Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control

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.

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Publication Details

Journal
Nature Metabolism
Published
2025-12-08
DOI
https://doi.org/10.1038/s42255-025-01413-8
Citations
3
Primary Topic
Gut microbiota and health
Type
article
Field-Weighted Citation Impact
2.42

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article

Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control

Nigel J. Gooderham, Jane Fearnside, Blerina Ahmetaj‐Shala, Robert C. Glen et al.
3 citations
Nature Metabolism
Gut microbiota and health
2.42
article

Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control

Nigel J. Gooderham, Jane Fearnside, Blerina Ahmetaj‐Shala, Robert C. Glen, Jeremy K. Nicholson, Naomi E. Chayen, Amandine Everard, Mark R. Thursz, Marc‐Emmanuel Dumas, Dominique Gauguier, Saroor A. Patel, Lata Govada, Jèssica Latorre, Massimo Federici, Viviana Casagrande, Sophie Caldérari, Ana Luísa Neves, Richard H. Barton, Hubert Plovier, François Brial, Selin Gencer, Alice Rothwell, Laura Martínez-Gili, Lesley Hoyles, Rossella Menghini, David Smyth, Patrice D. Cani, Mark J. Williamson, Liyong Zhang, Julian E. Fuchs, José María Moreno‐Navarrete, Christine Blancher, Julien Chilloux, José Manuel Fernández‐Real, Antonis Myridakis, Peter P. Liu, Claire L. Boulangé, Christelle Gérard, Petros Andrikopoulos
article en
3 citations

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.

Nature MetabolismVol. 7(12)
University of Rome Tor Vergata (IT), Centre National de la Recherche Scientifique (FR), Centre for Human Genetics (GB), University of Ottawa (CA), Inserm (FR), Université Paris Cité (FR), University of Cambridge (GB), Universitat de Girona (ES), Harry Perkins Institute of Medical Research (AU), Instituto de Salud Carlos III (ES), Microbiologie de l’alimentation au service de la santé (FR), University of Oxford (GB), Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR), Lung Institute (US), Institut d'Investigació Biomèdica de Girona (ES), Centro de Investigación Biomédica en Red (ES), Bioscar (FR), McGill Genome Centre (CA), Unit of Functional and Adaptive Biology (FR), Walloon Excellence in Lifesciences and Biotechnology (BE), Hospital Universitari de Girona Doctor Josep Trueta (ES), Mathématiques et Informatique Appliquées du Génome à l'Environnement (FR), European Genomic Institute for Diabetes (FR), Imperial College London (GB), McGill University (CA), Nottingham Trent University (GB), UCLouvain (BE)
Heart and Stroke Foundation of Canada, Université Catholique de Louvain, University of Ottawa, McGill University, Universitat de Girona, Genome Canada, Fondation Brain Canada, Nottingham Trent University, Wellcome Trust, Ontario Genomics, Australian Government, Université de Lille, European Genomic Institute for Diabetes, Government of Canada, Trent University, National Institute for Health and Care Research, British Heart Foundation, Imperial College London, University of Oxford, European Commission, Rosetrees Trust, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Murdoch University, Fonds De La Recherche Scientifique - FNRS, Institució Catalana de Recerca i Estudis Avançats, Centre National de la Recherche Scientifique, Università degli Studi di Roma Tor Vergata, Canada First Research Excellence Fund, Conseil Régional Hauts-de-France, Centre hospitalier régional universitaire de Lille, Institut Mérieux, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Walloon excellence in life sciences and biotechnology, Canadian Institutes of Health Research, Medical Research Council, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, European Regional Development Fund, NIHR Imperial Biomedical Research Centre, CHIST-ERA
Openalex Percentile: Top 10%
Gut microbiota and health
2.42
DOIOpen Access PDFOpenAlex
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