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

Chilloux, J, Brial, F, Everard, A, Smyth, D, Andrikopoulos, P, Zhang, L, Plovier, H, Myridakis, A, Hoyles, L ORCID: https://orcid.org/0000-0002-6418-342X, Moreno-Navarrete, JM, Luque, JL, Casagrande, V, Menghini, R, Ahmetaj-Shala, B, Blancher, C, Martinez-Gili, L, Gencer, S, Fearnside, JF, Barton, RH, Neves, AL, Rothwell, AR, Gérard, C, Calderari, S, Williamson, MJ, Fuchs, JE, Govada, L, Boulangé, CL, Patel, S, Scott, J, Thursz, M, Chayen, N, Glen, RC, Gooderham, NJ, Nicholson, JK, Federici, M, Fernández-Real, J-M, Gauguier, D, Liu, PP, Cani, PD and Dumas, M-E, 2025. Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control. Nature Metabolism. ISSN 2522-5812

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Abstract

The global type 2 diabetes epidemic is a major health crisis. Although the microbiome plays 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 (TMAO) associated with cardiovascular diseases, 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.

Item Type:	Journal article
Publication Title:	Nature Metabolism
Creators:	Chilloux, J., Brial, F., Everard, A., Smyth, D., Andrikopoulos, P., Zhang, L., Plovier, H., Myridakis, A., Hoyles, L., Moreno-Navarrete, J.M., Luque, J.L., Casagrande, V., Menghini, R., Ahmetaj-Shala, B., Blancher, C., Martinez-Gili, L., Gencer, S., Fearnside, J.F., Barton, R.H., Neves, A.L., Rothwell, A.R., Gérard, C., Calderari, S., Williamson, M.J., Fuchs, J.E., Govada, L., Boulangé, C.L., Patel, S., Scott, J., Thursz, M., Chayen, N., Glen, R.C., Gooderham, N.J., Nicholson, J.K., Federici, M., Fernández-Real, J.-M., Gauguier, D., Liu, P.P., Cani, P.D. and Dumas, M.-E.
Publisher:	Nature Research
Date:	8 December 2025
ISSN:	2522-5812
Identifiers:	Number Type 10.1038/s42255-025-01413-8 DOI 2518489 Other
Rights:	This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: https://doi.org/10.1038/s42255-025-01413-8
Divisions:	Schools > School of Science and Technology
Record created by:	Laura Borcherds
Date Added:	28 Oct 2025 16:22
Last Modified:	10 Dec 2025 11:35
URI:	https://irep.ntu.ac.uk/id/eprint/54639

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