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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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Cites
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“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
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“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.”
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“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…”
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“Other therapeutic effects of I3C and its precursors reported include modulation of inflammation in experimental animal models of multiple sclerosis (70) and other murine models (48) via AhR-dependent induction of FoxP3 regulatory T cells.”
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BackgroundThe WNT Framework in Shaping Immune Cell Responses During Bacterial Infections
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“The AHR pathway in IECs inhibited Wnt-b-catenin signaling and limited intestinal stem cell (ISC) proliferation by transcriptionally controlling Rnf43 and Znrf3 and E3 ubiquitin ligases that protect the stem cell niche and restore barrier homeostasis [122].”
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“Effective improvement of the intestinal barrier function is the key to alleviating pulmonary infection, such as intestinal permeability and intestinal mucosal immune (Manga et al., 2009; Metidji et al., 2018).”
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“Aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that, by restraining the Wnt/ β -catenin signaling pathway and epithelial differentiation, regulates stem cell proliferation and preserves the integrity of the intestinal barrier when activated [50].”
BackgroundHuang, F. (2024) · Biomedicines · doi:10.3390/biomedicines12122912 · Cited by 13
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T cell subsets and environmental factors in Citrobacter rodentium infection
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“AHR restrains the activity of the Wnt pathway by increasing the expression of the negative Wnt regulators Znrf3 and Rn43 [42].”
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“However, in addition to butyrate, other types of intestinal microbiota metabolites also play important roles in mediating the intestinal immune function, such as secondary bile acids (40) and tryptophan (41).”
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“Of note, AHR was found to be protective in suppression of the mutagen azoxymethane (AOM)induced colitis-associated colorectal carcinoma (CAC) [52].”
InfluentialSix Decades of Dopamine Hypothesis: Is Aryl Hydrocarbon Receptor the New D2?
Sfera, A. (2023) · Reports — Medical Cases Images and Videos · doi:10.3390/reports6030036 · Cited by 10
Building better barriers: how nutrition and undernutrition impact pediatric intestinal health
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“Furthermore, it is well demonstrated that AHR plays a protective role in IBD via modulation of intestinal immune response and barrier integrity (22, 42).”
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Myricetin protects mice against colitis by activating aryl hydrocarbon receptor signaling pathway
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“It was first identified as a mediator of dioxins, and increasing evidence shows that AhR is closely related with the intestinal inflammation (32–34).”
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“Mouse experiments have shown that IN acts on AHR ligands in intestinal epithelial cells to initiate Treg induction; AHR signaling plays an important role in the regeneration of intestinal epithelial cells 20 .”
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Targeting the Aryl Hydrocarbon Receptor in Stem Cells to Improve the Use of Food as Medicine
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“There is evidence that zinc and AHR activation have opposite functions in the cell proliferation since Zn activates the β -catenin/Wnt pathway which is inhibited by AHR [ 13,42 ].”
Liu, X., Zhou, J., Hou, Q., Zhou, Z., & Bai, Y. (2025) · Immunity & Ageing · doi:10.1186/s12979-025-00552-6 · Cited by 10
“AhR activation represents a fundamental signaling pathway that maintains intestinal immune homeostasis and epithelial barrier integrity [12].”
Wang, J., Jia, B., Miao, J., Li, D., Wang, Y., Han, L., Yin, Y., Zhang, Y., Wang, Y., Guo, L., et al. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05315-3 · Cited by 7
“Many studies have suggested that FOSB , RNF43 and RGCC are closely related to the inflammatory response of immune cells [47, 48].”
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“Restoring microbial AhR-ligand biosynthesis ameliorates DSS colitis [42], presumably because indole derivatives stimulate AhR in immune cells predominantly Group 3 Innate Lymphoid Cells (ILC3) to release IL-22 or activate AhR in IEC, thereby directing differentiation and function of ISC [43, 44].”
Dietary phytate primes epithelial antibacterial immunity in the intestine
Hashimoto‐Hill, S., Colapietro, L., Woo, V., Antonacci, S., Whitt, J., Engleman, L., & Alenghat, T. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.952994 · Cited by 6
“For example, microbiota-derived metabolites such as short-chain fatty acids (SCFAs) (13–15), indoles (16, 17), secondary bile acids (18, 19), and siderophores (20) have been described to protect during mouse models of infection.”
BackgroundMicrobiota and beneficial metabolites in colorectal cancer
González, A., Fullaondo, A., Odriozola, I., & Odriozola, A. (2024) · Advances in genetics · doi:10.1016/bs.adgen.2024.08.002 · Cited by 6
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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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