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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.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [653]
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“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 85
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 84
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 86
“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 79
“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 84
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
Shamoon, M., Martin, N. M., & O'Brien, C. L. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104344 · Cited by 73
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 77
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 76
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 73
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 75
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 81
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 71
“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 71
“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 71
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
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 73
“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 72
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 72
“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 81
“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 65
“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
Gargaro, M., Manni, G., Scalisi, G., Puccetti, P., & Fallarino, F. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094644 · Cited by 66
“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 68
“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 65
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
“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 58
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 62
“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 59
“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
“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 58
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 57
Metadata
- 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
- Health Sciences › Medicine › Gastroenterology › 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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