The Environmental Sensor AHR Protects from Inflammatory Damage by Maintaining Intestinal Stem Cell Homeostasis and Barrier Integrity
Open accessAbstract
The epithelium and immune compartment in the intestine are constantly exposed to a fluctuating external environment. Defective communication between these compartments at this barrier surface underlies susceptibility to infections and chronic inflammation. Environmental factors play a significant, but mechanistically poorly understood, role in intestinal homeostasis. We found that regeneration of intestinal epithelial cells (IECs) upon injury through infection or chemical insults was profoundly influenced by the environmental sensor aryl hydrocarbon receptor (AHR). IEC-specific deletion of Ahr resulted in failure to control C. rodentium infection due to unrestricted intestinal stem cell (ISC) proliferation and impaired differentiation, culminating in malignant transformation. AHR activation by dietary ligands restored barrier homeostasis, protected the stem cell niche, and prevented tumorigenesis via transcriptional regulation of of Rnf43 and Znrf3, E3 ubiquitin ligases that inhibit Wnt-β-catenin signaling and restrict ISC proliferation. Thus, activation of the AHR pathway in IECs guards the stem cell niche to maintain intestinal barrier integrity.
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Dietary supplementation with indole-3-carbinol activates the AHR in intestinal epithelial cells to restore intestinal barrier integrity in mice infected with Citrobacter rodentium.
“Dietary supplementation with indole-3-carbinol activates the AHR in intestinal epithelial cells to restore intestinal barrier integrity in mice infected with Citrobacter rodentium.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [653]
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Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche
Sato, T., Vries, R. G., Snippert, H. J., van de Wetering, M., Barker, N., Stange, D. E., van Es, J. H., Abo, A., Kujala, P., Peters, P. J., et al. (2009) · Nature · doi:10.1038/nature07935 · Cited by 7,204 · cited 1× · see citing works
“Wnt-b-Catenin Signaling The intestinal epithelium continuously renews itself from crypt stem cells that differentiate into short-lived specialized epithelial subtypes (Sato et al., 2009).”
BackgroundIdentification of stem cells in small intestine and colon by marker gene Lgr5
Barker, N., van Es, J. H., Kuipers, J., Kujala, P., van den Born, M., Cozijnsen, M., Haegebarth, A., Korving, J., Begthel, H., Peters, P. J., et al. (2007) · Nature · doi:10.1038/nature06196 · Cited by 5,687 · cited 6× · see citing works
“Since we were not able to maintain Ahr-deficient Lgr5Egfp-Ires-creErt2 reporter mice viable for long enough, we used mice heterozygous for Ahr deletion, which were partially affected.”
BackgroundMethodInfluentialZelante, T., Iannitti, R. G., Cunha, C., De Luca, A., Giovannini, G., Pieraccini, G., Zecchi, R., D’Angelo, C., Massi-Benedetti, C., Fallarino, F., et al. (2013) · Immunity · doi:10.1016/j.immuni.2013.08.003 · Cited by 2,614 · cited 2× · see citing works
“Although the AHR was originally described as a receptor for dioxin and other xenobiotics, it is now clear that physiological AHR ligands such as dietary components and tryptophan metabolites (Denison and Nagy, 2003; Hubbard et al., 2015; Lamas et al., 2016;McMillan and Bradfield, 2007; Moura-Alves et al., 2014; Zelant…”
BackgroundLiu, J. Z., van Sommeren, S., Huang, H., Ng, S. C., Alberts, R., Takahashi, A., Ripke, S., Lee, J. C., Jostins, L., Shah, T., et al. (2015) · Nature Genetics · doi:10.1038/ng.3359 · Cited by 2,603 · see citing works
Denison, M. S., & Nagy, S. R. (2003) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.43.100901.135828 · Cited by 1,895 · cited 2× · see citing works
“Although the AHR was originally described as a receptor for dioxin and other xenobiotics, it is now clear that physiological AHR ligands such as dietary components and tryptophan metabolites (Denison and Nagy, 2003; Hubbard et al., 2015; Lamas et al., 2016;McMillan and Bradfield, 2007; Moura-Alves et al., 2014; Zelant…”
BackgroundLamas, B., Richard, M. L., Leducq, V., Pham, H.-P., Michel, M.-L., Da Costa, G., Bridonneau, C., Jegou, S., Hoffmann, T. W., Natividad, J. M., et al. (2016) · Nature Medicine · doi:10.1038/nm.4102 · Cited by 1,482 · cited 2× · see citing works
“Although the AHR was originally described as a receptor for dioxin and other xenobiotics, it is now clear that physiological AHR ligands such as dietary components and tryptophan metabolites (Denison and Nagy, 2003; Hubbard et al., 2015; Lamas et al., 2016;McMillan and Bradfield, 2007; Moura-Alves et al., 2014; Zelant…”
BackgroundGrowing Self-Organizing Mini-Guts from a Single Intestinal Stem Cell: Mechanism and Applications
Sato, T., & Clevers, H. (2013) · Science · doi:10.1126/science.1234852 · Cited by 1,170 · cited 1× · see citing works
“In order to directly investigate the role of AHR in the process of crypt stem cell proliferation and differentiation, we generated colon organoids (Sato and Clevers, 2013).”
BackgroundTumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors
Koo, B., Spit, M., Jordens, I., Low, T. Y., Stange, D. E., van de Wetering, M., van Es, J. H., Mohammed, S., Heck, A. J. R., Maurice, M. M., et al. (2012) · Nature · doi:10.1038/nature11308 · Cited by 991 · cited 3× · see citing works
“Our results provide evidence that Wnt-b-catenin pathway dysregulation in Ahrdeficient IECs occurred upstream of b-catenin degradation, affecting the response to WNT signals themselves through the expression of the two related E3 ubiquitin ligases (ZNRF3 and RNF43) that degrade the Wnt frizzled receptors (Koo et al., 2…”
BackgroundZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner
Hao, H.-X., Xie, Y., Zhang, Y., Charlat, O., Oster, E., Avello, M., Lei, H., Mickanin, C., Liu, D., Ruffner, H., et al. (2012) · Nature · doi:10.1038/nature11019 · Cited by 962 · cited 2× · see citing works
“We focused on the tumor suppressors RNF43 and ZNRF3, which are transmembrane E3 ubiquitin ligases expressed in LGR5 stem cells that regulate WNT signals by targeting WNT receptors for degradation in an R-spondin-sensitive manner (Hao et al., 2012; Koo et al., 2012; Tsukiyama et al., 2015).”
BackgroundCancer as an overhealing wound: an old hypothesis revisited
Schäfer, M., & Werner, S. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2455 · Cited by 947 · see citing works
AH RECEPTOR SIGNALING PATHWAYS
Schmidt, J. V., & Bradfield, C. A. (1996) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.12.1.55 · Cited by 899 · cited 1× · see citing works
“AHR activation induces expression of a family of cytochrome P450 enzymes (CYP1 family), which metabolize AHR ligands, thereby terminating the stimulus (Schmidt and Bradfield, 1996).”
BackgroundThe Aryl Hydrocarbon Receptor Regulates Gut Immunity through Modulation of Innate Lymphoid Cells
Qiu, J., Heller, J. J., Guo, X., Chen, Z. E., Fish, K., Fu, Y., & Zhou, L. (2011) · Immunity · doi:10.1016/j.immuni.2011.11.011 · Cited by 860 · cited 2× · see citing works
“In the context of intestinal homeostasis, Ahr deficiency has detrimental consequences associated with loss of intraepithelial lymphocytes and ILC3 and absence of IL-22 production (Kiss et al., 2011; Lee et al., 2011; Li et al., 2011; Qiu et al., 2012).”
BackgroundHigh-fat diet enhances stemness and tumorigenicity of intestinal progenitors
Beyaz, S., Mana, M., Roper, J., Kedrin, D., Saadatpour, A., Hong, S., Bauer-Rowe, K. E., Xifaras, M. E., Akkad, A., Arias, E., et al. (2016) · Nature · doi:10.1038/nature17173 · Cited by 840 · cited 1× · see citing works
“, 2017) and in particular a diet high in fat was proposed to augment intestinal stem cell numbers and— in the context of Apc mutation—promote susceptibility to cancerogenesis (Beyaz et al., 2016).”
BackgroundExogenous Stimuli Maintain Intraepithelial Lymphocytes via Aryl Hydrocarbon Receptor Activation
Li, Y., Innocentin, S., Withers, D. R., Roberts, N. A., Gallagher, A., Grigorieva, E. F., Wilhelm, C., & Veldhoen, M. (2011) · Cell · doi:10.1016/j.cell.2011.09.025 · Cited by 816 · cited 2× · see citing works
“In the context of intestinal homeostasis, Ahr deficiency has detrimental consequences associated with loss of intraepithelial lymphocytes and ILC3 and absence of IL-22 production (Kiss et al., 2011; Lee et al., 2011; Li et al., 2011; Qiu et al., 2012).”
BackgroundSelf-citationNatural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles
Kiss, E. A., Vonarbourg, C., Kopfmann, S., Hobeika, E., Finke, D., Esser, C., & Diefenbach, A. (2011) · Science · doi:10.1126/science.1214914 · Cited by 801 · cited 2× · see citing works
“In the context of intestinal homeostasis, Ahr deficiency has detrimental consequences associated with loss of intraepithelial lymphocytes and ILC3 and absence of IL-22 production (Kiss et al., 2011; Lee et al., 2011; Li et al., 2011; Qiu et al., 2012).”
BackgroundLee, J. S., Cella, M., McDonald, K. G., Garlanda, C., Kennedy, G. D., Nukaya, M., Mantovani, A., Kopan, R., Bradfield, C. A., Newberry, R. D., et al. (2012) · Nature Immunology · doi:10.1038/ni.2187 · Cited by 777 · cited 1× · see citing works
“In the context of intestinal homeostasis, Ahr deficiency has detrimental consequences associated with loss of intraepithelial lymphocytes and ILC3 and absence of IL-22 production (Kiss et al., 2011; Lee et al., 2011; Li et al., 2011; Qiu et al., 2012).”
BackgroundBjeldanes, L. F., Kim, J. Y., Grose, K. R., Bartholomew, J. C., & Bradfield, C. A. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.21.9543 · Cited by 588 · cited 1× · see citing works
“Some of the strongest endogenous AHR ligands are derived from phytochemicals such as indole-3-carbinol (I3C) that is converted to the high-affinity AHR ligand ICZ by exposure to stomach acid (Bjeldanes et al., 1991; Kleman et al., 1994).”
BackgroundDioxin receptor is a ligand-dependent E3 ubiquitin ligase
Ohtake, F., Baba, A., Takada, I., Okada, M., Iwasaki, K., Miki, H., Takahashi, S., Kouzmenko, A., Nohara, K., Chiba, T., et al. (2007) · Nature · doi:10.1038/nature05683 · Cited by 585 · see citing works
Fruit, Vegetables, Dietary Fiber, and Risk of Colorectal Cancer
Terry, P., Giovannucci, E. L., Michels, K. B., Bergkvist, L., Hansen, H., Holmberg, L., & Wolk, A. (2001) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/93.7.525 · Cited by 578 · cited 1× · see citing works
“Dietary AHR Ligands Prevent Tumorigenesis and Restore Regulation of Wnt-b-Catenin Pathway The notion that a diet enriched in green vegetables reduces the risk of cancer formation is widely distributed, although scientific evidence from several clinical trials remains inconsistent (Mayne et al., 2016; Potter and Steinm…”
BackgroundFeedback control of AHR signalling regulates intestinal immunity
Schiering, C., Wincent, E., Metidji, A., Iseppon, A., Li, Y., Potocnik, A. J., Omenetti, S., Henderson, C. J., Wolf, C. R., Nebert, D. W., et al. (2017) · Nature · doi:10.1038/nature21080 · Cited by 537 · cited 4× · see citing works
“Our previous research established an important role of the AHR pathway in IECs as ‘‘gatekeeper’’ for the supply of ligands to intestinal immune cells (Schiering et al., 2017).”
BackgroundInfluentialSelf-citationNutrition, inflammation and cancer
Zitvogel, L., Pietrocola, F., & Kroemer, G. (2017) · Nature Immunology · doi:10.1038/ni.3754 · Cited by 446 · cited 1× · see citing works
“The impact of nutrition on tumorigenesis is widely documented (Zitvogel et al., 2017) and in particular a diet high in fat was proposed to augment intestinal stem cell numbers and— in the context of Apc mutation—promote susceptibility to cancerogenesis (Beyaz et al.”
BackgroundEmerging cytokine networks in colorectal cancer
West, N. R., McCuaig, S., Franchini, F., & Powrie, F. M. (2015) · Nature reviews. Immunology · doi:10.1038/nri3896 · Cited by 401 · cited 1× · see citing works
“This would explain why such mice expressed elevated levels of IL-6 that can promote malignant progression in colon cancer (West et al., 2015).”
BackgroundKryczek, I., Lin, Y., Nagarsheth, N., Peng, D., Zhao, L., Zhao, E., Vatan, L., Szeliga, W., Dou, Y., Owens, S. R., et al. (2014) · Immunity · doi:10.1016/j.immuni.2014.03.010 · Cited by 389 · cited 2× · see citing works
“IL-22 that has also been linked to colon cancer in mice and humans (Jiang et al., 2013; Kryczek et al., 2014) is elevated in VillinCreAhrfl/fl mice, probably due to increased levels of AHR ligands accessible to mucosal immune cells, as Ahr-deficient IECs do not express CYP1A1.”
BackgroundAdaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles
Hubbard, T. D., Murray, I. A., Bisson, W. H., Lahoti, T. S., Gowda, K., Amin, S. G., Patterson, A. D., & Perdew, G. H. (2015) · Scientific Reports · doi:10.1038/srep12689 · Cited by 377 · cited 2× · see citing works
“Although the AHR was originally described as a receptor for dioxin and other xenobiotics, it is now clear that physiological AHR ligands such as dietary components and tryptophan metabolites (Denison and Nagy, 2003; Hubbard et al., 2015; Lamas et al., 2016;McMillan and Bradfield, 2007; Moura-Alves et al., 2014; Zelant…”
BackgroundAhR sensing of bacterial pigments regulates antibacterial defence
Moura‐Alves, P., Fae, K. C., Houthuys, E., Dorhoi, A., Kreuchwig, A., Furkert, J., Barison, N., Diehl, A., Munder, A., Constant, P., et al. (2014) · Nature · doi:10.1038/nature13684 · Cited by 369 · cited 2× · see citing works
“Although the AHR was originally described as a receptor for dioxin and other xenobiotics, it is now clear that physiological AHR ligands such as dietary components and tryptophan metabolites (Denison and Nagy, 2003; Hubbard et al., 2015; Lamas et al., 2016;McMillan and Bradfield, 2007; Moura-Alves et al., 2014; Zelant…”
BackgroundNovellasdemunt, L., Antas, P., & Li, V. S. W. (2015) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00117.2015 · Cited by 339 · cited 1× · see citing works
“Aberrant Wnt-b-catenin activation is a hallmark of colorectal cancers, highlighting the importance of this pathway in intestinal homeostasis (Novellasdemunt et al., 2015).”
BackgroundSelf-citationIndole-3-carbinol as a chemopreventive and anti-cancer agent
Weng, J., Tsai, C.-H., Kulp, S. K., & Chen, C. (2008) · Cancer Letters · doi:10.1016/j.canlet.2008.01.033 · Cited by 328 · cited 1× · see citing works
“There are numerous reports on I3C as a cancer-preventive agent (Dı́az-Dı́az et al., 2016; Kim and Milner, 2005; Weng et al., 2008).”
BackgroundA constitutively active dioxin/aryl hydrocarbon receptor induces stomach tumors
Andersson, P., McGuire, J., Rubio, C., Gradin, K., Whitelaw, M. L., Pettersson, S., Hanberg, A., & Poellinger, L. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.152706299 · Cited by 310 · cited 1× · see citing works
“An important aspect of AHR activation is the necessity for negative feedback regulation as prolonged stimulation has detrimental effects (Andersson et al., 2002; Mitchell and Elferink, 2009).”
BackgroundKawajiri, K., Kobayashi, Y., Ohtake, F., Ikuta, T., Matsushima, Y., Mimura, J., Pettersson, S., Pollenz, R. S., Sakaki, T., Hirokawa, T., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0902132106 · Cited by 265 · cited 1× · see citing works
“In agreement with published data on increased levels of b-catenin in Ahr / mice (Kawajiri et al., 2009), both strains of mice with dysregulated AHR in IECs had substantially”
ResultDiet, nutrition, and cancer: past, present and future
Mayne, S. T., Playdon, M. C., & Rock, C. L. (2016) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.24 · Cited by 261 · cited 1× · see citing works
“Dietary AHR Ligands Prevent Tumorigenesis and Restore Regulation of Wnt-b-Catenin Pathway The notion that a diet enriched in green vegetables reduces the risk of cancer formation is widely distributed, although scientific evidence from several clinical trials remains inconsistent (Mayne et al., 2016; Potter and Steinm…”
BackgroundTargets for indole-3-carbinol in cancer prevention
Kim, Y. S., & Milner, J. A. (2005) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2004.10.007 · Cited by 236 · cited 1× · see citing works
“There are numerous reports on I3C as a cancer-preventive agent (Dı́az-Dı́az et al., 2016; Kim and Milner, 2005; Weng et al., 2008).”
BackgroundVegetables, fruit and phytoestrogens as preventive agents.
Potter, J. D., & Steinmetz, K. A. (1996) · PubMed · Cited by 220 · see citing works
Walisser, J. A., Glover, E., Pande, K., Liss, A. L., & Bradfield, C. A. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0504757102 · Cited by 212 · cited 1× · see citing works
“rodentium, such as FVB and AKR, express the low-affinity Ahr allele as do mice with a floxed Ahr locus (Walisser et al., 2005) and these are substantially more affected by C.”
BackgroundIL-22 is related to development of human colon cancer by activation of STAT3
Jiang, R., Wang, H., Deng, L., Hou, J., Shi, R., Yao, M., Gao, Y., Yao, A., Wang, X., Yu, L., et al. (2013) · BMC Cancer · doi:10.1186/1471-2407-13-59 · Cited by 183 · cited 1× · see citing works
“IL-22 that has also been linked to colon cancer in mice and humans (Jiang et al., 2013; Kryczek et al., 2014) is elevated in VillinAhr mice, probably due to increased levels of AHR ligands accessible to mucosal immune cells, as Ahr-deficient IECs do not express CYP1A1.”
BackgroundHost Susceptibility to the Attaching and Effacing Bacterial PathogenCitrobacter rodentium
Vallance, B. A., Deng, W., Jacobson, K., & Finlay, B. B. (2003) · Infection and Immunity · doi:10.1128/iai.71.6.3443-3453.2003 · Cited by 180 · cited 1× · see citing works
“rodentium is an attaching effacing pathogen that causes IEC apoptosis (Vallance et al., 2003) and necessitates replenishment of damaged IECs for maintenance of barrier integrity and repair processes.”
BackgroundThe Aryl Hydrocarbon Receptor sans Xenobiotics: Endogenous Function in Genetic Model Systems
McMillan, B. J., & Bradfield, C. A. (2007) · Molecular Pharmacology · doi:10.1124/mol.107.037259 · Cited by 177 · cited 1× · see citing works
“Although the AHR was originally described as a receptor for dioxin and other xenobiotics, it is now clear that physiological AHR ligands such as dietary components and tryptophan metabolites (Denison and Nagy, 2003; Hubbard et al., 2015; Lamas et al., 2016;McMillan and Bradfield, 2007; Moura-Alves et al., 2014; Zelant…”
BackgroundA Role of the Aryl Hydrocarbon Receptor in Attenuation of Colitis
Furumatsu, K., Nishiumi, S., Kawano, Y., Ooi, M., Yoshie, T., Shiomi, Y., Kutsumi, H., Ashida, H., Fujii‐Kuriyama, Y., Azuma, T., et al. (2011) · Digestive Diseases and Sciences · doi:10.1007/s10620-011-1643-9 · Cited by 166 · cited 12× · see citing works
“In order to accelerate the process of tumorigenesis, we applied the widely used AOM/DSS (dextran sulfate sodium) model in which one dose of AOM was followed by two cycles of DSS.”
BackgroundInfluentialPorcupine inhibitor suppresses paracrine Wnt-driven growth of Rnf43;Znrf3 -mutant neoplasia
Koo, B., van Es, J. H., van den Born, M., & Clevers, H. C. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1508113112 · Cited by 157 · see citing works
Automated brightfield morphometry of 3D organoid populations by OrganoSeg
Borten, M. A., Bajikar, S. S., Sasaki, N., Clevers, H. C., & Janes, K. A. (2018) · Scientific Reports · doi:10.1038/s41598-017-18815-8 · Cited by 150 · cited 1× · see citing works
“The percentage of viable organoids was determined using OrganoSeg software (Borten et al., 2018).”
MethodTiming is everything: Consequences of transient and sustained AhR activity
Mitchell, K. A., & Elferink, C. J. (2008) · Biochemical Pharmacology · doi:10.1016/j.bcp.2008.10.028 · Cited by 120 · cited 1× · see citing works
“An important aspect of AHR activation is the necessity for negative feedback regulation as prolonged stimulation has detrimental effects (Andersson et al., 2002; Mitchell and Elferink, 2009).”
BackgroundMolecular Role of RNF43 in Canonical and Noncanonical Wnt Signaling
Tsukiyama, T., Fukui, A., Terai, S., Fujioka, Y., Shinada, K., Takahashi, H., Yamaguchi, T. P., Ohba, Y., & Hatakeyama, S. (2015) · Molecular and Cellular Biology · doi:10.1128/mcb.00159-15 · Cited by 101 · cited 1× · see citing works
“We focused on the tumor suppressors RNF43 and ZNRF3, which are transmembrane E3 ubiquitin ligases expressed in LGR5 stem cells that regulate WNT signals by targeting WNT receptors for degradation in an R-spondin-sensitive manner (Hao et al., 2012; Koo et al., 2012; Tsukiyama et al., 2015).”
BackgroundDíaz-Díaz, C. J., Ronnekleiv‐Kelly, S. M., Nukaya, M., Geiger, P. G., Balbo, S., Dator, R., Megna, B. W., Carney, P. R., Bradfield, C. A., & Kennedy, G. D. (2016) · Annals of Surgery · doi:10.1097/sla.0000000000001874 · Cited by 96 · cited 3× · see citing works
“The progression from inflammation to tumorigenesis is well established (Sch€ afer and Werner, 2008) and our mice readily developed mixed colon adenomas/adenocarcinomas in the standard AOM/DSS model in line with previous data in global Ahr / mice (Dı́az-Dı́az et al., 2016) or even with the mutagen AOM alone.”
BackgroundResultR-Spondin 2 signaling mediates susceptibility to fatal infectious diarrhea
Papapietro, O., Teatero, S., Thanabalasuriar, A., Yuki, K., Diez, E., Zhu, L., Kang, E., Dhillon, S., Muise, A., Durocher, Y., et al. (2013) · Nature Communications · doi:10.1038/ncomms2816 · Cited by 66 · cited 2× · see citing works
“rodentium infection varies between different strains of mice and susceptible strains are characterized by aberrant R-spondin 2 (RSPO2)-mediated Wnt-b-catenin activation which causes excessive ISC proliferation and poor differentiation into epithelial subtypes (Papapietro et al., 2013).”
BackgroundLuecke-Johansson, S., Gralla, M., Rundqvist, H., Ho, J. C., Johnson, R. S., Gradin, K., & Poellinger, L. (2017) · Molecular and Cellular Biology · doi:10.1128/mcb.00630-16 · Cited by 64 · cited 1× · see citing works
“In vitro studies on cell lines proposed that AHR functions as part of an E3 ubiquitin ligase complex that serves to ubiquinate b-catenin and target it for degradation (Luecke-Johansson et al., 2017; Ohtake et al., 2007).”
BackgroundKleman, M. I., Poellinger, L., & Gustafsson, J.-Α. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)37666-4 · Cited by 40 · cited 1× · see citing works
“Some of the strongest endogenous AHR ligands are derived from phytochemicals such as indole-3-carbinol (I3C) that is converted to the high-affinity AHR ligand ICZ by exposure to stomach acid (Bjeldanes et al., 1991; Kleman et al., 1994).”
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Loh, J. S., Mak, W. Q., Tan, L. K. S., Ng, C. X., Chan, H. H., Yeow, S. H., Foo, J. B., Ong, Y. S., How, C. W., & Khaw, K. Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01743-1 · Cited by 1,193 · see citing works
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Kayama, H., Okumura, R., & Takeda, K. (2020) · Annual Review of Immunology · doi:10.1146/annurev-immunol-070119-115104 · Cited by 765 · see citing works
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Glencross, D. A., Ho, T.-R., Camiña, N., Hawrylowicz, C. M., & Pfeffer, P. E. (2020) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.01.179 · Cited by 726 · see citing works
Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway
Singh, R., Chandrashekharappa, S., Bodduluri, S. R., Baby, B. V., Hegde, B., Kotla, N. G., Hiwale, A. A., Saiyed, T., Patel, P., Vijay-Kumar, M., et al. (2019) · Nature Communications · doi:10.1038/s41467-018-07859-7 · Cited by 713 · see citing works
Laursen, M. F., Sakanaka, M., von Burg, N., Mörbe, U., Andersen, D., Moll, J. M., Pekmez, C. T., Rivollier, A., Michaelsen, K. F., Mølgaard, C., et al. (2021) · Nature Microbiology · doi:10.1038/s41564-021-00970-4 · Cited by 596 · see citing works
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Pabst, O., Hornef, M. W., Schaap, F. G., Cerovic, V., Clavel, T., & Bruns, T. (2023) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-023-00771-6 · Cited by 462 · see citing works
“Indole, which is derived from dietary tryptophan, activates the aryl hydrocarbon receptor in gut epithelial cells and contributes to their survival and proliferation 89 .”
BackgroundHost–microbiota maladaptation in colorectal cancer
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Hodgkinson, K. M., Abbar, F. E., Dobranowski, P., Manoogian, J., Butcher, J., Figeys, D., Mack, D. R., & Stintzi, A. (2022) · Clinical Nutrition · doi:10.1016/j.clnu.2022.10.024 · Cited by 447 · see citing works
AHR in the intestinal microenvironment: safeguarding barrier function
Stockinger, B., Shah, K., & Wincent, E. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00430-8 · Cited by 414 · see citing works
Self-citationImmune regulation through tryptophan metabolism
Seo, S., & Kwon, B. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-01028-7 · Cited by 416 · see citing works
Epithelial Toll-like receptors and their role in gut homeostasis and disease
Burgueño, J. F., & Abreu, M. T. (2020) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0261-4 · Cited by 404 · see citing works
Interleukin-22 protects intestinal stem cells against genotoxic stress
Gronke, K., Hernández, P. P., Zimmermann, J., Klose, C. S. N., Kofoed-Branzk, M., Guendel, F., Witkowski, M., Tizian, C., Amann, L., Schumacher, F., et al. (2019) · Nature · doi:10.1038/s41586-019-0899-7 · Cited by 373 · see citing works
Neuronal programming by microbiota regulates intestinal physiology
Obata, Y., Castaño, Á., Boeing, S., Bon‐Frauches, A. C., Fung, C., Fallesen, T. L., de Agüero, M. G., Yılmaz, B., Lopes, R., Huseynova, A., et al. (2020) · Nature · doi:10.1038/s41586-020-1975-8 · Cited by 356 · see citing works
Self-citationImplication of Intestinal Barrier Dysfunction in Gut Dysbiosis and Diseases
Stolfi, C., Maresca, C., Monteleone, G., & Laudisi, F. (2022) · Biomedicines · doi:10.3390/biomedicines10020289 · Cited by 353 · see citing works
“In particular, Ahrfl/fl-Villin-Cre+ mice showed impaired resistance against Citrobacter rodentium infection characterized by bacterial dissemination in the liver and in the spleen, increased epithelial damage, and decreased expression of Muc2 and Car4 genes, thus confirming a crucial role of AhR in the maintenance of…”
BackgroundMeng, D., Sommella, E., Salviati, E., Campiglia, P., Ganguli, K. A., Djebali, K., Zhu, W., & Walker, W. A. (2020) · Pediatric Research · doi:10.1038/s41390-019-0740-x · Cited by 338 · see citing works
Fructose stimulated de novo lipogenesis is promoted by inflammation
Todoric, J., Di Caro, G., Reibe, S., Henstridge, D. C., Green, C. R., Vrbanac, A., Ceteci, F., Conche, C., McNulty, R., Shalapour, S., et al. (2020) · Nature Metabolism · doi:10.1038/s42255-020-0261-2 · Cited by 328 · see citing works
Ehrlich, A. M., Pacheco, A. R., Henrick, B. M., Taft, D. H., Xu, G., Huda, M. N., Mishchuk, D. O., Goodson, M. L., Slupsky, C. M., Barile, D., et al. (2020) · BMC Microbiology · doi:10.1186/s12866-020-02023-y · Cited by 314 · see citing works
Intestinal epithelial cells: At the interface of the microbiota and mucosal immunity
Soderholm, A. T., & Pedicord, V. A. (2019) · Immunology · doi:10.1111/imm.13117 · Cited by 281 · see citing works
Michaudel, C., Danne, C., Agus, A., Magniez, A., Aucouturier, A., Spatz, M., Lefèvre, A., Kirchgesner, J., Rolhion, N., Wang, Y., et al. (2022) · Gut · doi:10.1136/gutjnl-2022-327337 · Cited by 269 · see citing works
Pernomian, L., Duarte-Silva, M., & Cardoso, C. R. D. B. (2020) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-020-08789-3 · Cited by 261 · see citing works
“quired for the development of this population from local stem cells [29].”
BackgroundThe Role of Microbiota in Infant Health: From Early Life to Adulthood
Yao, Y., Cai, X. T., Ye, Y., Wang, F., Chen, F., & Zheng, C. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.708472 · Cited by 264 · see citing works
Zhang, Z., Tang, H., Chen, P., Xie, H., & Tao, Y. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0074-5 · Cited by 251 · see citing works
Intestinal microbiota-derived tryptophan metabolites are predictive of Ah receptor activity
Dong, F., Hao, F., Murray, I. A., Smith, P. B. W., Koo, I., Tindall, A. M., Kris‐Etherton, P. M., Gowda, K., Amin, S., Patterson, A. D., et al. (2020) · Gut Microbes · doi:10.1080/19490976.2020.1788899 · Cited by 252 · see citing works
“In addition to promoting epithelial xenobiotic metabolism, AHR activity within the crypt-villi axis of the gastrointestinal tract regulates epithelial cell differentiation and repair.(11,24-26) In combination, these and other AHRmediated activities contribute to epithelial integrity and shape the immune/microbiota lan…”
BackgroundMicrobiota Metabolites in Health and Disease
McCarville, J. L., Chen, G. Y., Cuevas, V. D., Troha, K., & Ayres, J. S. (2020) · Annual Review of Immunology · doi:10.1146/annurev-immunol-071219-125715 · Cited by 251 · see citing works
The microbiota-immune axis as a central mediator of gut-brain communication
Fung, T. C. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104714 · Cited by 228 · see citing works
New Insights Into Gut-Bacteria-Derived Indole and Its Derivatives in Intestinal and Liver Diseases
Li, X., Zhang, B., Hu, Y., & Zhao, Y. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.769501 · Cited by 235 · see citing works
“The activation of the AhR pathway in intestinal epithelial cells (IECs) is vital for protecting the stem cell niched and maintaining intestinal barrier integrity (Metidji et al., 2018).”
BackgroundHan, J., Tao, Z., Wang, J., Zhang, L., Yu, C., Kang, Z., Xie, Y., Li, J., Lu, S., Cui, Y., et al. (2023) · Nature Microbiology · doi:10.1038/s41564-023-01363-5 · Cited by 218 · see citing works
Obesity II: Establishing causal links between chemical exposures and obesity
Heindel, J., Howard, S., Agay-Shay, K., Arrebola, J., Audouze, K., Babin, P. J., Barouki, R., Bansal, A., Blanc, E. B., Cave, M., et al. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.115015 · Cited by 173 · see citing works
The aryl hydrocarbon receptor as a mediator of host-microbiota interplay
Dong, F., & Perdew, G. H. (2020) · Gut Microbes · doi:10.1080/19490976.2020.1859812 · Cited by 193 · see citing works
“Importantly, AHR activation provides protection for the stem cell niche in the intestinal epithelium through restricting cell proliferation and influencing differentiation and enhances overall barrier function.(123) A different story emerges from studies designed to examine the influence of AHR activation in the liver…”
BackgroundLamas, B., Breyner, N. M., & Houdeau, É. (2020) · Particle and Fibre Toxicology · doi:10.1186/s12989-020-00349-z · Cited by 177 · see citing works
“Moreover, a diet rich in AhR ligands can prevent or decrease CRC in mice: first, by inhibiting the Wnt-β-catenin pathway, which is known to be crucial for the proliferation of intestinal stem cells [228], and second, by regulating components of the DNA damage response (DDR) in epithelial stem cells through a mechanism…”
BackgroundPanda, S. K., Peng, V., Sudan, R., Ulezko Antonova, A., Di Luccia, B., Ohara, T. E., Fachi, J. L., Grajales-Reyes, G. E., Jaeger, N., Trsan, T., et al. (2023) · Immunity · doi:10.1016/j.immuni.2023.01.023 · Cited by 174 · see citing works
Citrobacter rodentium–host–microbiota interactions: immunity, bioenergetics and metabolism
Mullineaux-Sanders, C., Sanchez‐Garrido, J., Hopkins, E. G. D., Shenoy, A. R., Barry, R. E., & Frankel, G. M. (2019) · Nature Reviews Microbiology · doi:10.1038/s41579-019-0252-z · Cited by 170 · see citing works
Vyhlídalová, B., Krasulová, K., Pečinková, P., Marcalíková, A., Vrzal, R., Zemánková, L., Vančo, J., Trávnı́ček, Z., Vondráček, J., Karasová, M., et al. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21072614 · Cited by 170 · see citing works
A gut microbiota-bile acid axis promotes intestinal homeostasis upon aspirin-mediated damage
Li, T., Ding, N., Guo, H., Hua, R., Lin, Z., Tian, H., Yu, Y., Fan, D., Yuan, Z., Gonzalez, F. J., et al. (2024) · Cell Host & Microbe · doi:10.1016/j.chom.2023.12.015 · Cited by 157 · see citing works
The aryl hydrocarbon receptor and the gut–brain axis
Barroso, A., Mahler, J. V., Fonseca-Castro, P. H., & Quintana, F. J. (2021) · Cellular & Molecular Immunology · doi:10.1038/s41423-020-00585-5 · Cited by 152 · see citing works
“In addition, these mice display defective differentiation of intestinal stem cells, resulting in the malignant transformation of IECs.(58) Conversely, AHR activation by dietary ligands limits intestinal stem cell proliferation by regulating the E3 ubiquitin ligases Rnf43 and Znrf3, suppressing Wnt/βCatenin signaling.”
BackgroundInfluentialIntestinal epithelial cell metabolism at the interface of microbial dysbiosis and tissue injury
Rath, E., & Haller, D. (2022) · Mucosal Immunology · doi:10.1038/s41385-022-00514-x · Cited by 149 · see citing works
Lai, W., Deng, W.-F., Xu, S., Zhao, J., Xu, D., Liu, Y., Guo, Y., Wang, M., He, F.-S., Ye, S.-W., et al. (2019) · Psychological Medicine · doi:10.1017/s0033291719003027 · Cited by 141 · see citing works
The Ah Receptor: Adaptive Metabolism, Ligand Diversity, and the Xenokine Model
Avilla, M. N., Malecki, K. M. C., Hahn, M. E., Wilson, R. H., & Bradfield, C. A. (2020) · Chemical Research in Toxicology · doi:10.1021/acs.chemrestox.9b00476 · Cited by 141 · see citing works
Epithelial cells: liaisons of immunity
Larsen, S. B., Cowley, C. J., & Fuchs, E. V. (2019) · Current Opinion in Immunology · doi:10.1016/j.coi.2019.11.004 · Cited by 142 · see citing works
Gut-Brain Connection: Microbiome, Gut Barrier, and Environmental Sensors
Gwak, M.-G., & Chang, S. (2021) · Immune Network · doi:10.4110/in.2021.21.e20 · Cited by 143 · see citing works
Aryl Hydrocarbon Receptor (AHR) Ligands as Selective AHR Modulators (SAhRMs)
Safe, S. H., Jin, U.-H., Park, H., Chapkin, R. S., & Jayaraman, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186654 · Cited by 136 · see citing works
Zhuang, H., Ren, X., Jiang, F., & Zhou, P. (2023) · Molecular Medicine · doi:10.1186/s10020-023-00614-9 · Cited by 137 · see citing works
Kynurenine emerges from the shadows – Current knowledge on its fate and function
Marszałek‐Grabska, M., Walczak, K., Gaweł, K., Wicha-Komsta, K., Wnorowska, S., Wnorowski, A., & Turski, W. A. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107845 · Cited by 126 · see citing works
Gut microbiota‐stem cell niche crosstalk: A new territory for maintaining intestinal homeostasis
Ma, N., Chen, X., Johnston, L. J., & Ma, X. (2022) · iMeta · doi:10.1002/imt2.54 · Cited by 123 · see citing works
“Fortunately, after supple-menting with microbial ‐ generated AhR ligands, regulation of Wnt ‐ β ‐ Catenin signaling can be restored and progression of tumorigenesis can be paused [109].”
BackgroundLi, X., Zhang, Z., Zabed, H. M., Yun, J., Zhang, G., & Qi, X. (2020) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.202000461 · Cited by 124 · see citing works
The path toward using microbial metabolites as therapies
Descamps, H. C., Herrmann, B. I., Wiredu, D., & Thaiss, C. A. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.05.063 · Cited by 121 · see citing works
“proliferation and differentiation [58] Squamous Cell Head and Neck Cancer, SCB01A, phase 2 NCT03020823”
BackgroundEndothelial AHR activity prevents lung barrier disruption in viral infection
Major, J., Crotta, S., Finsterbusch, K., Chakravarty, P., Shah, K., Frederico, B., D’Antuono, R., Green, M. J., Meader, L., Suárez‐Bonnet, A., et al. (2023) · Nature · doi:10.1038/s41586-023-06287-y · Cited by 122 · see citing works
Self-citationMicrobiota and cancer: host cellular mechanisms activated by gut microbial metabolites
Tsvetikova, S. A., & Koshel, E. I. (2020) · International Journal of Medical Microbiology · doi:10.1016/j.ijmm.2020.151425 · Cited by 111 · see citing works
Bock, K. W. (2019) · Biochemical Pharmacology · doi:10.1016/j.bcp.2019.06.015 · Cited by 110 · see citing works
Amino Acid Trp: The Far Out Impacts of Host and Commensal Tryptophan Metabolism
Grifka‐Walk, H. M., Jenkins, B. R., & Kominsky, D. J. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.653208 · Cited by 112 · see citing works
Tryptophan and its metabolites in normal physiology and cancer etiology
Perez‐Castro, L., Garcia, R., Venkateswaran, N., Barnes, S. D., & Conacci‐Sorrell, M. (2021) · FEBS Journal · doi:10.1111/febs.16245 · Cited by 104 · see citing works
Chen, C., Cao, Z., Lei, H., Zhang, C., Wu, M., Huang, S., Li, X., Xie, D., Liu, M., Zhang, L., et al. (2024) · Advanced Science · doi:10.1002/advs.202404545 · Cited by 105 · see citing works
The complex biology of aryl hydrocarbon receptor activation in cancer and beyond
Opitz, C. A., Holfelder, P., Prentzell, M. T., & Trump, S. (2023) · Biochemical Pharmacology · doi:10.1016/j.bcp.2023.115798 · Cited by 101 · see citing works
Okumura, R., & Takeda, K. (2024) · Seminars in Immunopathology · doi:10.1007/s00281-024-01026-5 · Cited by 100 · see citing works
“AHR deficiency in intestinal epithelial cells has been linked to increased susceptibility to pathogenic bacterial infection because of reduced expression of Muc2 and carbonic anhydrase 4 (Car4) [73].”
Wang, D., Li, D., Zhang, Y., Chen, J., Zhang, Y., Liao, C., Qin, S., Tian, Y., Zhang, Z., & Xu, F. (2020) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2020.07.017 · Cited by 94 · see citing works
Nutrition Regulates Innate Immunity in Health and Disease
Nobs, S. P., Zmora, N., & Elinav, E. (2020) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-120919-094440 · Cited by 89 · see citing works
“AHR ligands directly regulate resistance to enteric infection by promoting ILC3 and Th17 responses (162) as well as promoting intestinal barrier integrity (120).”
BackgroundThe aryl hydrocarbon receptor: structure, signaling, physiology and pathology
Coumoul, X., Barouki, R., Esser, C., Haarmann‐Stemmann, T., Lawrence, B. P., Lehmann, J., Moura‐Alves, P., Murray, I. A., Opitz, C. A., Perdew, G. H., et al. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02500-8 · Cited by 103 · see citing works
Endothelial sensing of AHR ligands regulates intestinal homeostasis
Wiggins, B. G., Wang, Y.-F., Burke, A., Grunberg, N., Vlachaki Walker, J. M., Dore, M., Chahrour, C., Pennycook, B. R., Sanchez-Garrido, J., Vernia, S., et al. (2023) · Nature · doi:10.1038/s41586-023-06508-4 · Cited by 89 · see citing works
Self-citationMolecular Mechanisms of Microbiota-Mediated Pathology in Irritable Bowel Syndrome
Mishima, Y., & Ishihara, S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228664 · Cited by 89 · see citing works
Modulating AHR function offers exciting therapeutic potential in gut immunity and inflammation
Chen, Y., Wang, Y., Fu, Y., Yin, Y., & Xu, K. (2023) · Cell & Bioscience · doi:10.1186/s13578-023-01046-y · Cited by 91 · see citing works
Tapinarof validates the aryl hydrocarbon receptor as a therapeutic target: A clinical review
Silverberg, J. I., Boguniewicz, M., Quintana, F. J., Clark, R. A., Gross, L., Hirano, I., Tallman, A. M., Brown, P. M., Fredericks, D., Rubenstein, D. S., et al. (2023) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2023.12.013 · Cited by 87 · see citing works
Aryl hydrocarbon receptor: Its roles in physiology
Kou, Z., & Dai, W. H. (2021) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114428 · Cited by 91 · see citing works
The microbiome: an integral player in immune homeostasis and inflammation in the respiratory tract
Perdijk, O., Azzoni, R., & Marsland, B. J. (2023) · Physiological Reviews · doi:10.1152/physrev.00020.2023 · Cited by 88 · see citing works
Innate Lymphoid Cell-Epithelial Cell Modules Sustain Intestinal Homeostasis
Diefenbach, A., Gnafakis, S., & Shomrat, O. (2020) · Immunity · doi:10.1016/j.immuni.2020.02.016 · Cited by 82 · see citing works
Iyer, N. R., & Corr, S. C. (2021) · Nutrients · doi:10.3390/nu13124259 · Cited by 80 · see citing works
“GPR35 (predicted), Aryl hydrocarbon receptor (AHR), Pregnane X receptor (PXR) [106,111] - Indole derivatives promote expression of anti-microbials [108] - Indoles regulate epithelial repair and differentiation [109,112] - Indoles promote IL-10 signalling to increase goblet cell differentiation and strengthen mucus bar…”
BackgroundGut microbiota: sculptors of the intestinal stem cell niche in health and inflammatory bowel disease
Markandey, M., Bajaj, A., Ilott, N. E., Kedia, S., Travis, S. P. L., Powrie, F. M., & Ahuja, V. (2021) · Gut Microbes · doi:10.1080/19490976.2021.1990827 · Cited by 79 · see citing works
Padhi, P., Worth, C., Zenitsky, G. D., Jin, H., Sambamurti, K., Anantharam, V., Kanthasamy, A., & Kanthasamy, A. G. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.836605 · Cited by 80 · see citing works
Microbial Tryptophan Metabolism Tunes Host Immunity, Metabolism, and Extraintestinal Disorders
Liu, M., Nieuwdorp, M., de Vos, W. M., & Rampanelli, E. (2022) · Metabolites · doi:10.3390/metabo12090834 · Cited by 83 · see citing works
“In mice, IEC-specific AhR deletion leads to aberrant inflammation and impairs IEC differentiation, rendering mice more susceptible to pathogenic infection due to a defective intestinal barrier and malignant transformation due to uncontrolled intestinal stem cell proliferation [104].”
BackgroundZhang, L., Ji, Q., Chen, Q., Wei, Z., Liu, S., Zhang, L., Zhang, Y., Li, Z., Liu, H., & Sui, H. (2023) · International Journal of Biological Sciences · doi:10.7150/ijbs.85712 · Cited by 78 · see citing works
“Genotyping was performed at 4 weeks by PCR for AhR fl/fl mice and villin-CreER mice, as described previously [27,28].”
Microbial metabolites in colorectal tumorigenesis and cancer therapy
Liu, Y., Lau, H. C.-H., & Yu, J. Q. (2023) · Gut Microbes · doi:10.1080/19490976.2023.2203968 · Cited by 80 · see citing works
Sun, X., Zhao, D.-Y., Zhou, Y.-C., Wang, Q., Qin, G., & Yao, S. (2020) · World Journal of Gastroenterology · doi:10.3748/wjg.v26.i45.7173 · Cited by 75 · see citing works
Shamoon, M., Martin, N. M., & O'Brien, C. L. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104344 · Cited by 73 · see citing works
Manipulation of epithelial integrity and mucosal immunity by host and microbiota‐derived metabolites
Kayama, H., & Takeda, K. (2020) · European Journal of Immunology · doi:10.1002/eji.201948478 · Cited by 74 · see citing works
The role of mucosal barriers in human gut health
Seo, K., Seo, J.-M., Yeun, J., Choi, H., Kim, Y., & Chang, S.-Y. (2021) · Archives of Pharmacal Research · doi:10.1007/s12272-021-01327-5 · Cited by 75 · see citing works
Ji, C., Deng, Y., Yang, A., Lu, Z., Chen, Y., Liu, X., Han, L., & Zou, C. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.01092 · Cited by 72 · see citing works
The Role of the Microbiome in Food Allergy: A Review
Nance, C. L., Deniskin, R., Diaz, V. C., Paul, M., Anvari, S., & Anagnostou, A. (2020) · Children · doi:10.3390/children7060050 · Cited by 71 · see citing works
Direct and indirect effects of pathogenic bacteria on the integrity of intestinal barrier
Shu, L.-Z., Ding, Y.-D., Xue, Q.-M., Cai, W., & Deng, H. (2023) · Therapeutic Advances in Gastroenterology · doi:10.1177/17562848231176427 · Cited by 77 · see citing works
Modulation of Immune Responses by Nutritional Ligands of Aryl Hydrocarbon Receptor
de Juan, A., & Segura, É. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.645168 · Cited by 69 · see citing works
“Importantly, AhR activation in intestinal epithelial cells is also involved in barrier repair during colitis (39).”
BackgroundQian, M., Liu, J., Zhao, D., Cai, P., Pan, C., Jia, W., Gao, Y., Zhang, Y., Zhang, N., Zhang, Y., et al. (2021) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2021.08.014 · Cited by 69 · see citing works
“mRNA levels of stem cell markers, although 1 previous study showed that Ahr deletion in IECs enhanced stem cell proliferation upon injury through infection or chemical insults.(12) The gene expression of Il22 and Il17 in the proximal small intestine was not different between ethanol-fed Ahr mice and control mice.”
BackgroundMethodResultInfluentialThe aryl hydrocarbon receptor contributes to tissue adaptation of intestinal eosinophils in mice
Diny, N. L., Schonfeldova, B., Shapiro, M., Winder, M. L., Varsani-Brown, S., & Stockinger, B. (2022) · The Journal of Experimental Medicine · doi:10.1084/jem.20210970 · Cited by 69 · see citing works
Self-citationXun, W., Fu, Q., Shi, L., Cao, T., Jiang, H., & Ma, Z. (2021) · International Immunopharmacology · doi:10.1016/j.intimp.2021.107989 · Cited by 68 · see citing works
Pinto, C. J. G., Ávila‐Gálvez, M. Á., Lian, Y., Moura‐Alves, P., & dos Santos, C. N. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102622 · Cited by 69 · see citing works
“The AHR modulates the expression of negative regulators of WNT signalling, E3 ubiquitin ligases ring finger protein 43 (RNF43) and zinc/ring finger protein 3 (ZNRF3) to ensure a coordinated IECs regeneration [95].”
BackgroundGut/rumen-mammary gland axis in mastitis: Gut/rumen microbiota–mediated “gastroenterogenic mastitis”
Hu, X., He, Z., Zhao, C., He, Y., Qiu, M., Xiang, K., Zhang, N., & Fu, Y. (2023) · Journal of Advanced Research · doi:10.1016/j.jare.2023.02.009 · Cited by 70 · see citing works
Targeting AhR as a Novel Therapeutic Modality against Inflammatory Diseases
Cannon, A. S., Nagarkatti, P. S., & Nagarkatti, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms23010288 · Cited by 67 · see citing works
“Studies have implicated I3C in intestinal stem cell development and proposed regulatory mechanisms such as Wnt and Notch signalling [75,76].”
BackgroundThe Kynurenine Pathway and Indole Pathway in Tryptophan Metabolism Influence Tumor Progression
Lu, Z., Zhang, C., Zhang, J., Su, W., Wang, G., & Wang, Z. (2025) · Cancer Medicine · doi:10.1002/cam4.70703 · Cited by 74 · see citing works
“When the intestinal barrier is damaged, the lack of AhR downregulates tumor suppressor genes Znrf3 and Rnf43 [197], resulting in abnormal activation of the Wnt- β-catenin signaling pathway, which disrupts epithelial cell differentiation from crypt stem cells and worsens gut barrier repair [196].”
Dvořák, Z., Sokol, H., & Mani, S. (2020) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2020.09.013 · Cited by 64 · see citing works
“The roles of the AhR in the pathogenesis of inflammatory bowel diseases are widely known(16), and the insufficient or inappropriate activation of the AhR is associated with inflammatory conditions (8).”
BackgroundDepletion of dietary aryl hydrocarbon receptor ligands alters microbiota composition and function
Brawner, K. M., Yeramilli, V. A., Duck, L. W., Van Der Pol, W., Smythies, L. E., Morrow, C. D., Elson, C. O., & Martin, C. A. (2019) · Scientific Reports · doi:10.1038/s41598-019-51194-w · Cited by 64 · see citing works
Gargaro, M., Manni, G., Scalisi, G., Puccetti, P., & Fallarino, F. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094644 · Cited by 64 · see citing works
“AhR is expressed in immune and non-immune cell types, such as intestinal epithelial cells (IECs) [73], macrophages (MΦ) [74], dendritic cells (DCs) [75], T cells [76], double- positive intraepithelial lymphocytes (DP IELs) [77], and innate lymphoid cells (ILCs) [32].”
BackgroundHan, H., Safe, S. H., Jayaraman, A., & Chapkin, R. S. (2021) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-043020-090050 · Cited by 63 · see citing works
“Limiting AhR ligand availability promotes colitis-associated colorectal tumorigenesis in R26LSL-Cyp1a1Villin-Cre compound mice, while supplementation with I3C suppressed colorectal tumorigenesis in those mice (88).”
BackgroundInfluentialTryptophan metabolism in brain tumors — IDO and beyond
Platten, M., Friedrich, M., Wainwright, D. A., Panitz, V., & Opitz, C. A. (2021) · Current Opinion in Immunology · doi:10.1016/j.coi.2021.03.005 · Cited by 62 · see citing works
Yi, Y., Lu, W., Shen, L., Wu, Y. F., & Zhang, Z. (2023) · Experimental Hematology and Oncology · doi:10.1186/s40164-023-00410-5 · Cited by 62 · see citing works
“Reportedly, indole compounds as ligands to aryl hydrocarbon receptor-mediated transcriptional activity enhance proliferation of intestinal stem cells (ISCs) [48] and promote anti-oxidant and antiinflammatory immune responses [49, 50].”
BackgroundShah, K., Maradana, M. R., Delàs, M. J., Metidji, A., Graelmann, F. J., Llorian, M., Chakravarty, P., Li, Y., Tolaini, M., Shapiro, M., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-29098-7 · Cited by 57 · see citing works
Self-citationAryl hydrocarbon receptor utilises cellular zinc signals to maintain the gut epithelial barrier
Hu, X., Xiao, W., Lei, Y., Green, A., Lee, X., Maradana, M. R., Gao, Y., Xie, X., Wang, R., Chennell, G., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-41168-y · Cited by 61 · see citing works
“Generation and culture of mouse ileum organoids mouse ileum crypts were isolated from the ileum segment of WT and villin cre Ahr fl / fl miceinaPBSsolutioncontaining2 mMEDTA 24 .”
BackgroundMethodSelf-citationPostbiotic-Enabled Targeting of the Host-Microbiota-Pathogen Interface: Hints of Antibiotic Decline?
Puccetti, M., Xiroudaki, S., Ricci, M., & Giovagnoli, S. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12070624 · Cited by 70 · see citing works
“Considering the previously discussed activity of AhR in protecting from inflammatory damage and maintaining barrier integrity [131], it is not surprising that a diet rich in AhR ligands can prevent or halt tumorigenesis [293] and that restoring AhR signaling rescues metabolic syndrome [294], a disorder characterized b…”
BackgroundFei, Y., Zhang, S., Han, S., Qiu, B., Lu, Y., Huang, W., Li, F., Chen, D., Berglund, B., Xiao, H., et al. (2022) · Research · doi:10.34133/2022/9863845 · Cited by 57 · see citing works
“Activation of AHR induces expression of CYP1A1, a family of cytochrome P450 enzymes [19].”
BackgroundIndole scaffolds as a promising class of the aryl hydrocarbon receptor ligands
Dvořák, Z., Poulíková, K., & Mani, S. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113231 · Cited by 56 · see citing works
Urbauer, E., Aguanno, D., Mindermann, N., Omer, H., Metwaly, A., Krammel, T., Faro, T., Remke, M., Reitmeier, S., Bärthel, S., et al. (2024) · Cell Host & Microbe · doi:10.1016/j.chom.2024.06.013 · Cited by 55 · see citing works
- Authors
- Metidji, A., Omenetti, S., Crotta, S., Li, Y., Nye, E., Ross, E., Li, V., Maradana, M. R., Schiering, C., & Stockinger, B.
- Affiliations
- The Francis Crick Institute (GB)
- University of London (GB)
- Corresponding author
- Schiering, Chris
- Stockinger, Brigitta
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2018-08
- Volume
- 49
- Issue
- 2
- Pages
- 353-362.e5
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC6104739
- OpenAlex
- W2887221348
- Cited by
- 402
- References
- 45
- Citations by year
- 2026: 37 · 2025: 50 · 2024: 56 · 2023: 63 · 2022: 55 · 2021: 60 · 2020: 50 · 2019: 30
- FWCI
- 12.45
- Type
- journal article
- Language
- en
- Update notices
- erratum (2019-06-18)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Immunity (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Cancer Research UK (FC001105, FC001159, 103156/B/13/Z, 19691)
- Fondation Acteria
- Medical Research Council
- Wellcome Trust (100910/Z/13/Z)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Keywords
- aryl hydrocarbon receptor, intestinal stem cells, intestinal barrier integrity, intestinal homeostasis, intestinal inflammation, RNF43, ZNRF3, Wnt/β-catenin signaling, E3 ubiquitin ligase, stem cell niche, intestinal tumorigenesis
- MeSH terms
- Animals, Cell Differentiation, Cell Line, Enterobacteriaceae Infections, Epithelial Cells, Humans, Intestinal Mucosa, Mice, Inbred C57BL, Stem Cells, Receptors, Aryl Hydrocarbon, Mice, Knockout, Tight Junctions, Citrobacter rodentium, Ubiquitin-Protein Ligases, Cell Proliferation, Mice, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors, HEK293 Cells, Wnt Signaling Pathway, Carcinogenesis
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