Microbial molecule offers new hope for diabetes

Imperial-led team uncovers TMA’s role in blunting inflammation and improving metabolic health.

Our work opens exciting possibilities with kinases as a new repertoire of targets accessible by microbiome-based therapeutic interventions in obesity and diabetes.” Professor Marc-Emmanuel Dumas Chair in Systems Medicine, Department of Metabolism, Digestion and Reproduction

An international research team led by Professor Marc-Emmanuel Dumas at Imperial College London & CNRS has uncovered a surprising ally in the fight against insulin resistance and type 2 diabetes: a microbial metabolite called trimethylamine (TMA). Published in Nature Metabolism, the study reveals that TMA, produced by gut bacteria from dietary choline can block a key immune pathway and improve blood sugar control.

The researchers, including Professor Patrice Cani (Imperial & University of Louvain, UCLouvain), Dr. Dominique Gauguier (Imperial & INSERM, Paris) and Professor Peter Liu (University of Ottawa Heart Institute), found that TMA acts as a natural inhibitor of IRAK4, a protein that drives inflammation in response to sensing microbes or high-fat diets. Using a combination of human cell models, mouse studies, and kinase screening, the researchers demonstrated that TMA directly binds and inhibits IRAK4, dampening inflammation triggered by high-fat diets and restoring the response to insulin. The team has shown that a microbial metabolite can target a central kinase in immunity which rewires metabolic responses to diet.

The discovery challenges long-held assumptions about TMA and its oxidized counterpart TMAO, which has been linked to cardiovascular disease. Unlike TMAO, TMA appears to play a protective role in metabolic health. The team also found that genetic deletion or pharmacological inhibition of IRAK4 mimicked the beneficial effects of TMA, a validated drug target in the pharmaceutical industry.

Professor Dumas, Chair in Systems Medicine in Imperial’s Department of Metabolism, Digestion and Reproduction, said: “This flips the narrative. We’ve shown that a molecule from our gut microbes can actually protect against the harmful effects of a poor diet through a new mechanism. It’s a new way of thinking about how the microbiome influences our health. Our work opens exciting possibilities with kinases as a new repertoire of targets accessible by microbiome-based therapeutic interventions in obesity and diabetes.”

Professor Patrice Cani, co-senior author and visiting professor at Imperial said: “This shows how nutrition and our gut microbes can work together by producing molecules that fight inflammation and improve metabolic health!”

Professor Peter Liu, Scientific Director of the Brain-Heart Interconnectome at the University of Ottawa Heart Institute, said: “In view of the growing threat of diabetes worldwide and its devastating complications for the whole patient, including the brain and heart, a new solution is direly needed. Our team’s work connecting Western-style foods, TMA produced by the microbiome, and its effect on the immune switch IRAK4, may open entirely new ways to treat or prevent diabetes, a known risk factor for heart disease."

The implications are far-reaching. With over 500 million people affected by diabetes worldwide, the identification of TMA as a microbial signal that modulates host immunity and metabolism could pave the way for novel treatments. Dietary strategies or drugs that enhance TMA production, or inhibit its conversion to TMAO, may offer a new route to tackle insulin resistance and its complications.

“What we eat shapes our microbes and some of their molecules can protect us from diabetes. That’s nutrition in action.” said Professor Cani.

This research was supported by international collaborations across Europe and North America, including institutions in Belgium, Canada, France, Italy, and Spain, including the CNRS–Imperial International Research Project in Integrative Metabolism. The project Is also supported by the Brain-Heart Interconnectome through the Canada First Research Excellence Fund (Federal Government of Canada). This provides both a proof-of-concept and a paradigm shift in our understanding of host–microbiome interactions, underscoring the power of systems medicine and microbiome science to uncover the chemical handshake between microbes and their human hosts. 

Chilloux, J., Brial, F., Everard, A. et al. Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control. Nat Metab (2025). https://doi.org/10.1038/s42255-025-01413-8