Article Dans Une Revue Nature Metabolism Année : 2025

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

1 Imperial College London
2 BIOSCAR (UMR_S_1132 / U1132) - Biologie de l'Os et du Cartilage : Régulations et Ciblages Thérapeutiques
3 UCLouvain - Université Catholique de Louvain = Catholic University of Louvain
4 WELRI - WEL Research Institute
5 University of Ottawa Heart Institute
6 Nottingham Trent University
7 ISCIII - Instituto de Salud Carlos III [Madrid]
8 JTUH - Josep Trueta University Hospital [Girona, Spain]
9 IDIBGI - Institut d'Investigació Biomèdica de Girona Dr. Josep Trueta - Girona Biomedical Research Institute
10 CIBERObn - Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition - Centro de investigación Biomédica en Red de Fisiopatalogía de la Obesidad y Nutrición
11 Università degli Studi di Roma Tor Vergata [Roma, Italia] = University of Rome Tor Vergata [Rome, Italy] = Université de Rome Tor Vergata [Rome, Italie]
12 The Wellcome Trust Centre for Human Genetics [Oxford]
13 University of Oxford
14 BFA (UMR_8251 / U1133) - Unité de Biologie Fonctionnelle et Adaptative
15 Université Paris-Saclay
16 CAM - University of Cambridge [Cambridge, UK]
17 Murdoch University [Perth]
18 UdG - Universitat de Girona = University of Girona
19 McGill University = Université McGill [Montréal, Canada]
20 EGENODIA (GI3M) - Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283
21 EGID - Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508
22 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
Julien Chilloux
Petros Andrikopoulos
Liyong Zhang
Antonis Myridakis
Laura Martinez-Gili
Sophie Calderari
Lata Govada
Naomi Chayen

Résumé

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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hal-05408577 , version 1 (04-05-2026)

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Julien Chilloux, Francois Brial, Amandine Everard, David Smyth, Petros Andrikopoulos, et al.. Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control. Nature Metabolism, 2025, 7 (12), pp.2531-2547. ⟨10.1038/s42255-025-01413-8⟩. ⟨hal-05408577⟩
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