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 (Forthcoming)

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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:	22 October 2025
ISSN:	2522-5812
Identifiers:	Number Type 2518489 Other
Divisions:	Schools > School of Science and Technology
Record created by:	Laura Borcherds
Date Added:	28 Oct 2025 16:22
Last Modified:	28 Oct 2025 16:22
URI:	https://irep.ntu.ac.uk/id/eprint/54639

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