A microbial metabolite long linked to cardiovascular risk emerges as a surprising ally against metabolic inflammation, revealing how gut–host signaling can reset glucose control by targeting a single immune kinase.
Study: Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control. Image Credit: Ahmet Misirligul / Shutterstock
A new study published in the journal Nature Metabolism identifies a gut microbial metabolite that improves glycaemic control and modulates innate immune–driven inflammatory responses in obese mice by targeting a central kinase involved in innate immune signaling.
Global Diabetes Burden and Inflammatory Mechanisms
Diabetes, a chronic metabolic disease characterized by high blood glucose levels, has become a major public health crisis worldwide. According to the World Health Organization (WHO), about 529 million people in the global population are currently living with diabetes, and 1.6 million deaths occur every year due to this condition.
Unhealthy lifestyle factors, including unhealthy diet and physical inactivity, are primarily associated with the increasing prevalence of various metabolic diseases, including diabetes and obesity.
The microbial community residing in the gastrointestinal tract (gut microbiota) plays a crucial role in triggering chronic, low-grade inflammation and insulin resistance, which are major hallmarks of diabetes. Existing evidence indicates that the interaction between bacterial lipopolysaccharides (LPS) and dietary fats triggers low-grade inflammation and insulin resistance by activating toll-like receptor 4 (TLR4), a key protein in the body’s innate immune system.
Although some of the functional signaling molecules mediating gut microbial–host chemical crosstalk have been characterized, it remains largely unknown which microbial metabolites control these processes.
Trimethylamine (TMA) is one of the most abundant metabolites produced by the gut microbiota during the metabolism of dietary choline and carnitine. TMA serves as a precursor of trimethylamine N-oxide (TMAO), which is known to have adverse effects on cardiovascular health. Existing evidence also suggests a link between TMA and insulin resistance.
Given the potential role of TMA and related metabolites in the pathogenesis of cardiometabolic diseases, the current study was designed to explore the mechanistic association between TMA and high-fat-diet-induced glucose intolerance, insulin resistance, and obesity-associated metabolic dysfunction.
Experimental Approach to TMA–IRAK4 Interactions
The study was conducted on mice that were kept on high-fat diets with either low or high choline content, alongside standard chow-fed controls, to induce obesity and glucose intolerance and to examine the impact of choline-driven TMA production.
The experimental analysis revealed that the microbial metabolite TMA attenuated high-fat-diet-induced low-grade inflammation and insulin resistance by inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4), a key kinase in the toll-like receptor (TLR) pathway that recognizes danger signals from foreign invaders such as pathogens.
By genetically silencing and chemically inhibiting IRAK4, the study found similar improvements in metabolic and immune functions in mice fed a high-fat diet. These findings further support the newly identified roles of TMA and its target kinase in immunometabolism.
Furthermore, the study found that a single dose of TMA significantly improved survival in mice with LPS-induced septic shock.
Choline Intake, TMA Production, and Immune Modulation
By feeding mice low- and high-choline high-fat diets, the study demonstrated that choline supplementation improved high-fat-diet-induced inflammation. Further analysis of choline-related metabolic pathways revealed a 20-fold induction in circulating TMA levels in mice fed a high-choline diet compared with those in mice fed a low-choline diet.
These observations indicate an increased microbial conversion of dietary choline into TMA, suggesting that TMA could mediate the metabolic and immune benefits of choline supplementation. In other words, these observations indicate that TMA generated through gut microbial metabolism of dietary choline can act as a signaling molecule that hijacks the TLR signaling pathway to improve glycaemic control and dampen inflammatory responses in the host.
Context-Dependent Roles of TMA and TMAO
In the liver, TMA is oxidized to produce TMAO, which is a well-established risk factor for cardiovascular disease. However, TMAO has also been found to have beneficial effects, including reduced blood–brain barrier permeability, which helps prevent inflammation. In contrast, TMA has been found to disrupt the blood–brain barrier. Overall, existing evidence suggests that TMAO may require underlying pathology for its detrimental effects to become overt.
In apparent contrast to the current study’s findings, some previous studies have shown that choline-enriched standard laboratory animal diets impair glucose tolerance and pancreatic beta-cell function in mice by increasing plasma TMAO levels.
Overall, these observations, together with the current study’s findings, suggest that TMA and TMAO may play contrasting roles that are context- and mechanism-dependent.
Mechanistic Insights Into TMA’s Independent Pathway
In the liver, flavin-containing mono-oxygenase 3 (FMO3) converts TMA into TMAO by triggering oxidation reactions. Existing evidence suggests that inactivation of this hepatic enzyme, which increases TMA levels relative to TMAO, is associated with several metabolic benefits.
These observations suggest that the metabolic benefits of FMO3 inactivation cannot be attributed exclusively to TMAO depletion, highlighting an independent mechanism for TMA. The current study finds that TMA binds to and inhibits IRAK4, whereas TMAO does not, further highlighting an independent mechanism for TMA.
Implications for Dietary Strategies and Future Trials
Overall, the current study findings provide a strong foundation for future clinical trials to investigate anti-diabetic effects and improvement of obesity-associated metabolic dysfunction through dietary interventions that aim to increase TMA bioavailability, while acknowledging that current evidence in humans is limited to in vitro experiments.