Endothelial sensing of AHR ligands regulates intestinal homeostasis

Wiggins, Benjamin G.; Wang, Yi-Fang; Burke, Alice; Grunberg, Nil; Vlachaki Walker, Julia M.; Dore, Marian; Chahrour, Catherine; Pennycook, Betheney R.; Sanchez-Garrido, Julia; Vernia, Santiago; Barr, Alexis R.; Frankel, Gad; Birdsey, Graeme M.; Randi, Anna M.; Schiering, Chris

doi:10.1038/s41586-023-06508-4

Cited by 89Barrier Structure and Function StudiesToxic Organic Pollutants ImpactInflammatory Bowel Disease

Endothelial sensing of AHR ligands regulates intestinal homeostasis

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Wiggins, Benjamin G., Wang, Yi-Fang, Burke, Alice, Grunberg, Nil, Vlachaki Walker, Julia M., Dore, Marian, Chahrour, Catherine, Pennycook, Betheney R. +7 more·2023·Nature

DOI 10.1038/s41586-023-06508-4PMC PMC10533400

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Abstract

Endothelial cells line the blood and lymphatic vasculature, and act as an essential physical barrier, control nutrient transport, facilitate tissue immunosurveillance and coordinate angiogenesis and lymphangiogenesis 1,2 . In the intestine, dietary and microbial cues are particularly important in the regulation of organ homeostasis. However, whether enteric endothelial cells actively sense and integrate such signals is currently unknown. Here we show that the aryl hydrocarbon receptor (AHR) acts as a critical node for endothelial cell sensing of dietary metabolites in adult mice and human primary endothelial cells. We first established a comprehensive single-cell endothelial atlas of the mouse small intestine, uncovering the cellular complexity and functional heterogeneity of blood and lymphatic endothelial cells. Analyses of AHR-mediated responses at single-cell resolution identified tissue-protective transcriptional signatures and regulatory networks promoting cellular quiescence and vascular normalcy at steady state. Endothelial AHR deficiency in adult mice resulted in dysregulated inflammatory responses and the initiation of proliferative pathways. Furthermore, endothelial sensing of dietary AHR ligands was required for optimal protection against enteric infection. In human endothelial cells, AHR signalling promoted quiescence and restrained activation by inflammatory mediators. Together, our data provide a comprehensive dissection of the effect of environmental sensing across the spectrum of enteric endothelia, demonstrating that endothelial AHR signalling integrates dietary cues to maintain tissue homeostasis by promoting endothelial cell quiescence and vascular normalcy.

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Dietary supplementation with indole-3-carbinol also triggers the activation of endothelial AHR in LPS-treated mice, leading to reduced inflammatory activation in endothelial cells and improved gut vascular barrier integrity.
“dietary supplementation with indole-3-carbinol also triggers the activation of endothelial AHR in LPS-treated mice. This leads to reduced inflammatory activation in endothelial cells, resulting in improved gut vascular barrier integrity.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [654]

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Aryl hydrocarbon receptor mediates laminar fluid shear stress-induced CYP1A1 activation and cell cycle arrest in vascular endothelial cells
Han, Z., Miwa, Y., Obikane, H., Mitsumata, M., Takahashi‐Yanaga, F., Morimoto, S., & Sasaguri, T. (2007) · Cardiovascular Research · doi:10.1093/cvr/cvm095 · Cited by 60 · see citing works
ADAMTS18+ villus tip telocytes maintain a polarized VEGFA signaling domain and fenestrations in nutrient-absorbing intestinal blood vessels
Bernier‐Latmani, J., Mauri, C., Marcone, R., Renevey, F., Durot, S., He, L., Vanlandewijck, M., Maclachlan, C., Davanture, S., Zamboni, N., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-31571-2 · Cited by 59 · see citing works
Cell-intrinsic Aryl Hydrocarbon Receptor signalling is required for the resolution of injury-induced colonic stem cells
Shah, 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
NRP2 as an Emerging Angiogenic Player; Promoting Endothelial Cell Adhesion and Migration by Regulating Recycling of α5 Integrin
Alghamdi, A. A. A., Benwell, C. J., Atkinson, S. J., et al. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00395 · Cited by 53 · see citing works
CD36 as a Therapeutic Target for Endothelial Dysfunction in Stroke
Cho, S. (2012) · Current Pharmaceutical Design · doi:10.2174/138161212802002760 · Cited by 52 · see citing works
SOX Transcription Factors in Endothelial Differentiation and Endothelial-Mesenchymal Transitions
Yao, Y., Yao, J., & Boström, K. I. (2019) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2019.00030 · Cited by 46 · see citing works
A novel concept in antiangiogenic and antitumoral therapy: multitarget destabilization of short-lived mRNAs by the zinc finger protein ZFP36L1
Planel, S., Salomon, A., Jalinot, P., Feige, J., & Cherradi, N. (2010) · Oncogene · doi:10.1038/onc.2010.341 · Cited by 45 · see citing works
Endothelial cell-specific aryl hydrocarbon receptor knockout mice exhibit hypotension mediated, in part, by an attenuated angiotensin II responsiveness
Agbor, L. N., Elased, K. M., & Walker, M. K. (2011) · Biochemical Pharmacology · doi:10.1016/j.bcp.2011.06.011 · Cited by 45 · see citing works
TAK1 Prevents Endothelial Apoptosis and Maintains Vascular Integrity
Naito, H., Iba, T., Wakabayashi, T., Tai-Nagara, I., Suehiro, J., Jia, W., Eino, D., Sakimoto, S., Muramatsu, F., Kidoya, H., et al. (2019) · Developmental Cell · doi:10.1016/j.devcel.2018.12.002 · Cited by 45 · see citing works
Antiproliferative and antiangiogenic effects of 3-methylcholanthrene, an aryl-hydrocarbon receptor agonist, in human umbilical vascular endothelial cells
Juan, S., Lee, J.-L., Ho, P.-Y., Lee, Y., & Lee, W. (2005) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2005.11.023 · Cited by 44 · see citing works
Palbociclib-mediated cell cycle arrest can occur in the absence of the CDK inhibitors p21 and p27
Pennycook, B. R., & Barr, A. R. (2021) · Open Biology · doi:10.1098/rsob.210125 · Cited by 43 · see citing works
Self-citation
Endothelial cells in the eyes of an immunologist
Young, M. R. (2012) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-012-1335-0 · Cited by 43 · see citing works
Transcriptional regulation of neural stem cell expansion in the adult hippocampus
Guo, N., McDermott, K. D., Shih, Y.-T., Zanga, H., Ghosh, D., Herber, C., Coleman, J., Zagouras, A., Meara, W. R., Wong, L. P., et al. (2022) · eLife · doi:10.7554/elife.72195 · Cited by 42 · see citing works
Flow cytometric analysis of T lymphocyte proliferation in vivo by EdU incorporation
Sun, X., Zhang, C., Jin, H., et al. (2016) · International Immunopharmacology · doi:10.1016/j.intimp.2016.10.019 · Cited by 38 · see citing works
Foxp4 Is Dispensable for T Cell Development, but Required for Robust Recall Responses
Wiehagen, K. R., Corbo‐Rodgers, E., Li, S., Staub, E., Hunter, C. A., Morrisey, E. E., & Maltzman, J. S. (2012) · PLoS ONE · doi:10.1371/journal.pone.0042273 · Cited by 38 · see citing works
p21 Cip1 Levels Differentially Regulate Turnover of Mature Endothelial Cells, Endothelial Progenitor Cells, and In Vivo Neovascularization
Brühl, T., Heeschen, C., Aicher, A., Jadidi, A., Haendeler, J., Hoffmann, J., Schneider, M. D., Zeiher, A. M., Dimmeler, S., & Rössig, L. (2004) · Circulation Research · doi:10.1161/01.res.0000119922.71855.56 · Cited by 36 · see citing works
All Yersinia Are Not Created Equal: Phenotypic Adaptation to Distinct Niches Within Mammalian Tissues
Davis, K. M. (2018) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2018.00261 · Cited by 33 · see citing works
ITE Suppresses Angiogenic Responses in Human Artery and Vein Endothelial Cells: Differential Roles of AhR
Li, Y., Wang, K., Zou, Q., et al. (2017) · Reproductive Toxicology · doi:10.1016/j.reprotox.2017.09.010 · Cited by 32 · see citing works
Roles of aryl hydrocarbon receptor in endothelial angiogenic responses
Li, Y., Zhou, C., Lei, W., Wang, K., & Zheng, J. J. (2020) · Biology of Reproduction · doi:10.1093/biolre/ioaa128 · Cited by 30 · see citing works
Caspase‐8 in endothelial cells maintains gut homeostasis and prevents small bowel inflammation in mice
Tisch, N., Mogler, C., Stojanovic, A., Luck, R., Korhonen, E. A., Ellerkmann, A., Adler, H., Singhal, M., Schermann, G., Erkert, L., et al. (2022) · EMBO Molecular Medicine · doi:10.15252/emmm.202114121 · Cited by 26 · see citing works
Apelin-driven endothelial cell migration sustains intestinal progenitor cells and tumor growth
Bernier‐Latmani, J., Cisarovsky, C., Mahfoud, S., Ragusa, S., Dupanloup, I., Barras, D., Renevey, F., Nassiri, S., Anderle, P., Squadrito, M. L., et al. (2022) · Nature Cardiovascular Research · doi:10.1038/s44161-022-00061-5 · Cited by 26 · see citing works
Epithelial Vegfa specifies a distinct endothelial population in the mouse lungPreprint
Ellis, L. V., Cain, M. P., Hutchison, V., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/840033 · Cited by 16 · see citing works
Application of a novel regulatable Cre recombinase system to define the role of liver and gut metabolism in drug oral bioavailability
Henderson, C. J., McLaughlin, L. A., Osuna‐Cabello, M., Taylor, M., Gilbert, I. H., McLaren, A. W., & Wolf, C. R. (2014) · Biochemical Journal · doi:10.1042/bj20140582 · Cited by 15 · see citing works
A single-cell transcriptional roadmap of the mouse and human lymph node lymphatic vasculaturePreprint
Xiang, M., Grosso, R. A., Takeda, A., Pan, J., Bekkhus, T., Brulois, K., Đermadi, D., Nordling, S., Vanlandewijck, M., Jalkanen, S., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2019.12.31.892166 · Cited by 15 · see citing works
NRP2 as an emerging angiogenic player; promoting endothelial cell adhesion and migration by regulating recycling of α5 integrinPreprint
Alghamdi, A. A. A., Benwell, C. J., Atkinson, S. J., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/744763 · Cited by 4 · see citing works
Cell-intrinsic Aryl Hydrocarbon Receptor signalling is required for the resolution of injury-induced colonic stem cellsPreprint
Shah, K., Maradana, M. R., Delàs, M. J., Metidji, A., Graelmann, F. J., Llorian, M., Chakravarty, P., Li, Y., Tolaini, M., Shapiro, M., et al. (2021) · Research Square · doi:10.21203/rs.3.rs-827700/v1 · Cited by 3 · see citing works

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Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases
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
Gastrointestinal and brain barriers: unlocking gates of communication across the microbiota–gut–brain axis
Aburto, M. R., & Cryan, J. F. (2024) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-023-00890-0 · Cited by 391 · see citing works
A systems view of the vascular endothelium in health and disease
Augustin, H. G., & Koh, G. Y. (2024) · Cell · doi:10.1016/j.cell.2024.07.012 · Cited by 370 · see citing works
Endothelial 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
AHR activation relieves deoxynivalenol-induced disruption of porcine intestinal epithelial barrier functions
Hu, Z.-Y., Yang, S.-J., Chang, Y., Wang, X., Liu, R.-Q., Jiang, F., Chen, M., Wang, J.-X., Liu, S., Zhu, H., et al. (2024) · Journal of Hazardous Materials · doi:10.1016/j.jhazmat.2024.136095 · Cited by 64 · see citing works
Activation of the aryl hydrocarbon receptor in inflammatory bowel disease: insights from gut microbiota
Hou, J., Ma, A.-H., & Qin, Y. (2023) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2023.1279172 · Cited by 42 · see citing works
“Further, they uncovered: 1) AHR ligands act directly on endothelial cells to promote quiescence and anti-in ﬂ ammatory programs; 2) AHR facilitates vasculoprotective pathways in human endothelial cells (Wiggins et al., 2023).”
Background
Bile acid receptor FXR promotes intestinal epithelial ferroptosis and subsequent ILC3 dysfunction in neonatal necrotizing enterocolitis
Zhang, Y., Jing, Y., He, J., Dong, R., Li, T., Li, F., Zheng, X., Liu, G., Jia, R., Xu, J., et al. (2025) · Immunity · doi:10.1016/j.immuni.2025.02.003 · Cited by 44 · see citing works
The influence of AHR on immune and tissue biology
Stockinger, B., Diaz, O. E., & Wincent, E. (2024) · EMBO Molecular Medicine · doi:10.1038/s44321-024-00135-w · Cited by 43 · see citing works
“Recent studies established that AHR signalling in endothelial cells promotes cellular quiescence and protects against cellular leakage, whereas disruption of AHR signalling causes a dysregulated stress response with in ﬂ ammation (Major et al, 2023; Wiggins et al, 2023).”
Indole-3-Carboxaldehyde Alleviates LPS-Induced Intestinal Inflammation by Inhibiting ROS Production and NLRP3 Inflammasome Activation
Cao, J., Bao, Q.-Y., & Hao, H. (2024) · Antioxidants · doi:10.3390/antiox13091107 · Cited by 44 · see citing works
“The AhR is a key transcription factor for regulating intestinal homeostasis [61].”
Background
Role of Uremic Toxins in Vascular Inflammation Associated with Chronic Kidney Disease
Chermiti, R., Burtey, S., & Dou, L. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm13237149 · Cited by 36 · see citing works
Mechanisms and functions of intestinal vascular specialization
Bernier‐Latmani, J., González‐Loyola, A., & Petrova, T. V. (2023) · The Journal of Experimental Medicine · doi:10.1084/jem.20222008 · Cited by 32 · see citing works
“…) and water and glycerol ( Aqp1 , Aqp7 ) transport similar to those observed in muscle-and white adipose tissue – specific endothelial cells (Fan et al., 2021; Kalucka et al., 2020; Wiggins et al., 2023), suggesting they perform nutrient transport to support intestinal smooth muscle metabolism.”
BackgroundInfluential
A Comprehensive Review on Dietary Polysaccharides as Prebiotics, Synbiotics, and Postbiotics in Infant Formula and Their Influences on Gut Microbiota
Zhang, W., Zhang, Y. L., Zhao, Y., Liang, L., Zhang, Z., Hettinga, K. A., Yang, H., & Deng, J. (2024) · Nutrients · doi:10.3390/nu16234122 · Cited by 29 · see citing works
Technological advances and challenges in constructing complex gut organoid systems
Zheng, L., Zhan, Y., Wang, C., Fan, Q., Sun, D., Li, Y., & Xiong, Y. (2024) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1432744 · Cited by 25 · see citing works
“…complex system, where the functionality of gut epithelial cells is in ﬂ uenced not only by dietary habits but also signi ﬁ cantly by the interplay among immune cells, neural cells, and vascular endothelial cells (Bar-Ephraim et al., 2019; Liu et al., 2021; Lei et al., 2022; Wiggins et al., 2023).”
Background
Engineered probiotics remodel the intestinal epithelial barrier and enhance bacteriotherapy for inflammatory bowel diseases
Chen, Y., Bi, S., Zhang, X., Chen, J., Xin, J., Liu, Z., Guan, Q., Qiu, P., Wang, P., & Liu, J. (2025) · Acta Biomaterialia · doi:10.1016/j.actbio.2025.04.016 · Cited by 24 · see citing works
Targeting aryl hydrocarbon receptor to prevent cancer in barrier organs
Congues, F., Wang, P., Lee, J., Lin, D., Shahid, A., Xie, J., & Huang, Y. S. (2024) · Biochemical Pharmacology · doi:10.1016/j.bcp.2024.116156 · Cited by 24 · see citing works
A guide to uraemic toxicity
Glorieux, G., Burtey, S., Evenepoel, P., Jankowski, J., Koppe, L., Masereeuw, R., & Vanholder, R. C. (2025) · Nature Reviews Nephrology · doi:10.1038/s41581-025-01006-4 · Cited by 24 · see citing works
“Furthermore, loss of AHR in the endothelial capillaries of the gut leads to activation of the endothelium associated with an increased risk of death in a mouse model of gut infection 132 .”
Indole-3-lactic acid protects the gut vascular barrier following intestinal ischemia injury through AhR/Nrf2/STAT3 mediated claudin 2 downregulation
Jia, Y., He, M., Wang, F., et al. (2025) · Cell Communication and Signaling · doi:10.1186/s12964-025-02454-y · Cited by 19 · see citing works
“…such as indole and its derivatives have been identified as ligands for the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that plays a pivotal role in maintaining intestinal barrier integrity, regulating intestinal homeostasis and mediating hosts’ immune response [16].”
Microbial metabolites as modulators of host physiology
Joyce, S. A., & Clarke, D. J. (2024) · Advances in microbial physiology/Advances in Microbial Physiology · doi:10.1016/bs.ampbs.2023.12.001 · Cited by 18 · see citing works
Discovery of a novel AhR–CYP1A1 axis activator for mitigating inflammatory diseases using an in situ functional imaging assay
Feng, Z., Zhao, B., Fan, Y., Qin, L., Shi, J., Chen, L., Xu, L., Jin, X., Sun, M., Deng, H., et al. (2024) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2024.09.014 · Cited by 16 · see citing works
The aryl hydrocarbon receptor: a new frontier in male reproductive system
Bustani, G. S., Alghetaa, H., Mohammed, A. K., Nagarkatti, M., & Nagarkatti, P. S. (2025) · Reproductive Biology and Endocrinology · doi:10.1186/s12958-025-01401-3 · Cited by 19 · see citing works
“…the biological effects of AhR have been extensively studied across various physiological functions such as the nervous system [3, 4], immune system [5, 6], digestive system [7, 8], hepatic function [9–11], respiratory system [5, 12, 13], renal system [14, 15], skin health [16], and others [17].”
Gut microbiota-derived tryptophan metabolite indole-3-carboxaldehyde enhances intestinal barrier function via aryl hydrocarbon receptor/AMP-activated protein kinase signaling activation
Shi, D., Cui, Y., Liang, H.-P., Wei, Q., Huang, J.-Z., & Cao, J. (2025) · Animal bioscience · doi:10.5713/ab.25.0225 · Cited by 18 · see citing works
“AhR is a key transcription factor for maintaining barrier function and regulating intestinal homeostasis [39].”
Thrombopoietin mimetic reduces mouse lung inflammation and fibrosis after radiation by attenuating activated endothelial phenotypes
English, J., Dhanikonda, S., Tanaka, K. E., Koba, W. R., Eichenbaum, G. M., Yang, W., & Guha, C. (2024) · JCI Insight · doi:10.1172/jci.insight.181330 · Cited by 13 · see citing works
Physiological activation of Aryl hydrocarbon receptor by food-derived ligands is essential for the efficacy of anti-PD1 therapy
de Juan, A., Coillard, A., Cros, A., Rigamonti, A., Alaoui, L., Sampaio, J. L., Monot, N., Balvay, A., Foussier, A., Rieux-Laucat, M., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-66854-x · Cited by 12 · see citing works
Recent advances in flavonoids benefiting intestinal homeostasis
Luo, Y., Li, Y., Shi, C., Min, S., Li, B., Lu, Y., BingHai, C., Su, H., & He, Y. (2025) · Trends in Food Science & Technology · doi:10.1016/j.tifs.2025.105311 · Cited by 11 · see citing works
Molecular mechanisms and therapeutic potential of tryptophan metabolism in gut-brain signaling transduction: a narrative review
Zhang, J.-B., Zhou, Y.-N., Mei, X., Yan, S., Mao, J., Li, Y., Bian, Z.-H., Li, L., Ji, D., Lu, T.-L., et al. (2026) · Journal of Neuroinflammation · doi:10.1186/s12974-026-03763-w · Cited by 12 · see citing works
“Consistently, in murine models of enteric infection, AhR deficiency markedly exacerbates host susceptibility to pathogens, whereas dietary supplementation with AhR ligands such as indole−3-carbinol significantly improves survival rates [143].”
Sele-targeted siRNA liposome nanoparticles inhibit pathological scars formation via blocking the cross-talk between monocyte and endothelial cells: a preclinical study based on a novel mice scar model
Li, L., Wang, Y., Meng, J., Wang, X., Wu, X., Wo, Y., Shang, Y., & Zhang, Z. (2024) · Journal of Nanobiotechnology · doi:10.1186/s12951-024-03003-4 · Cited by 11 · see citing works
“Previous studies thought that endothelial cells form the lining of blood vessels and have more opportunities for contact with external substances [71], studies also have shown that siRNA delivered via liposomes can preferentially target endothelial cells in organs [72], partly due to the unique…”
Self-citation
Activation of aryl hydrocarbon receptor attenuates intestinal inflammation by enhancing IRF4-mediated macrophage M2 polarization
Li, J., Wang, L., Wang, M., & Zhang, H. (2025) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2025.167735 · Cited by 10 · see citing works
Emerging approaches for antagonizing the aryl hydrocarbon receptor
Dvořák, Z., Mani, S., & Vondráček, J. (2025) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2025.05.003 · Cited by 11 · see citing works
Aryl hydrocarbon receptor attenuates cholestatic liver injury by regulating bile acid metabolism
Han, Q., Yan, X., Wang, L., Zhang, N., Zhang, W., Li, H., Chen, W., You, H., & Yang, A. (2023) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2023.10.030 · Cited by 9 · see citing works
Sucralose triggers insulin resistance leading to follicular dysplasia in mice
Yang, L., Wang, S., Jin, J., Wang, J., Chen, W., Xue, Y., Sheng, L., Zhai, Y., & Yao, W. (2024) · Reproductive Toxicology · doi:10.1016/j.reprotox.2024.108644 · Cited by 9 · see citing works
Maternal Gut Inflammation Aggravates Acute Liver Failure Through Facilitating Ferroptosis via Altering Gut Microbial Metabolism in Offspring
Zhao, C., Bao, L., Shan, R., Zhao, Y., Wu, K., Shang, S., Li, H., Liu, Y., Chen, K., Zhang, N., et al. (2025) · Advanced Science · doi:10.1002/advs.202411985 · Cited by 9 · see citing works
The Janus-facedness of the aryl hydrocarbon receptor pathway Report of the 6th International AHR Meeting: Research, Prevention, Therapy
Haarmann‐Stemmann, T., Reichert, D., Coumoul, X., Lawrence, B. P., Perdew, G. H., Sherr, D. H., Weighardt, H., Rolfes, K. M., & Esser, C. (2025) · Biochemical Pharmacology · doi:10.1016/j.bcp.2025.116808 · Cited by 9 · see citing works
ITE-mediated AhR activation attenuates atherosclerosis by promoting macrophage M2-like polarization through NF-κB/LCN2 pathway suppression
Zheng, Q., Lin, Y., Zeng, L., Chen, S., Chen, L., Lin, X., Zhu, J., Lin, J., Weng, X., & Chai, D. (2025) · Life Sciences · doi:10.1016/j.lfs.2025.123715 · Cited by 7 · see citing works
Niuhuang Jiedu Tablet's compatibility alleviates realgar-induced intestinal toxicity by activating aryl hydrocarbon receptor pathway via Akkermansia and indole−3−lactate
Li, J., Ma, Y., Deng, N., Wang, F., Tao, Y., Zhu, H., Xu, W., Shan, J., Li, Y., & Wu, X. M. (2025) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2025.120260 · Cited by 7 · see citing works
Lymphatic Endothelial Cells and Organ-Associated Lymphangiogenesis in Tumor Microenvironment
Ji, R. (2025) · Cells · doi:10.3390/cells15010028 · Cited by 7 · see citing works
“In recent years, the development of ScRNA-seq techniques has greatly increased our knowledge of cellular heterogeneity, cell subtypes, and states by tissue decomposition, especially on new functions of LECs in health and disease [22–24].”
Microbial metabolite oxindole curbs acute lung injury by suppressing CXCL13
Tang, S., Zhang, J., He, Z., Liu, G., Nie, S., Shi, X., Zhang, K., Pi, D., Gui, X., He, Y., et al. (2026) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2519332123 · Cited by 8 · see citing works
“In the enteric epithelium, AhR sensing of dietary ligands is pivotal for maintaining barrier homeostasis and activating anti - inflammatory pathways (36, 37).”
AhR inhibition promotes axon regeneration via a stress–growth switch
Halawani, D., Wang, Y., Li, J., Halperin, D. S., Ni, H., Estill, M. S., Ramakrishnan, A., Shen, L., Sefiani, A., Geoffroy, C. G., et al. (2026) · Nature · doi:10.1038/s41586-026-10295-z · Cited by 7 · see citing works
“More broadly, our findings align with protective effects of AhR inhibition reported in stroke 49 , Huntington’s disease 50 , gut–lung 51 and endothelial responses 52,53 .”
Self-citation
Bioluminescence imaging of Cyp1a1-luciferase reporter mice demonstrates prolonged activation of the aryl hydrocarbon receptor in the lung
Veland, N., Gleneadie, H. J., Brown, K. E., Sardini, A., Pombo, J., Dimond, A., Burns, V., Sarkisyan, K. S., Schiering, C., Webster, Z., et al. (2024) · Communications Biology · doi:10.1038/s42003-024-06089-6 · Cited by 8 · see citing works
“Althoughinthesestudieswehaveused concentrationsofAHRligandsthatwerede ﬁ ned by others 72,80 – 82 , our observation that Cyp1a1 luminescence was induced in animals maintained on control diets but switched to a non-SPF facility, suggests that this model can detect endogenously-generated and…”
Self-citation
The role of aryl hydrocarbon receptor in the occurrence and development of periodontitis
Wu, L., Li, X., Li, J., Wang, Y., Yang, C., Zhao, C., & Gao, L. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1494570 · Cited by 7 · see citing works
Self-citation
Inflammatory bowel disease through the lens of microbe-host interactions: immunomodulation, metabolic effects, and genetic susceptibility in microbiota dysbiosis
Zou, Q., Zhang, W., Xie, H., Ying, S., Zeng, X., Yao, Y., Zeng, D., Wang, J., Zhang, C., & Meng, F. (2026) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2026.1745929 · Cited by 7 · see citing works
“AHR ligands may provide a method to inhibit endothelial activation and avoid sustained in ﬂ ammatory responses to intestinal pathogens (Wiggins et al., 2023).”
The Antioxidant PAPLAL Protects against Allergic Contact Dermatitis in Experimental Models
Shibuya, S., Watanabe, K., & Shimizu, T. (2024) · Antioxidants · doi:10.3390/antiox13060748 · Cited by 6 · see citing works
“AHR, a ligand-activated transcriptional factor widely expressed at barrier sites and in the immune system, contributes to the maintenance of barrier function and homeostasis in the lungs and intestines [26,27].”
Background
A comprehensive transcriptome characterization of individual nuclear receptor pathways in the human small intestine
Willemsen, S., Yengej, F. A. Y., Puschhof, J., Rookmaaker, M. B., Verhaar, M. C., van Es, J. H., Beumer, J., & Clevers, H. C. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2411189121 · Cited by 5 · see citing works
Liver matrin-3 protects mice against hepatic steatosis and stress response via constitutive androstane receptor
Cheng, X., Baki, V. B., Moran, M., Liu, B., Yu, J., Zhao, M., Li, Q., Riethoven, J.-J. M., Gurumurth, C. B., Harris, E. N., et al. (2024) · Molecular Metabolism · doi:10.1016/j.molmet.2024.101977 · Cited by 5 · see citing works
“…the expression of the target genes of PXR (Egr1 and Gstm2) [42], LXR (Abcg5 and Abcg8) [43], FXR (Abcb4 and Shp) [44,45], and AHR (Tiparp) [46,47] (Figure S8A e S8D), while it reduced the expression of CAR target genes such as Cyp2b10, Cyp2c55 in the liver of HFD-fed or TCPOBOP-treated mice…”
Lactylation of MYH9 and its impact on FOXO3a/Bim signaling in sepsis-induced gut-vascular barrier injury
Ding, R., Zhao, C., Jing, Y., Weng, Z., Chen, R., & Meng, Q. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2025.115384 · Cited by 4 · see citing works
Endothelial cell–ILC3 crosstalk via the ET-1/EDNRA axis promotes NKp46+ILC3 glycolysis to alleviate intestinal inflammation
Li, X., Chen, Y., He, J., Tang, J., Chen, C., Meng, L., Lu, Y., Lyu, X., Guo, Y., & He, Y. (2025) · Cellular and Molecular Immunology · doi:10.1038/s41423-025-01345-z · Cited by 4 · see citing works
“A previously described scoring system was used to determine the histological scores [24].”
ALDH3A1-dependent Nrf2/HO-1/GPX4 pathway supports AHR as a promising therapeutic target for ferroptosis and promotes imperatorin-mediated lung protection
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Authors: 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., Barr, A. R., Frankel, G., Birdsey, G. M., Randi, A. M., & Schiering, C.
Affiliations: MRC London Institute of Medical Sciences (GB)
Imperial College London (GB)
Corresponding author: Wiggins, Benjamin G.
Schiering, Chris
ORCID: Wiggins, Benjamin G.
Wang, Yi-Fang
Grunberg, Nil
Chahrour, Catherine
Pennycook, Betheney R.
Sanchez-Garrido, Julia
Vernia, Santiago
Barr, Alexis R.
Frankel, Gad
Birdsey, Graeme M.
Randi, Anna M.
Schiering, Chris
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2023-08-16
Volume: 621
Issue: 7980
Pages: 821-829
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-023-06508-4
PMC: PMC10533400
OpenAlex: W4385879248
Cited by: 89
References: 99
Citations by year: 2026: 27 · 2025: 30 · 2024: 25 · 2023: 7
FWCI: 9.17
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0 (tdm)
creativecommons.org/licenses/by/4.0 (vor)
Locations: Nature (publishedVersion, cc-by)
Research Square (acceptedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Spiral (Imperial College London) (submittedVersion, cc-by)
Funders: University of Pennsylvania
Harvard University
Wellcome Trust (224282/Z/21/Z, 211080/Z/18/Z)
Cancer Research UK (25729)
National Institute for Health and Care Research
British Heart Foundation (FS/PhD/22/29242, PG/20/16/35047, RG/17/4/32662)
Imperial College London
Medical Research Council
NIHR Imperial Biomedical Research Centre
Topics: Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
Keywords: aryl hydrocarbon receptor, endothelial cells, intestinal homeostasis, dietary metabolites, AhR ligands, single-cell atlas, lymphatic endothelium, endothelial quiescence, vascular homeostasis, intestinal inflammation, gastrointestinal infections, human endothelial cells, environmental sensing
MeSH terms: Animals, Homeostasis, Humans, Intestines, Ligands, Signal Transduction, Receptors, Aryl Hydrocarbon, Endothelial Cells, Mice

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Endothelial sensing of AHR ligands regulates intestinal homeostasis

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