Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control.
(2025) Nature Metabolism — p. 1-29 (2025)
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Chilloux, Julien 
Dumas, Marc-Emmanuel
- 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.
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Citations
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., et al. (2025). Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control. Nature Metabolism, 1-29. https://doi.org/10.1038/s42255-025-01413-8 (Original work published 2025)