chapkin RS. 2018. Aryl hydrocarbon receptor (AhR) ligands as selective AhR modulators: genomic studies. Curr. Opin. Toxicol 11–12:10–20
    [Google Scholar]
  116. 116. 
    Safe S, Lee SO, Jin UH. 2013. Role of the aryl hydrocarbon receptor in carcinogenesis and potential as a drug target. Toxicol. Sci. 135:1–16
    [Google Scholar]
  117. 117. 
    Schirmer M, Garner A, Vlamakis H, Xavier RJ. 2019. Microbial genes and pathways in inflammatory bowel disease. Nat. Rev. Microbiol. 17:497–511
    [Google Scholar]
  118. 118. 
    Schroeder JC, DiNatale BC, Murray IA, Flaveny CA, Liu Q et al. 2010. The uremic toxin 3-indoxyl sulfate is a potent endogenous agonist for the human aryl hydrocarbon receptor. Biochemistry 49:393–400
    [Google Scholar]
  119. 119. 
    Scott SA, Fu J, Chang PV 2020. Microbial tryptophan metabolites regulate gut barrier function via the aryl hydrocarbon receptor. PNAS 117:19376–87
    [Google Scholar]
  120. 120. 
    Sender R, Fuchs S, Milo R 2016. Revised estimates for the number of human and bacteria cells in the body. PLOS Biol 14:e1002533
    [Google Scholar]
  121. 121. 
    Seok S-H, Lee W, Jiang L, Molugu K, Zheng A et al. 2017. Structural hierarchy controlling dimerization and target DNA recognition in the AHR transcriptional complex. PNAS 114:5431–36
    [Google Scholar]
  122. 122. 
    Shiizaki K, Kido K, Mizuta Y. 2019. Insight into the relationship between aryl-hydrocarbon receptor and β-catenin in human colon cancer cells. PLOS ONE 14:e0224613
    [Google Scholar]
  123. 123. 
    Simon G, Peter M, Kathrin B, Harald S, Dietmar F, Johanna MG 2015. Serum tryptophan, kynurenine, phenylalanine, tyrosine and neopterin concentrations in 100 healthy blood donors. Pteridines 26:31–36
    [Google Scholar]
  124. 124. 
    Singh NP, Singh UP, Singh B, Price RL, Nagarkatti M, Nagarkatti PS. 2011. Activation of aryl hydrocarbon receptor (AhR) leads to reciprocal epigenetic regulation of FoxP3 and IL-17 expression and amelioration of experimental colitis. PLOS ONE 6:e23522
    [Google Scholar]
  125. 125. 
    Singh R, Chandrashekharappa S, Bodduluri SR, Baby BV, Hegde B et al. 2019. Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway. Nat. Commun. 10:89
    [Google Scholar]
  126. 126. 
    Soshilov A, Denison MS. 2008. Role of the Per/Arnt/Sim domains in ligand-dependent transformation of the aryl hydrocarbon receptor. J. Biol. Chem. 283:32995–3005
    [Google Scholar]
  127. 127. 
    Soshilov AA, Denison MS. 2014. Ligand promiscuity of aryl hydrocarbon receptor agonists and antagonists revealed by site-directed mutagenesis. Mol. Cell. Biol. 34:1707–19
    [Google Scholar]
  128. 128. 
    Spaepen S, Vanderleyden J, Remans R. 2007. Indole-3-acetic acid in microbial and microorganism-plant signaling. FEMS Microbiol. Rev. 31:425–48
    [Google Scholar]
  129. 129. 
    Stedtfeld RD, Stedtfeld TM, Fader KA, Williams MR, Bhaduri P et al. 2017. TCDD influences reservoir of antibiotic resistance genes in murine gut microbiome. FEMS Microbiol. Ecol. 93:fix058
    [Google Scholar]
  130. 130. 
    Stefanich EG, Rae J, Sukumaran S, Lutman J, Lekkerkerker A et al. 2018. Pre-clinical and translational pharmacology of a human interleukin-22 IgG fusion protein for potential treatment of infectious or inflammatory diseases. Biochem. Pharmacol. 152:224–35
    [Google Scholar]
  131. 131. 
    Sugihara K, Kitamura S, Yamada T, Okayama T, Ohta S et al. 2004. Aryl hydrocarbon receptor-mediated induction of microsomal drug-metabolizing enzyme activity by indirubin and indigo. Biochem. Biophys. Res. Commun. 318:571–78
    [Google Scholar]
  132. 132. 
    Sugimoto K, Ogawa A, Mizoguchi E, Shimomura Y, Andoh A et al. 2008. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J. Clin. Investig. 118:534–44
    [Google Scholar]
  133. 133. 
    Sun Y, Tang L, Liu Y, Hu C, Zhou B et al. 2019. Activation of aryl hydrocarbon receptor by dioxin directly shifts gut microbiota in zebrafish. Environ. Pollut. 255:113357
    [Google Scholar]
  134. 134. 
    Takamura T, Harama D, Matsuoka S, Shimokawa N, Nakamura Y et al. 2010. Activation of the aryl hydrocarbon receptor pathway may ameliorate dextran sodium sulfate-induced colitis in mice. Immunol. Cell Biol. 88:685–89
    [Google Scholar]
  135. 135. 
    Tlaskalová-Hogenová H, Stěpánková R, Kozáková H, Hudcovic T, Vannucci L et al. 2011. The role of gut microbiota (commensal bacteria) and the mucosal barrier in the pathogenesis of inflammatory and autoimmune diseases and cancer: contribution of germ-free and gnotobiotic animal models of human diseases. Cell. Mol. Immunol. 8:110–20
    [Google Scholar]
  136. 136. 
    van Baren N, Van den Eynde BJ. 2016. Tryptophan-degrading enzymes in tumoral immune resistance. Front. Immunol. 6:34
    [Google Scholar]
  137. 137. 
    Van der Sluis M, De Koning BAE, De Bruijn ACJM, Velcich A, Meijerink JPP et al. 2006. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 131:117–29
    [Google Scholar]
  138. 138. 
    Wagage S, John B, Krock BL, Hall AO, Randall LM et al. 2014. The aryl hydrocarbon receptor promotes IL-10 production by NK cells. J. Immunol. 192:1661–70
    [Google Scholar]
  139. 139. 
    Wang S-Q, Cheng L-S, Liu Y, Wang J-Y, Jiang W. 2016. Indole-3-carbinol (I3C) and its major derivatives: their pharmacokinetics and important roles in hepatic protection. Curr. Drug Metab. 17:401–9
    [Google Scholar]
  140. 140. 
    Wei H-X, Wang B, Li B 2020. IL-10 and IL-22 in mucosal immunity: driving protection and pathology. Front. Immunol. 11:1315
    [Google Scholar]
  141. 141. 
    Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA et al. 2009. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. PNAS 106:3698–703
    [Google Scholar]
  142. 142. 
    Williams BB, Van Benschoten AH, Cimermancic P, Donia MS, Zimmermann M et al. 2014. Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine. Cell Host Microbe 16:495–503
    [Google Scholar]
  143. 143. 
    Wilson SR, Joshi AD, Elferink CJ. 2013. The tumor suppressor Kruppel-like factor 6 is a novel aryl hydrocarbon receptor DNA binding partner. J. Pharmacol. Exp. Ther. 345:419–29
    [Google Scholar]
  144. 144. 
    Wlodarska M, Luo C, Kolde R, d'Hennezel E, Annand JW et al. 2017. Indoleacrylic acid produced by commensal Peptostreptococcus species suppresses inflammation. Cell Host Microbe 22:25–37.e6
    [Google Scholar]
  145. 145. 
    Xavier RJ, Podolsky DK. 2007. Unravelling the pathogenesis of inflammatory bowel disease. Nature 448:427–34
    [Google Scholar]
  146. 146. 
    Xie G, Peng Z, Raufman JP. 2012. Src-mediated aryl hydrocarbon and epidermal growth factor receptor cross talk stimulates colon cancer cell proliferation. Am. J. Physiol. Gastrointest. Liver Physiol. 302:G1006–1006
    [Google Scholar]
  147. 147. 
    Xu J, Ye Y, Huang F, Chen H, Wu H et al. 2016. Association between dioxin and cancer incidence and mortality: a meta-analysis. Sci. Rep. 6:38012
    [Google Scholar]
  148. 148. 
    Yamaguchi M, Hankinson O. 2019. 2,3,7,8-tetrachlorodibenzo-p-dioxin suppresses the growth of human colorectal cancer cells in vitro: implication of the aryl hydrocarbon receptor signaling. Int. J. Oncol. 54:1422–32
    [Google Scholar]
  149. 149. 
    Yeste A, Mascanfroni ID, Nadeau M, Burns EJ, Tukpah A-M et al. 2014. IL-21 induces IL-22 production in CD4+ T cells. Nat. Commun. 5:3753
    [Google Scholar]
  150. 150. 
    SW Yi, Ohrr H. 2014. Agent Orange exposure and cancer incidence in Korean Vietnam veterans: a prospective cohort study. Cancer 120:3699–706
    [Google Scholar]
  151. 151. 
    Yin J, Sheng B, Han B, Pu A, Yang K et al. 2016. The AhR is involved in the regulation of LoVo cell proliferation through cell cycle-associated proteins. Cell Biol. Int. 40:560–68
    [Google Scholar]
  152. 152. 
    Yu M, Wang Q, Ma Y, Li L, Yu K et al. 2018. Aryl hydrocarbon receptor activation modulates intestinal epithelial barrier function by maintaining tight junction integrity. Int. J. Biol. Sci. 14:69–77
    [Google Scholar]
  153. 153. 
    Yuan X, Dou Y, Wu X, Wei Z, Dai Y. 2017. Tetrandrine, an agonist of aryl hydrocarbon receptor, reciprocally modulates the activities of STAT3 and STAT5 to suppress Th17 cell differentiation. J. Cell. Mol. Med. 21:2172–83
    [Google Scholar]
  154. 154. 
    Zelante T, Iannitti RG, Cunha C, De Luca A, Giovannini G et al. 2013. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39:372–85
    [Google Scholar]
  155. 155. 
    Zhang L, Nichols RG, Correll J, Murray IA, Tanaka N et al. 2015. Persistent organic pollutants modify gut microbiota–host metabolic homeostasis in mice through aryl hydrocarbon receptor activation. Environ. Health Perspect. 123:679–88
    [Google Scholar]
  156. 156. 
    Zhang P, Jin T, Kumar Sahu S, Xu J, Shi Q et al. 2019. The distribution of tryptophan-dependent indole-3-acetic acid synthesis pathways in bacteria unraveled by large-scale genomic analysis. Molecules 24:1411
    [Google Scholar]
  157. 157. 
    Zhang S, Qin C, Safe SH. 2003. Flavonoids as aryl hydrocarbon receptor agonists/antagonists: effects of structure and cell context. Environ. Health Perspect. 111:1877–82
    [Google Scholar]
  158. 158. 
    Zhou Y, Li S, Huang L, Yang Y, Zhang L et al. 2018. A splicing mutation in aryl hydrocarbon receptor associated with retinitis pigmentosa. Hum. Mol. Genet. 27:2563–72
    [Google Scholar]
  159. 159. 
    Zhu J, Luo L, Tian L, Yin S, Ma X et al. 2018. Aryl hydrocarbon receptor promotes IL-10 expression in inflammatory macrophages through Src-STAT3 signaling pathway. Front. Immunol. 9:2033
    [Google Scholar]
  160. 160. 
    Zindl CL, Lai J-F, Lee YK, Maynard CL, Harbour SN et al. 2013. IL-22–producing neutrophils contribute to antimicrobial defense and restitution of colonic epithelial integrity during colitis. PNAS 110:1276873
    [Google Scholar]
/content/journals/10.1146/annurev-nutr-043020-090050
Loading
/content/journals/10.1146/annurev-nutr-043020-090050
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error