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

Julien Chilloux; Francois Brial; Amandine Everard; David Smyth; Petros Andrikopoulos; Liyong Zhang; Hubert Plovier; Antonis Myridakis; Lesley Hoyles; José Maria Moreno-Navarrete; Jèssica Latorre Luque; Viviana Casagrande; Rossella Menghini; Blerina Ahmetaj-Shala; Christine Blancher; Laura Martinez-Gili; Selin Gencer; Jane F Fearnside; Richard H Barton; Ana Luisa Neves; Alice R Rothwell; Christelle Gérard; Sophie Calderari; Mark J Williamson; Julian E Fuchs; Lata Govada; Claire L Boulangé; Saroor Patel; James Scott; Mark Thursz; Naomi Chayen; Robert C Glen; Nigel J Gooderham; Jeremy K Nicholson; Massimo Federici; José Manuel Fernández-Real; Dominique Gauguier; Peter P Liu; Patrice D Cani; Marc-Emmanuel Dumas

doi:10.1038/s42255-025-01413-8

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

Journal article

Open access

Peer reviewed

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

Julien Chilloux, Francois Brial, Amandine Everard, David Smyth, Petros Andrikopoulos, Liyong Zhang, Hubert Plovier, Antonis Myridakis, Lesley Hoyles, José Maria Moreno-Navarrete, …

Nature Metabolism, Vol.7(12), pp.2531-2547

2025

DOI: https://doi.org/10.1038/s42255-025-01413-8

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Abstract

Kinases

Metabolism

Metabolomics

Microbiome

Type 2 diabetes

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.

Details

Title: Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control
Authors/Creators: Julien Chilloux
Francois Brial
Amandine Everard
David Smyth
Petros Andrikopoulos
Liyong Zhang
Hubert Plovier
Antonis Myridakis
Lesley Hoyles
José Maria Moreno-Navarrete
Jèssica Latorre Luque
Viviana Casagrande
Rossella Menghini
Blerina Ahmetaj-Shala
Christine Blancher
Laura Martinez-Gili
Selin Gencer
Jane F Fearnside
Richard H Barton
Ana Luisa Neves
Alice R Rothwell
Christelle Gérard
Sophie Calderari
Mark J Williamson
Julian E Fuchs
Lata Govada
Claire L Boulangé
Saroor Patel
James Scott
Mark Thursz
Naomi Chayen
Robert C Glen
Nigel J Gooderham
Jeremy K Nicholson
Massimo Federici
José Manuel Fernández-Real
Dominique Gauguier
Peter P Liu
Patrice D Cani
Marc-Emmanuel Dumas
Publication Details: Nature Metabolism, Vol.7(12), pp.2531-2547
Publisher: Springer Nature
Number of pages: 29
Identifiers: 991005850545507891
Murdoch Affiliation: Health Futures Institute
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.120 Inflammatory Bowel Diseases & Infections; 1.120.384 Gut Microbiota
Web Of Science research areas: Endocrinology & Metabolism
ESI research areas: Biology & Biochemistry