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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\u2014unlike its liver co-metabolite trimethylamine\n                    <jats:italic>N<\/jats:italic>\n                    -oxide, which is associated with cardiovascular disease\u2014improves immune tone and glycemic control in diet-induced obesity. Altogether, this study supports the emerging role of the kinome in the microbial\u2013mammalian chemical crosstalk.\n                  <\/jats:p>","DOI":"10.1038\/s42255-025-01413-8","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T10:02:37Z","timestamp":1765188157000},"page":"2531-2547","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic 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