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<p>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 <i>N</i>-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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月8日

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  • Julien Chilloux,
  • Francois Brial,
  • Amandine Everard,
  • David Smyth,
  • Petros Andrikopoulos,
  • Liyong Zhang,
  • Hubert Plovier,
  • Antonis Myridakis,
  • Lesley Hoyles,
  • José Maria Moreno-Navarrete,
  • Jèssica Latorre Luque,
  • Viviana Casagrande,
  • Rossella Menghini,
  • Blerina Ahmetaj-Shala,
  • Christine Blancher,
  • Laura Martinez-Gili,
  • Selin Gencer,
  • Jane F. Fearnside,
  • Richard H. Barton,
  • Ana Luisa Neves,
  • Alice R. Rothwell,
  • Christelle Gérard,
  • Sophie Calderari,
  • Mark J. Williamson,
  • Julian E. Fuchs,
  • Lata Govada,
  • Claire L. Boulangé,
  • Saroor Patel,
  • James Scott,
  • Mark Thursz,
  • Naomi Chayen,
  • Robert C. Glen,
  • Nigel J. Gooderham,
  • Jeremy K. Nicholson,
  • Massimo Federici,
  • José Manuel Fernández-Real,
  • Dominique Gauguier,
  • Peter P. Liu,
  • Patrice D. Cani,
  • Marc-Emmanuel Dumas

摘要

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.