Microbiome inhibition of IRAK-4 by trimethylamine mediates metabolic and immune benefits in high-fat-diet-induced insulin resistance

The interaction between high-fat diet (HFD) feeding and the gut microbiomehas a strong impact on the onset of insulin resistance (IR). In particular, bacterial lipopolysaccharides (LPS) and dietary fats trigger low-grade inflammation through activation of Toll-like receptor 4 (TLR4), a process called metabolic endotoxemia. However, little is known about how the microbiomecan mitigate this process. Here, we investigate longitudinal physiological and metabotypical responses of C57BL/6 mice to HFD feeding. A series of in vivo experiments with choline supplementation, then blocking trimethylamine(TMA) production and administering TMA, demonstrate that this microbiome-associated metabolite decouples inflammation and IR from obesity in HFD. Through in vitro kinomescreens and in silico molecular dynamics studies, we reveal TMA specifically inhibits Interleukin-1 Receptor-associated Kinase 4 (IRAK-4), a central kinase integrating signals from various TLRs and cytokine receptors. Consistent with this, genetic ablation and chemical inhibition of IRAK-4 result in similar metabolic and immune improvements in HFD. In summary, TMA appears as a key microbial effector inhibiting IRAK-4 and mediating metabolic and immune effects with benefits upon HFD. Thereby we highlight the critical contribution of the microbial signalling metabolome in homeostatic regulation of host disease and the emerging role of the kinomein microbial--mammalian chemical crosstalk.