ArticleNature metabolism2025
Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control.
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Article in Nature metabolism, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Gut microbiota-generated trimethylamineAmerican journal of physiology. Endocrinology and metabolism · 2026Trial
- The evolving landscape of obesity pharmacotherapy.Nature reviews. Drug discovery · 2026Review
- Chronic choline restriction remodels hepatic lipid metabolism and drives insulin resistance through a CD36-ETNPPL regulatory axis.Molecular metabolism · 2026Article
- β-cell FMO3-produced TMAO prevents NF-κB-mediated senescence and inflammation in ageing and diabetic conditions.Nature communications · 2026Article
- Associations of cumulative exposure and dynamic trajectories of the cholesterol-HDL-glucose index and its obesity-related derivatives with cardiovascular disease: a nationwide prospective cohort study.Cardiovascular diabetology · 2026Article
- Metabolic Reprogramming-Driven Cardiovascular Immune Damage: From Glyco-Lipotoxicity and Epigenetic Memory to Multidimensional Cross-Organ Communication Networks.International journal of molecular sciences · 2026Review
- Gut Microbial Choline TMA-Lyase CutC: From Metabolic Mechanism to a Novel Therapeutic Target for Diseases.Nutrients · 2026Review
- Associations of cumulative exposure and dynamic trajectories of cholesterol-HDL-glucose (CHG) index with cardiovascular disease in middle-aged and older Chinese adults: a longitudinal analysis.Cardiovascular diabetology · 2026Article
- Modulation of gut-heart axis by synbiotic (Lactiplantibacillus plantarum M10 and Isomaltose) in high cholesterol diet induced atherosclerotic murine model.BMC microbiology · 2026Article
- Lac-Phe: An Emerging Appetite-Regulating Exerkine with Health and Therapeutic Benefits.Current obesity reports · 2026Review
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Authors and funding
40 authors.
Julien Chilloux *Section of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.ORCID http://orcid.org/0000-0002-0384-7317
Francois Brial *University Paris Cité, INSERM U1132, Biologie de l'os et du cartilage (BIOSCAR), Paris, France.
Amandine Everard *Université catholique de Louvain, Louvain Drug Research Institute, Metabolism and Nutrition Research Group, Brussels, Belgium.ORCID http://orcid.org/0000-0001-8925-8144
David Smyth *University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
Petros Andrikopoulos *Section of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.ORCID http://orcid.org/0000-0002-1555-3498
Liyong ZhangUniversity of Ottawa Heart Institute, Ottawa, Ontario, Canada.ORCID http://orcid.org/0000-0002-7498-6496
Hubert PlovierUniversité catholique de Louvain, Louvain Drug Research Institute, Metabolism and Nutrition Research Group, Brussels, Belgium.
Antonis MyridakisSection of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.ORCID http://orcid.org/0000-0003-1690-6651
Lesley HoylesSection of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.ORCID http://orcid.org/0000-0002-6418-342X
José Maria Moreno-NavarreteDepartment of Endocrinology, Diabetes and Nutrition, University Hospital of Girona 'Dr Josep Trueta', Girona, Spain.ORCID http://orcid.org/0000-0002-2883-511X
Jèssica Latorre LuqueDepartment of Endocrinology, Diabetes and Nutrition, University Hospital of Girona 'Dr Josep Trueta', Girona, Spain.ORCID http://orcid.org/0000-0002-7603-1458
Viviana CasagrandeDepartment of Systems Medicine, University of Rome Tor Vergata, Via Montpellier, Rome, Italy.
Rossella MenghiniDepartment of Systems Medicine, University of Rome Tor Vergata, Via Montpellier, Rome, Italy.
Blerina Ahmetaj-ShalaSection of Cardio-Respiratory Interface, National Heart & Lung Institute, Imperial College London, London, UK.
Christine BlancherWellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, UK.ORCID http://orcid.org/0000-0003-3971-2518
Laura Martinez-GiliSection of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.ORCID http://orcid.org/0000-0001-5271-9672
Selin GencerSection of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
Jane F FearnsideWellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, UK.
Richard H BartonSection of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
Ana Luisa NevesSection of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
Alice R RothwellWellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, UK.
Christelle GérardUniversity Paris Cité, Functional and Adaptive Biology, CNRS UMR 8251, Paris, France.
Sophie CalderariUniversity Paris-Saclay, INRAE, Jouy-en-Josas, France.ORCID http://orcid.org/0000-0002-9669-681X
Mark J WilliamsonCentre for Molecular Informatics, Department of Chemistry, University of Cambridge, Cambridge, UK.
Julian E FuchsCentre for Molecular Informatics, Department of Chemistry, University of Cambridge, Cambridge, UK.
Lata GovadaSection of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.ORCID http://orcid.org/0000-0002-8077-0480
Claire L BoulangéSection of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
Saroor PatelSection of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
James ScottCentre for Molecular Informatics, Department of Chemistry, University of Cambridge, Cambridge, UK.
Mark ThurszSection of Hepatology & Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
Naomi ChayenSection of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.ORCID http://orcid.org/0000-0003-2861-2458
Robert C GlenSection of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.ORCID http://orcid.org/0000-0003-1759-2914
Nigel J GooderhamSection of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
Jeremy K NicholsonSection of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.ORCID http://orcid.org/0000-0002-8123-8349
Massimo FedericiDepartment of Systems Medicine, University of Rome Tor Vergata, Via Montpellier, Rome, Italy.ORCID http://orcid.org/0000-0003-4989-5194
José Manuel Fernández-RealDepartment of Endocrinology, Diabetes and Nutrition, University Hospital of Girona 'Dr Josep Trueta', Girona, Spain.ORCID http://orcid.org/0000-0002-7442-9323
Dominique GauguierWellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, UK.
Peter P LiuUniversity of Ottawa Heart Institute, Ottawa, Ontario, Canada.
Patrice D CaniSection of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.ORCID http://orcid.org/0000-0003-2040-2448
Marc-Emmanuel DumasSection of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK. m.dumas@imperial.ac.uk.ORCID http://orcid.org/0000-0001-9523-7024
Funding
Agence Nationale de la Recherche (French National Research Agency) ANR-10-LABX-46Agence Nationale de la Recherche (French National Research Agency) ANR-16-IDEX-0004-ULNEAgence Nationale de la Recherche (French National Research Agency) ANR-18-IBHU-0001DH | National Institute for Health Research (NIHR) Imperial Biomedical Research CentreEuropean Commission (EC) METACARDIS HEALTH-F4-2012-305312Fonds De La Recherche Scientifique - FNRS (Belgian National Fund for Scientific Research) EOS: program no. 40007505Fonds De La Recherche Scientifique - FNRS (Belgian National Fund for Scientific Research) FRFS-WELBIO: WELBIO-CR-2022A-02PFonds De La Recherche Scientifique - FNRS (Belgian National Fund for Scientific Research) T.0115.24Fonds De La Recherche Scientifique - FNRS (Belgian National Fund for Scientific Research) WELBIO X.1517.24Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada) MOP-142471Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada) MOP-49413RCUK | Medical Research Council (MRC) MR/K020919/1RCUK | Medical Research Council (MRC) MR/L01632X/1RCUK | Medical Research Council (MRC) MR/M501797/1RCUK | Medical Research Council (MRC) MR/W022532/1RCUK | Medical Research Council (MRC) MR/Y001028/1RCUK | Medical Research Council (MRC) MR/Y010051/1Région Hauts-de-France 20002845Région Hauts-de-France Agreement 20001891/NP0025517Wellcome TrustWellcome Trust 057733Wellcome Trust (Wellcome) 06678
Abstract
The global type 2 diabetes epidemic is a major health crisis. Although the microbiome has roles in the onset of insulin resistance (IR), low-grade inflammation and diabetes, the microbial compounds controlling these processes remain to be discovered. Here, we show that the microbial metabolite trimethylamine (TMA) decouples inflammation and IR from diet-induced obesity by inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4), a central kinase in the Toll-like receptor pathway sensing danger signals. TMA blunts TLR4 signalling in primary human hepatocytes and peripheral blood monocytic cells and rescues mouse survival after lipopolysaccharide-induced septic shock. Genetic deletion and chemical inhibition of IRAK4 result in metabolic and immune improvements in high-fat diets. Remarkably, our results suggest that TMA-unlike its liver co-metabolite trimethylamine N-oxide, which is associated with cardiovascular disease-improves immune tone and glycemic control in diet-induced obesity. Altogether, this study supports the emerging role of the kinome in the microbial-mammalian chemical crosstalk.
Indexed as
Glycemic ControlInflammationInterleukin-1 Receptor-Associated KinasesMethylaminesAnimalsDiet, High-FatHepatocytesHumansInsulin ResistanceMaleMiceMice, Inbred C57BLObesityInterleukin-1 Receptor-Associated KinasesIrak4 protein, mouseMethylaminestrimethylamine
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