Skip to main content

Advertisement

SpringerLink
Log in

The Aryl Hydrocarbon Receptor (AHR) as a Potential Target for the Control of Intestinal Inflammation: Insights from an Immune and Bacteria Sensor Receptor

  • Published:
Clinical Reviews in Allergy & Immunology Aims and scope Submit manuscript

Abstract

The aryl hydrocarbon receptor (AHR) is widely expressed in immune and non-immune cells of the gut and its activation has been correlated to the outcome of inflammatory bowel diseases (IBD). In ulcerative colitis and Crohn’s disease, there is an excessive chronic inflammation with massive accumulation of leukocytes in the gut, in an attempt to constrain the invasion of pathogenic microorganisms on the damaged organ. Accordingly, it is known that dietary components, xenobiotics, and some chemicals or metabolites can activate AHR and induce the modulation of inflammatory responses. In fact, the AHR triggering by specific ligands during inflammatory conditions results in decreased IFNγ, IL-6, IL-12, TNF, IL-7, and IL-17, along with reduced microbial translocation and fibrosis in the gut. Moreover, upon AHR activation, there are increased regulatory mechanisms such as IL-10, IL-22, prostaglandin E2, and Foxp3, besides the production of anti-microbial peptides and epithelial repair. Most interestingly, commensal bacteria or their metabolites may also activate this receptor, thus contributing to the restoration of gut normobiosis and homeostasis. In line with that, Lactobacillus reuteri, Lactobacillus bulgaricus, or microbial products such as tryptophan metabolites, indole-3-pyruvic acid, urolithin A, short-chain fatty acids, dihydroxyquinoline, and others may regulate the inflammation by mechanisms dependent on AHR activation. Hence, here we discussed the potential modulatory role of AHR on intestinal inflammation, focused on the reestablishment of homeostasis through the receptor triggering by microbial metabolites. Finally, the development of AHR-based therapies derived from bacteria products could represent an important future alternative for controlling IBD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Dever DP, Adham ZO, Thompson B, Genestine M, Cherry J, Olschowka JA et al (2016) Aryl hydrocarbon receptor deletion in cerebellar granule neuron precursors impairs neurogenesis. Dev Neurobiol 76(5):533–550. https://doi.org/10.1002/dneu.22330

    Article  CAS  PubMed  Google Scholar 

  2. Kewley RJ, Whitelaw ML, Chapman-Smith A (2004) The mammalian basic helix-loop-helix/PAS family of transcriptional regulators. Int J Biochem Cell Biol 36(2):189–204

    Article  CAS  Google Scholar 

  3. Huang Z, Jiang Y, Yang Y, Shao J, Sun X, Chen J, Dong L, Zhang J (2013) 3,3′-Diindolylmethane alleviates oxazolone-induced colitis through Th2/Th17 suppression and Treg induction. Mol Immunol 53(4):335–344. https://doi.org/10.1016/j.molimm.2012.09.007

    Article  CAS  PubMed  Google Scholar 

  4. Rannug U, Rannug A, Sjoberg U, Li H, Westerholm R, Bergman J (1995) Structure elucidation of two tryptophan-derived, high affinity Ah receptor ligands. Chem Biol 2(12):841–845

    Article  CAS  Google Scholar 

  5. Schiering C, Wincent E, Metidji A, Iseppon A, Li Y, Potocnik AJ et al (2017) Feedback control of AHR signalling regulates intestinal immunity. Nature 542(7640):242–245. https://doi.org/10.1038/nature21080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yi T, Wang J, Zhu K, Tang Y, Huang S, Shui X et al (2018) Aryl hydrocarbon receptor: a new player of pathogenesis and therapy in cardiovascular diseases. Biomed Res Int 2018:6058784. https://doi.org/10.1155/2018/6058784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zorlu N, Hoffjan S, Haghikia A, Deyneko IV, Epplen JT (2019) Evaluation of variation in genes of the arylhydrocarbon receptor pathway for an association with multiple sclerosis. J Neuroimmunol 334:576979. https://doi.org/10.1016/j.jneuroim.2019.576979

    Article  CAS  PubMed  Google Scholar 

  8. Hui W, Dai Y (2019) Therapeutic potential of aryl hydrocarbon receptor ligands derived from natural products in rheumatoid arthritis. Basic Clin Pharmacol Toxicol. https://doi.org/10.1111/bcpt.13372

  9. Chaves Filho AJM, Lima CNC, Vasconcelos SMM, de Lucena DF, Maes M, Macedo D (2018) IDO chronic immune activation and tryptophan metabolic pathway: a potential pathophysiological link between depression and obesity. Prog Neuro-Psychopharmacol Biol Psychiatry 80(Pt C):234–249. https://doi.org/10.1016/j.pnpbp.2017.04.035

    Article  CAS  Google Scholar 

  10. Peppers J, Paller AS, Maeda-Chubachi T, Wu S, Robbins K, Gallagher K, Kraus JE (2019) A phase 2, randomized dose-finding study of tapinarof (GSK2894512 cream) for the treatment of atopic dermatitis. J Am Acad Dermatol 80(1):89–98 e3. https://doi.org/10.1016/j.jaad.2018.06.047

    Article  CAS  PubMed  Google Scholar 

  11. Smith SH, Jayawickreme C, Rickard DJ, Nicodeme E, Bui T, Simmons C, Coquery CM, Neil J, Pryor WM, Mayhew D, Rajpal DK, Creech K, Furst S, Lee J, Wu D, Rastinejad F, Willson TM, Viviani F, Morris DC, Moore JT, Cote-Sierra J (2017) Tapinarof is a natural AhR agonist that resolves skin inflammation in mice and humans. J Invest Dermatol 137(10):2110–2119. https://doi.org/10.1016/j.jid.2017.05.004

    Article  CAS  PubMed  Google Scholar 

  12. Natividad JM, Agus A, Planchais J, Lamas B, Jarry AC, Martin R, Michel ML, Chong-Nguyen C, Roussel R, Straube M, Jegou S, McQuitty C, le Gall M, da Costa G, Lecornet E, Michaudel C, Modoux M, Glodt J, Bridonneau C, Sovran B, Dupraz L, Bado A, Richard ML, Langella P, Hansel B, Launay JM, Xavier RJ, Duboc H, Sokol H (2018) Impaired aryl hydrocarbon receptor ligand production by the gut microbiota is a key factor in metabolic syndrome. Cell Metab 28(5):737–749 e4. https://doi.org/10.1016/j.cmet.2018.07.001

    Article  CAS  PubMed  Google Scholar 

  13. Takenaka MC, Gabriely G, Rothhammer V, Mascanfroni ID, Wheeler MA, Chao CC, Gutiérrez-Vázquez C, Kenison J, Tjon EC, Barroso A, Vandeventer T, de Lima KA, Rothweiler S, Mayo L, Ghannam S, Zandee S, Healy L, Sherr D, Farez MF, Prat A, Antel J, Reardon DA, Zhang H, Robson SC, Getz G, Weiner HL, Quintana FJ (2019) Control of tumor-associated macrophages and T cells in glioblastoma via AHR and CD39. Nat Neurosci 22(5):729–740. https://doi.org/10.1038/s41593-019-0370-y

    Article  CAS  PubMed  Google Scholar 

  14. Meyers JL, Winans B, Kelsaw E, Murthy A, Gerber S, Lawrence BP (2018) Environmental cues received during development shape dendritic cell responses later in life. PLoS One 13(11):e0207007. https://doi.org/10.1371/journal.pone.0207007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yu H, Jiang L, Liu R, Yang A, Yang X, Wang L, Zhang W, Che T (2019) Association between the ratio of aryl hydrocarbon receptor (AhR) in Th17 cells to AhR in Treg cells and SLE skin lesions. Int Immunopharmacol 69:257–262. https://doi.org/10.1016/j.intimp.2019.01.039

    Article  CAS  PubMed  Google Scholar 

  16. Li S, Bostick JW, Ye J, Qiu J, Zhang B, Urban JF Jr et al (2018) Aryl hydrocarbon receptor signaling cell intrinsically inhibits intestinal group 2 innate lymphoid cell function. Immunity 49(5):915–28 e5. https://doi.org/10.1016/j.immuni.2018.09.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mohinta S, Kannan AK, Gowda K, Amin SG, Perdew GH, August A (2015) Differential regulation of Th17 and T regulatory cell differentiation by aryl hydrocarbon receptor dependent xenobiotic response element dependent and independent pathways. Toxicol Sci 145(2):233–243. https://doi.org/10.1093/toxsci/kfv046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Benson JM, Shepherd DM (2011) Aryl hydrocarbon receptor activation by TCDD reduces inflammation associated with Crohn’s disease. Toxicol Sci 120(1):68–78. https://doi.org/10.1093/toxsci/kfq360

    Article  CAS  PubMed  Google Scholar 

  19. Ho SM, Lewis JD, Mayer EA, Plevy SE, Chuang E, Rappaport SM et al (2019) Challenges in IBD research: environmental triggers. Inflamm Bowel Dis 25(Supplement_2):S13–S23. https://doi.org/10.1093/ibd/izz076

    Article  PubMed  PubMed Central  Google Scholar 

  20. Giuffrida P, Cococcia S, Delliponti M, Lenti MV, Di Sabatino A (2019) Controlling gut inflammation by restoring anti-inflammatory pathways in inflammatory bowel disease. Cells 8(5). https://doi.org/10.3390/cells8050397

  21. de Souza PR, Guimaraes FR, Sales-Campos H, Bonfa G, Nardini V, Chica JEL et al (2018) Absence of NOD2 receptor predisposes to intestinal inflammation by a deregulation in the immune response in hosts that are unable to control gut dysbiosis. Immunobiology 223(10):577–585. https://doi.org/10.1016/j.imbio.2018.07.003

    Article  CAS  PubMed  Google Scholar 

  22. 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. https://doi.org/10.1038/srep33969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhang L, Nichols RG, Correll J, Murray IA, Tanaka N, Smith PB et al (2015) Persistent organic pollutants modify gut microbiota-host metabolic homeostasis in mice through aryl hydrocarbon receptor activation. Environ Health Perspect 123(7):679–688. https://doi.org/10.1289/ehp.1409055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Coqueiro AY, Raizel R, Bonvini A, Tirapegui J, Rogero MM (2019) Probiotics for inflammatory bowel diseases: a promising adjuvant treatment. Int J Food Sci Nutr 70(1):20–29. https://doi.org/10.1080/09637486.2018.1477123

    Article  PubMed  Google Scholar 

  25. Saez-Lara MJ, Gomez-Llorente C, Plaza-Diaz J, Gil A (2015) The role of probiotic lactic acid bacteria and bifidobacteria in the prevention and treatment of inflammatory bowel disease and other related diseases: a systematic review of randomized human clinical trials. Biomed Res Int (2015):505878. https://doi.org/10.1155/2015/505878

  26. Abraham BP, Quigley EMM (2017) Probiotics in inflammatory bowel disease. Gastroenterol Clin N Am 46(4):769–782. https://doi.org/10.1016/j.gtc.2017.08.003

    Article  Google Scholar 

  27. Lichtenstein L, Avni-Biron I, Ben-Bassat O (2016) Probiotics and prebiotics in Crohn’s disease therapies. Best Pract Res Clin Gastroenterol 30(1):81–88. https://doi.org/10.1016/j.bpg.2016.02.002

    Article  PubMed  Google Scholar 

  28. Lechuga S, Ivanov AI (2017) Disruption of the epithelial barrier during intestinal inflammation: quest for new molecules and mechanisms. Biochim Biophys Acta, Mol Cell Res 1864(7):1183–1194. https://doi.org/10.1016/j.bbamcr.2017.03.007

    Article  CAS  Google Scholar 

  29. Metidji A, Omenetti S, Crotta S, Li Y, Nye E, Ross E et al (2018) The environmental sensor AHR protects from inflammatory damage by maintaining intestinal stem cell homeostasis and barrier integrity. Immunity 49(2):353–362 e5. https://doi.org/10.1016/j.immuni.2018.07.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yin J, Yang K, Zhou C, Xu P, Xiao W, Yang H (2019) Aryl hydrocarbon receptor activation alleviates dextran sodium sulfate-induced colitis through enhancing the differentiation of goblet cells. Biochem Biophys Res Commun 514(1):180–186. https://doi.org/10.1016/j.bbrc.2019.04.136

    Article  CAS  PubMed  Google Scholar 

  31. Furumatsu K, Nishiumi S, Kawano Y, Ooi M, Yoshie T, Shiomi Y, Kutsumi H, Ashida H, Fujii-Kuriyama Y, Azuma T, Yoshida M (2011) A role of the aryl hydrocarbon receptor in attenuation of colitis. Dig Dis Sci 56(9):2532–2544. https://doi.org/10.1007/s10620-011-1643-9

    Article  CAS  PubMed  Google Scholar 

  32. Ji T, Xu C, Sun L, Yu M, Peng K, Qiu Y, Xiao W, Yang H (2015) Aryl hydrocarbon receptor activation down-regulates IL-7 and reduces inflammation in a mouse model of DSS-induced colitis. Dig Dis Sci 60(7):1958–1966. https://doi.org/10.1007/s10620-015-3632-x

    Article  CAS  PubMed  Google Scholar 

  33. Li Y, Innocentin S, Withers DR, Roberts NA, Gallagher AR, Grigorieva EF, Wilhelm C, Veldhoen M (2011) Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 147(3):629–640. https://doi.org/10.1016/j.cell.2011.09.025

    Article  CAS  PubMed  Google Scholar 

  34. Chen W, Pu A, Sheng B, Zhang Z, Li L, Liu Z, Wang Q, Li X, Ma Y, Yu M, Sun L, Qiu Y, Yang H (2017) Aryl hydrocarbon receptor activation modulates CD8alphaalpha(+)TCRalphabeta(+) IELs and suppression of colitis manifestations in mice. Biomed Pharmacother 87:127–134. https://doi.org/10.1016/j.biopha.2016.12.061

    Article  CAS  PubMed  Google Scholar 

  35. Hamabata T, Nakamura T, Masuko S, Maeda S, Murata T (2018) Production of lipid mediators across different disease stages of dextran sodium sulfate-induced colitis in mice. J Lipid Res 59(4):586–595. https://doi.org/10.1194/jlr.M079095

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Takamura T, Harama D, Matsuoka S, Shimokawa N, Nakamura Y, Okumura K, Ogawa H, Kitamura M, Nakao A (2010) Activation of the aryl hydrocarbon receptor pathway may ameliorate dextran sodium sulfate-induced colitis in mice. Immunol Cell Biol 88(6):685–689. https://doi.org/10.1038/icb.2010.35

    Article  CAS  PubMed  Google Scholar 

  37. Li J, Ueno A, Iacucci M, Fort Gasia M, Jijon HB, Panaccione R, Kaplan GG, Beck PL, Luider J, Barkema HW, Qian J, Gui X, Ghosh S (2017) Crossover subsets of CD4(+) T lymphocytes in the intestinal lamina propria of patients with Crohn’s disease and ulcerative colitis. Dig Dis Sci 62(9):2357–2368. https://doi.org/10.1007/s10620-017-4596-9

    Article  CAS  PubMed  Google Scholar 

  38. Monteleone I, Rizzo A, Sarra M, Sica G, Sileri P, Biancone L et al (2011) Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract. Gastroenterology 141(1):237–248, 48 e1. https://doi.org/10.1053/j.gastro.2011.04.007

    Article  CAS  PubMed  Google Scholar 

  39. 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(8):e23522. https://doi.org/10.1371/journal.pone.0023522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Goettel JA, Gandhi R, Kenison JE, Yeste A, Murugaiyan G, Sambanthamoorthy S et al (2016) AHR activation is protective against colitis driven by T cells in humanized mice. Cell Rep 17(5):1318–1329. https://doi.org/10.1016/j.celrep.2016.09.082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ye J, Qiu J, Bostick JW, Ueda A, Schjerven H, Li S et al (2017) The aryl hydrocarbon receptor preferentially marks and promotes gut regulatory T cells. Cell Rep 21(8):2277–2290. https://doi.org/10.1016/j.celrep.2017.10.114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Oh-Oka K, Kojima Y, Uchida K, Yoda K, Ishimaru K, Nakajima S et al (2017) Induction of colonic regulatory T cells by mesalamine by activating the aryl hydrocarbon receptor. Cell Mol Gastroenterol Hepatol 4(1):135–151. https://doi.org/10.1016/j.jcmgh.2017.03.010

    Article  PubMed  PubMed Central  Google Scholar 

  43. Parks OB, Pociask DA, Hodzic Z, Kolls JK, Good M (2015) Interleukin-22 signaling in the regulation of intestinal health and disease. Front Cell Dev Biol 3:85. https://doi.org/10.3389/fcell.2015.00085

    Article  PubMed  Google Scholar 

  44. Yeste A, Mascanfroni ID, Nadeau M, Burns EJ, Tukpah AM, Santiago A et al (2014) IL-21 induces IL-22 production in CD4+ T cells. Nat Commun 5:3753. https://doi.org/10.1038/ncomms4753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Qiu J, Guo X, Chen ZM, He L, Sonnenberg GF, Artis D 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(2):386–399. https://doi.org/10.1016/j.immuni.2013.08.002

    Article  CAS  PubMed  Google Scholar 

  46. Nizzoli G, Burrello C, Cribiu FM, Lovati G, Ercoli G, Botti F et al (2018) Pathogenicity of in vivo generated intestinal Th17 lymphocytes is IFNgamma dependent. J Crohns Colitis 12(8):981–992. https://doi.org/10.1093/ecco-jcc/jjy051

    Article  PubMed  Google Scholar 

  47. Lanis JM, Alexeev EE, Curtis VF, Kitzenberg DA, Kao DJ, Battista KD et al (2017) Tryptophan metabolite activation of the aryl hydrocarbon receptor regulates IL-10 receptor expression on intestinal epithelia. Mucosal Immunol 10(5):1133–1144. https://doi.org/10.1038/mi.2016.133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Monteleone I, Zorzi F, Marafini I, Di Fusco D, Dinallo V, Caruso R et al (2016) Aryl hydrocarbon receptor-driven signals inhibit collagen synthesis in the gut. Eur J Immunol 46(4):1047–1057. https://doi.org/10.1002/eji.201445228

    Article  CAS  PubMed  Google Scholar 

  49. Han B, Sheng B, Zhang Z, Pu A, Yin J, Wang Q, Yang K, Sun L, Yu M, Qiu Y, Xiao W, Yang H (2016) Aryl hydrocarbon receptor activation in intestinal obstruction ameliorates intestinal barrier dysfunction via suppression of MLCK-MLC phosphorylation pathway. Shock 46(3):319–328. https://doi.org/10.1097/SHK.0000000000000594

    Article  CAS  PubMed  Google Scholar 

  50. Ma Y, Wang Q, Yu K, Fan X, Xiao W, Cai Y, Xu P, Yu M, Yang H (2018) 6-Formylindolo(3,2-b)carbazole induced aryl hydrocarbon receptor activation prevents intestinal barrier dysfunction through regulation of claudin-2 expression. Chem Biol Interact 288:83–90. https://doi.org/10.1016/j.cbi.2018.04.020

    Article  CAS  PubMed  Google Scholar 

  51. Yu M, Wang Q, Ma Y, Li L, Yu K, Zhang Z et al (2018) Aryl hydrocarbon receptor activation modulates intestinal epithelial barrier function by maintaining tight junction integrity. Int J Biol Sci 14(1):69–77. https://doi.org/10.7150/ijbs.22259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Blossom SJ, Gilbert KM (2018) Epigenetic underpinnings of developmental immunotoxicity and autoimmune disease. Curr Opin Toxicol 10:23–30. https://doi.org/10.1016/j.cotox.2017.11.013

    Article  PubMed  Google Scholar 

  53. Ishimaru N, Takagi A, Kohashi M, Yamada A, Arakaki R, Kanno J et al (2009) Neonatal exposure to low-dose 2,3,7,8-tetrachlorodibenzo-p-dioxin causes autoimmunity due to the disruption of T cell tolerance. J Immunol 182(10):6576–6586. https://doi.org/10.4049/jimmunol.0802289

    Article  CAS  PubMed  Google Scholar 

  54. Mustafa A, Holladay SD, Witonsky S, Sponenberg DP, Karpuzoglu E, Gogal RM Jr (2011) A single mid-gestation exposure to TCDD yields a postnatal autoimmune signature, differing by sex, in early geriatric C57BL/6 mice. Toxicology 290(2–3):156–168. https://doi.org/10.1016/j.tox.2011.08.021

    Article  CAS  PubMed  Google Scholar 

  55. Mustafa A, Holladay S, Witonsky S, Zimmerman K, Manari A, Countermarsh S, Karpuzoglu E, Gogal R (2011) Prenatal TCDD causes persistent modulation of the postnatal immune response, and exacerbates inflammatory disease, in 36-week-old lupus-like autoimmune SNF1 mice. Birth Defects Res B Dev Reprod Toxicol 92(1):82–94. https://doi.org/10.1002/bdrb.20285

    Article  CAS  PubMed  Google Scholar 

  56. Holladay SD, Mustafa A, Gogal RM Jr (2011) Prenatal TCDD in mice increases adult autoimmunity. Reprod Toxicol 31(3):312–318. https://doi.org/10.1016/j.reprotox.2010.08.001

    Article  CAS  PubMed  Google Scholar 

  57. Mustafa A, Holladay SD, Witonsky S, Zimmerman K, Reilly CM, Sponenberg DP et al (2009) Gestational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin disrupts B-cell lymphopoiesis and exacerbates autoimmune disease in 24-week-old SNF1 mice. Toxicol Sci 112(1):133–143. https://doi.org/10.1093/toxsci/kfp177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Chinen I, Nakahama T, Kimura A, Nguyen NT, Takemori H, Kumagai A, Kayama H, Takeda K, Lee S, Hanieh H, Ripley B, Millrine D, Dubey PK, Nyati KK, Fujii-Kuriyama Y, Chowdhury K, Kishimoto T (2015) The aryl hydrocarbon receptor/microRNA-212/132 axis in T cells regulates IL-10 production to maintain intestinal homeostasis. Int Immunol 27(8):405–415. https://doi.org/10.1093/intimm/dxv015

    Article  CAS  PubMed  Google Scholar 

  59. Stedtfeld RD, Chai B, Crawford RB, Stedtfeld TM, Williams MR, Xiangwen S et al (2017) Modulatory influence of segmented filamentous bacteria on transcriptomic response of gnotobiotic mice exposed to TCDD. Front Microbiol 8:1708. https://doi.org/10.3389/fmicb.2017.01708

    Article  PubMed  PubMed Central  Google Scholar 

  60. Ianiro G, Tilg H, Gasbarrini A (2016) Antibiotics as deep modulators of gut microbiota: between good and evil. Gut 65(11):1906–1915. https://doi.org/10.1136/gutjnl-2016-312297

    Article  CAS  PubMed  Google Scholar 

  61. Silva MJ, Carneiro MB, dos Anjos PB, Pereira Silva D, Lopes ME, dos Santos LM (2015) The multifaceted role of commensal microbiota in homeostasis and gastrointestinal diseases. J Immunol Res 2015:321241. https://doi.org/10.1155/2015/321241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Marinelli L, Martin-Gallausiaux C, Bourhis JM, Beguet-Crespel F, Blottiere HM, Lapaque N (2019) Identification of the novel role of butyrate as AhR ligand in human intestinal epithelial cells. Sci Rep 9(1):643. https://doi.org/10.1038/s41598-018-37019-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Krishnan S, Ding Y, Saedi N, Choi M, Sridharan GV, Sherr DH et al (2018) Gut microbiota-derived tryptophan metabolites modulate inflammatory response in hepatocytes and macrophages. Cell Rep 23(4):1099–1111. https://doi.org/10.1016/j.celrep.2018.03.109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lamas B, Richard ML, Leducq V, Pham HP, Michel ML, Da Costa G et al (2016) CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat Med 22(6):598–605. https://doi.org/10.1038/nm.4102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Islam J, Sato S, Watanabe K, Watanabe T, Ardiansyah HK et al (2017) Dietary tryptophan alleviates dextran sodium sulfate-induced colitis through aryl hydrocarbon receptor in mice. J Nutr Biochem 42:43–50. https://doi.org/10.1016/j.jnutbio.2016.12.019

    Article  CAS  PubMed  Google Scholar 

  66. Cheng Y, Jin UH, Allred CD, Jayaraman A, Chapkin RS, Safe S (2015) Aryl hydrocarbon receptor activity of tryptophan metabolites in young adult mouse colonocytes. Drug Metab Dispos 43(10):1536–1543. https://doi.org/10.1124/dmd.115.063677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Cervantes-Barragan L, Chai JN, Tianero MD, Di Luccia B, Ahern PP, Merriman J et al (2017) Lactobacillus reuteri induces gut intraepithelial CD4(+)CD8alphaalpha(+) T cells. Science 357(6353):806–810. https://doi.org/10.1126/science.aah5825

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Liang H, Dai Z, Liu N, Ji Y, Chen J, Zhang Y et al (2018) Dietary L-tryptophan modulates the structural and functional composition of the intestinal microbiome in weaned piglets. Front Microbiol 9:1736. https://doi.org/10.3389/fmicb.2018.01736

    Article  PubMed  PubMed Central  Google Scholar 

  69. Ozcam M, Tocmo R, Oh JH, Afrazi A, Mezrich JD, Roos S et al (2019) Gut symbionts Lactobacillus reuteri R2lc and 2010 encode a polyketide synthase cluster that activates the mammalian aryl hydrocarbon receptor. Appl Environ Microbiol 85(10). https://doi.org/10.1128/AEM.01661-18

  70. Takamura T, Harama D, Fukumoto S, Nakamura Y, Shimokawa N, Ishimaru K et al (2011) Lactobacillus bulgaricus OLL1181 activates the aryl hydrocarbon receptor pathway and inhibits colitis. Immunol Cell Biol 89(7):817–822. https://doi.org/10.1038/icb.2010.165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Aoki R, Aoki-Yoshida A, Suzuki C, Takayama Y (2018) Indole-3-pyruvic acid, an aryl hydrocarbon receptor activator, suppresses experimental colitis in mice. J Immunol 201(12):3683–3693. https://doi.org/10.4049/jimmunol.1701734

    Article  CAS  PubMed  Google Scholar 

  72. Fukumoto S, Toshimitsu T, Matsuoka S, Maruyama A, Oh-Oka K, Takamura T, Nakamura Y, Ishimaru K, Fujii-Kuriyama Y, Ikegami S, Itou H, Nakao A (2014) Identification of a probiotic bacteria-derived activator of the aryl hydrocarbon receptor that inhibits colitis. Immunol Cell Biol 92(5):460–465. https://doi.org/10.1038/icb.2014.2

    Article  CAS  PubMed  Google Scholar 

  73. Ananthakrishnan AN, Khalili H, Konijeti GG, Higuchi LM, de Silva P, Korzenik JR et al (2013) A prospective study of long-term intake of dietary fiber and risk of Crohn’s disease and ulcerative colitis. Gastroenterology 145(5):970–977. https://doi.org/10.1053/j.gastro.2013.07.050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, de Roos P et al (2013) Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504(7480):451–455. https://doi.org/10.1038/nature12726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly YM et al (2013) The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341(6145):569–573. https://doi.org/10.1126/science.1241165

    Article  CAS  Google Scholar 

  76. Jin UH, Cheng Y, Park H, Davidson LA, Callaway ES, Chapkin RS et al (2017) Short chain fatty acids enhance aryl hydrocarbon (Ah) responsiveness in mouse colonocytes and Caco-2 human colon cancer cells. Sci Rep 7(1):10163. https://doi.org/10.1038/s41598-017-10824-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Singh R, Chandrashekharappa S, Bodduluri SR, Baby BV, Hegde B, Kotla NG et al (2019) Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway. Nat Commun 10(1):89. https://doi.org/10.1038/s41467-018-07859-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Hubbard TD, Liu Q, Murray IA, Dong F, Miller C 3rd, Smith PB et al (2019) Microbiota metabolism promotes synthesis of the human ah receptor agonist 2,8-dihydroxyquinoline. J Proteome Res 18(4):1715–1724. https://doi.org/10.1021/acs.jproteome.8b00946

    Article  CAS  PubMed  Google Scholar 

  79. Wei YL, Chen YQ, Gong H, Li N, Wu KQ, Hu W et al (2018) Fecal microbiota transplantation ameliorates experimentally induced colitis in mice by upregulating AhR. Front Microbiol 9:1921. https://doi.org/10.3389/fmicb.2018.01921

    Article  PubMed  PubMed Central  Google Scholar 

  80. Wang J, Wang P, Tian H, Tian F, Zhang Y, Zhang L, Gao X, Wang X (2018) Aryl hydrocarbon receptor/IL-22/Stat3 signaling pathway is involved in the modulation of intestinal mucosa antimicrobial molecules by commensal microbiota in mice. Innate Immunol 24(5):297–306. https://doi.org/10.1177/1753425918785016

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We would like to acknowledge the financial agencies and the Biosciences and Biotechnology Post Graduation Program from the Faculty of Pharmaceutical Sciences of Ribeirão Preto at the University of São Paulo that supported this work.

Funding

This work was supported by CAPES financial code 001, CNPq (310174/2016-3) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 2017/08651.1).

Author information

Authors and Affiliations

  1. Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil

    Larissa Pernomian & Cristina Ribeiro de Barros Cardoso

  2. Department of Biochemistry and Immunology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil

    Murillo Duarte-Silva

Authors
  1. Larissa Pernomian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Murillo Duarte-Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cristina Ribeiro de Barros Cardoso
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LP designed and wrote the review; MDS wrote and discussed the work; CRBC wrote, discussed, and reviewed the manuscript.

Corresponding author

Correspondence to Cristina Ribeiro de Barros Cardoso.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pernomian, L., Duarte-Silva, M. & de Barros Cardoso, C.R. The Aryl Hydrocarbon Receptor (AHR) as a Potential Target for the Control of Intestinal Inflammation: Insights from an Immune and Bacteria Sensor Receptor. Clinic Rev Allerg Immunol 59, 382–390 (2020). https://doi.org/10.1007/s12016-020-08789-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12016-020-08789-3

Keywords

Search

Navigation