Examining the role for the gut microbial metabolite imidazole propionate in vascular dysfunction and inflammation in type 2 diabetes

Despite optimal glycaemic, lipid, and blood pressure control, cardiovascular disease (CVD) remains the leading cause of death in individuals with type 2 diabetes (T2D), reflecting a persistent residual inflammatory risk. Emerging evidence links gut dysbiosis to chronic inflammation and CVD. Imidazole propionate (ImP), a gut-derived histidine metabolite elevated in T2D, impairs insulin signalling and is associated with increased cardiovascular risk. However, its role in vascular inflammation, immune-endothelial crosstalk, and activation of pathways underpinning residual inflammatory risk remains poorly defined. This PhD will test the hypothesis that ImP drives vascular inflammation in T2D by activating the NLRP3-inflammasome in macrophages, disrupting endothelial function, and promoting maladaptive immune-vascular interactions. Using human donor monocyte-derived macrophages and aortic endothelial cells, we will assess the effect of ImP on inflammasome activation, cytokine secretion, barrier integrity, and endothelial-to-mesenchymal transition under pro-inflammatory and hyperglycaemic conditions. To evaluate therapeutic modulation, we will examine whether the sodium/glucose co-transporter-2 inhibitor Empagliflozin and the lipid-lowering agent icosapent ethyl (Vazkepa) can directly suppress ImP-induced inflammation. We will also assess whether serum from T2D-CVD patients post-treatment modulates ImP-driven inflammation via proteomic shifts. Our work will clarify how an important gut-derived metabolite contributes to residual risk and will inform new adjunctive strategies for T2D-CVD prevention.