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

Abstract

Referenced abstract The interaction between high-fat diet (HFD) feeding and the gut microbiome has a strong impact on the onset of insulin resistance (IR)1-3. In particular, bacterial lipopolysaccharides (LPS) and dietary fats trigger low-grade inflammation4 through activation of Toll-like receptor 4 (TLR4), a process called metabolic endotoxemia5. However, little is known about how the microbiome can 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 kinome screens 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 kinome6 in microbial–mammalian chemical crosstalk.

Metabolic retroconversion of trimethylamine N-oxide and the gut microbiota

“…Based on work done in mice [10,36], metabolic retroconversion of TMAO may be protective, and may even go some way to explaining why TMA and TMAO are detected at low levels in urine in the absence of dietary methylamines [17]. Chronic exposure of high-fat-fed mice to TMAO reduced diet-associated endoplasmic stress and adipogenesis, and improved glucose tolerance [10].…”

“…Chronic exposure of high-fat-fed mice to TMAO reduced diet-associated endoplasmic stress and adipogenesis, and improved glucose tolerance [10]. Exposure of high-fat-fed mice to TMA reduced low-grade inflammation and insulin resistance via inhibition of interleukin-1 receptor-associated kinase 4 (IRAK-4) [36]. Concentrations of the microbial signalling metabolite TMA used by Chilloux et al [36] were comparable to those found in normal human plasma.…”

“…Exposure of high-fat-fed mice to TMA reduced low-grade inflammation and insulin resistance via inhibition of interleukin-1 receptor-associated kinase 4 (IRAK-4) [36]. Concentrations of the microbial signalling metabolite TMA used by Chilloux et al [36] were comparable to those found in normal human plasma. Continual exposure of the human system to TMA/TMAO may bring similar benefits to host metabolic and inflammatory responses; these remain to be studied.…”

Structure-Guided Identification of a Small Molecule That Inhibits Anaerobic Choline Metabolism by Human Gut Bacteria

“…Described as a specific inhibitor of TMA production, DMB has been used in additional animal studies. 24,25 Unexpectedly, we found DMB did not reduce TMA production from choline by CutC in vitro or in E. coli . This result may be explained by the inability of DMB to engage in critical hydrogen bonding interactions within CutC’s polar active site.…”

Human pluripotent stem cells identify molecular targets of trisomy 12 in chronic lymphocytic leukemia patients

“…Teratomas were established for 24 days and confirmed through palpation prior to drug administration, which was given daily by oral gavage for 21 days at 15 mg/kg for both EDNRB-i and IRAK4-i. This dose was selected as a low-to-moderate dose based on previous animal studies (Chilloux et al, 2018;Serafim et al, 2015) and clinical trial of arthritis patients (ClinicalTrials.gov: NCT02996500). This treatment regimen was sublethal and did not interfere with recipient mouse health or overall body weight (Figure S5B).…”