A recent study published in Nature Metabolism has identified a gut microbial metabolite, trimethylamine (TMA), as having a beneficial effect on blood sugar control and inflammation in obese mice. The research found that TMA, produced by gut bacteria from dietary choline and carnitine, can improve glycemic control and reduce innate immune-driven inflammatory responses by targeting interleukin-1 receptor-associated kinase 4 (IRAK4), an important enzyme in the body's immune signaling pathways.
Diabetes remains a major global health concern, with approximately 529 million people living with the disease worldwide and about 1.6 million deaths each year, according to the World Health Organization. The increase in diabetes and related metabolic diseases is largely attributed to unhealthy diets and physical inactivity.
The gut microbiota plays a significant role in chronic inflammation and insulin resistance—key features of diabetes. Previous studies have shown that interactions between bacterial components like lipopolysaccharides (LPS) and dietary fats activate toll-like receptor 4 (TLR4), contributing to low-grade inflammation and impaired insulin function.
While some molecules involved in communication between gut microbes and their host have been studied, there is still limited knowledge about which specific microbial metabolites influence these processes. TMA is known as one of the most abundant metabolites produced by gut bacteria during the breakdown of choline-rich foods. It serves as a precursor for trimethylamine N-oxide (TMAO), which has been linked to cardiovascular risks but also has complex effects on health.
In this study, researchers used mice fed high-fat diets with varying choline content to investigate how increased TMA production affects metabolism. They found that higher levels of TMA were associated with reduced inflammation and improved insulin sensitivity through inhibition of IRAK4. Genetically or chemically blocking IRAK4 produced similar benefits, reinforcing its central role.
The study also showed that a single dose of TMA improved survival rates in mice experiencing septic shock induced by LPS exposure. Mice fed high-choline diets had much higher circulating TMA levels compared to those on low-choline diets, indicating increased conversion of dietary choline into TMA by gut microbes.
These results suggest that TMA generated from dietary choline may act as a signaling molecule capable of influencing host immune pathways to enhance glucose regulation and reduce inflammation. However, while TMAO—a product formed from TMA in the liver—has been recognized as a cardiovascular risk factor, it may also provide certain protective effects depending on context.
Previous research has reported contrasting findings regarding choline supplementation: some studies observed negative impacts on glucose tolerance when plasma TMAO levels rise due to choline-enriched diets. This highlights the complexity of these metabolites' roles, which appear dependent on biological context and underlying mechanisms.
The liver enzyme flavin-containing mono-oxygenase 3 (FMO3) converts TMA into TMAO; its inactivity leads to increased levels of TMA relative to TMAO, which has been associated with metabolic benefits not solely explained by lower TMAO concentrations. The current study clarifies that only TMA—not TMAO—binds directly to IRAK4.
Researchers note that their findings lay groundwork for future clinical trials aimed at exploring anti-diabetic strategies based on increasing bioavailable TMA through diet or other interventions. They caution that evidence for such effects in humans remains limited at this stage.
