ArticleNature2017
Endothelial TLR4 and the microbiome drive cerebral cavernous malformations.
Registry-linked trialOpen access · greenAbstract read
In one paragraph
Article in Nature, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT01764529 (Modifiers of Disease Severity and Progression in Cerebral Cavernous Malformations), which is not on this map. Cited by 186 papers, 4 of them syntheses that pooled it.
0numbers the graph read from it
0cells of the map it votes in
186citing papers in PubMed, 4 pooled it
22.7field-weighted citation impact, top 1% of its field
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Modifiers of Disease Severity and Progression in Cerebral Cavernous Malformations
Who cites it
186 citing papers in PubMed, 4 syntheses or guidelines pooled it, 294 citations in OpenAlex.
- Molecular Pathways and Circulating Biomarkers in Cerebral Cavernous Malformations-A Systematic Review.International journal of molecular sciences · 2026Pooled it
- Eagle jugular syndrome accompanied by de novo brainstem cavernous malformation: a case-based systematic review.Acta neurochirurgica · 2024Pooled it
- Gut microbes in cerebrovascular diseases: Gut flora imbalance, potential impact mechanisms and promising treatment strategies.Frontiers in immunology · 2022Pooled it
- At the Intersection of Gut Microbiome and Stroke: A Systematic Review of the Literature.Frontiers in neurology · 2021Pooled it
- Gut Microbiota Modulation in CNS Disorders: Therapeutic Strategies and Implications for Drug Efficacy.Molecular neurobiology · 2026Review
- Cerebral cavernous malformations: epidemiology, molecular pathogenesis, diagnosis and therapy.Molecular biomedicine · 2026Review
- Inhibition of MEKK3 Prevents Cerebral Cavernous Malformation Progression Via Restoring Endothelial Integrity and Restricting Microglial Activation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- MicroRNA-21-3p regulation of NADPH oxidase 4 and vascular endothelial growth factor A contributes to hemorrhage in cerebral cavernous malformations.Non-coding RNA research · 2026Article
- Growth of PIK3CA-driven cerebral cavernous malformations does not require microbiome stimulation.JCI insight · 2026Article
- Article
- Review
- Ischemic stroke: molecular mechanisms of blood-brain barrier dysfunction and opportunities for drug development.Fluids and barriers of the CNS · 2026Review
- CXCL13⁺ CD4⁺ T cells are associated with B-cell recruitment and lesion progression in cerebral cavernous malformations.Journal of neuroinflammation · 2026Article
- Rapamycin Partially Reverts Cavernoma Endothelial Cell Phenotype and, When Combined With Lapatinib, Ameliorates Chronic Lesions.Journal of cellular and molecular medicine · 2026Article
- Influence of ginger root extract supplementation on the microbiota-gut-brain axis in individuals with sciatica: Study protocol for a double-blind, placebo-controlled randomized trial.Clinical nutrition ESPEN · 2026Article
- Role of Microbial Toxins in Neurodegenerative Diseases: Insights and Future Perspectives.Biomolecules · 2026Review
- Article
- Strategies for blood-brain barrier rejuvenation and repair.Nature reviews. Drug discovery · 2026Review
- Multi-omics profiling of gut microbiota and host transcriptome identifies diagnostic signatures and mechanistic links in moyamoya disease.BMC microbiology · 2026Article
- MEKK3 bridges gut-brain communication and cerebral cavernous malformation pathogenesis.Cell death discovery · 2026Review
126 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
30 authors at 11 institutions in 5 countries.
Alan T TangDepartment of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA.
Jaesung P ChoiLaboratory of Cardiovascular Signaling, Centenary Institute, Sydney, New South Wales 2050, Australia.
Jonathan J KotzinDepartment of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Yiqing YangDepartment of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA.
Courtney C HongDepartment of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA.
Nicholas HobsonNeurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago School of Medicine and Biological Sciences, Chicago, Illinois 60637, USA.
Romuald GirardNeurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago School of Medicine and Biological Sciences, Chicago, Illinois 60637, USA.
Hussein A ZeineddineNeurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago School of Medicine and Biological Sciences, Chicago, Illinois 60637, USA.
Rhonda LightleNeurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago School of Medicine and Biological Sciences, Chicago, Illinois 60637, USA.
Thomas MooreNeurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago School of Medicine and Biological Sciences, Chicago, Illinois 60637, USA.
Ying CaoNeurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago School of Medicine and Biological Sciences, Chicago, Illinois 60637, USA.
Robert ShenkarNeurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago School of Medicine and Biological Sciences, Chicago, Illinois 60637, USA.
Mei ChenDepartment of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA.
Patricia MerickoDepartment of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA.
Jisheng YangDepartment of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA.
Li LiDepartment of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA.
Ceylan TanesCHOP Microbiome Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
Dmytro KobuleyInstitute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Urmo VõsaDepartment of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
Kevin J WhiteheadDivision of Cardiovascular Medicine and the Program in Molecular Medicine, University of Utah, Salt Lake City, Utah 84112, USA.
Dean Y LiDivision of Cardiovascular Medicine and the Program in Molecular Medicine, University of Utah, Salt Lake City, Utah 84112, USA.
Lude FrankeDepartment of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
Blaine HartDepartment of Neurology and Pediatrics, University of New Mexico, Albuquerque, New Mexico 87131, USA.
Markus SchwaningerInstitute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, 23562 Lübeck, Germany.
Jorge Henao-MejiaDepartment of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Leslie MorrisonDepartment of Neurology and Pediatrics, University of New Mexico, Albuquerque, New Mexico 87131, USA.
Helen KimCenter for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California 94143, USA.
Issam A AwadNeurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago School of Medicine and Biological Sciences, Chicago, Illinois 60637, USA.
Xiangjian ZhengLaboratory of Cardiovascular Signaling, Centenary Institute, Sydney, New South Wales 2050, Australia.
Mark L KahnDepartment of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA.
University of Chicago · USUniversity of Pennsylvania · USChildren's Hospital of Philadelphia · USUniversity of New Mexico · USUniversity of Utah · USCentenary Institute · AUTianjin Medical University · CNUniversity Medical Center Groningen · NLUniversity of California, San Francisco · USUniversity of Groningen · NLUniversity of Lübeck · DE
Funding
VIRAL VECTOR COREP30DK019525 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI MITCHELL A. LAZAR · 1986 to 2026
$48.3MVCRC Administration UnitU54NS065705 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KIM, HELEN · 2009 to 2023
$20.8MHEMATOLOGY CLINICAL RESEARCH TRAINING PROGRAMT32HL007439 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI LAWRENCE F BRASS, PETER S KLEIN · 1985 to 2026
$17.1MSomatic mutation(s) and cellular changes in CCM pathogenesisP01NS092521 · NINDS · DUKE UNIVERSITY · PI AWAD, ISSAM A · 2015 to 2024
$12.9MPREDOCTORAL TRAINING PROGRAM IN PHARMACOLOGYT32GM008076 · NIGMS · UNIVERSITY OF PENNSYLVANIA · PI BLENDY, JULIE A · 1985 to 2023
$10.8MHEMATOPOIESIS TRAINING GRANTT32DK007780 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI TONG, WEI · 1999 to 2023
$6.7MHeg-CCM Signaling in Cardiovascular Development and DiseaseR01HL094326 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI KAHN, MARK L · 2009 to 2018
$3.5MTLR4 and the microbiome in CCM diseaseR01NS100949 · NINDS · UNIVERSITY OF PENNSYLVANIA · PI KAHN, MARK L · 2017 to 2021
$2.8MMolecular mechanisms of CCM signalingR01HL102138 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI KAHN, MARK L · 2010 to 2014
$2.6MRegulation of short-lived myeloid cells by the novel long non-coding RNA MorrbidR01HL136572 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI HENAO-MEJIA, JORGE · 2017 to 2021
$2.0MKRIT1 in Vascular Development and DysfunctionR01NS075168 · NINDS · UNIVERSITY OF UTAH · PI WHITEHEAD, KEVIN J · 2011 to 2015
$1.6MRegulation of adipose tissue inflammation by the miR-181 familyR21DK111755 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI HENAO-MEJIA, JORGE · 2016 to 2018
$604kNational Institute of Health T32HL07439NHLBI NIH HHS R01 HL094326NHLBI NIH HHS R01 HL102138NHLBI NIH HHS R01 HL136572NHLBI NIH HHS T32 HL007439NIAID NIH HHS R21 AI128060NIDDK NIH HHS P30 DK019525NIDDK NIH HHS R21 DK111755NIDDK NIH HHS T32 DK007780NIGMS NIH HHS T32 GM008076NINDS NIH HHS F30 NS100252NINDS NIH HHS P01 NS092521NINDS NIH HHS R01 NS075168NINDS NIH HHS R01 NS100949NINDS NIH HHS U54 NS065705
Abstract
Cerebral cavernous malformations (CCMs) are a cause of stroke and seizure for which no effective medical therapies yet exist. CCMs arise from the loss of an adaptor complex that negatively regulates MEKK3-KLF2/4 signalling in brain endothelial cells, but upstream activators of this disease pathway have yet to be identified. Here we identify endothelial Toll-like receptor 4 (TLR4) and the gut microbiome as critical stimulants of CCM formation. Activation of TLR4 by Gram-negative bacteria or lipopolysaccharide accelerates CCM formation, and genetic or pharmacologic blockade of TLR4 signalling prevents CCM formation in mice. Polymorphisms that increase expression of the TLR4 gene or the gene encoding its co-receptor CD14 are associated with higher CCM lesion burden in humans. Germ-free mice are protected from CCM formation, and a single course of antibiotics permanently alters CCM susceptibility in mice. These studies identify unexpected roles for the microbiome and innate immune signalling in the pathogenesis of a cerebrovascular disease, as well as strategies for its treatment.
Indexed as
Immunity, InnateAnimalsAnti-Bacterial AgentsDisease SusceptibilityEndothelial CellsFemaleGastrointestinal MicrobiomeGerm-Free LifeGram-Negative BacteriaHemangioma, Cavernous, Central Nervous SystemHumansInjections, IntravenousLipopolysaccharide ReceptorsLipopolysaccharidesMaleMiceAnti-Bacterial AgentsLipopolysaccharide ReceptorsLipopolysaccharidesTLR4 protein, humanToll-Like Receptor 4
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Read underepoch 390
Registered trials
NCT01764529ClinicalTrials.gov
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.