Background and aims:
Emerging evidence highlights the gut microbiome and its bioactive metabolites as key modulators of cardiometabolic and cardiovascular diseases, including atherosclerosis and heart failure (HF). Alterations in microbial composition and function have been associated with the onset and progression of HF through metabolic and inflammatory pathways. Among these metabolites, imidazole propionate (ImP), a product of microbial histidine metabolism, has been implicated in insulin resistance and type 2 diabetes, endothelial dysfunction and atherogenesis. Recent studies suggest that ImP may also contribute to HF progression. However, the molecular mechanisms by which ImP impairs cardiac structure and function remain unclear. Here, we investigated the link between circulating ImP levels and HF severity in a patient cohort as well as its mechanistic impact on cardiac fibrosis and remodeling using both in vitro and in vivo experimental models.
Methods and results:
In our clinical cohort of 831 patients with cardiac dysfunction and heart failure (HF), classified according to the New York Heart Association (NYHA) criteria, plasma imidazole propionate (ImP) levels were significantly higher in individuals with reduced left ventricular ejection fraction (LVEF) and advanced HF (NYHA III–IV). These findings indicate a strong association between elevated ImP concentrations and HF severity in humans. Experimental studies further support this association: adult C57BL/6J mice (n=8) treated with ImP in drinking water for 6 weeks showed marked reductions in LVEF and stroke volume compared with controls, demonstrating that ImP directly impairs cardiac function in vivo. To identify the underlying pathomechanism, primary human cardiac fibroblasts (HCFs) and murine cardiac tissues were analyzed. HCFs exposed to increasing ImP concentrations (25–500 nM) for 24 hours displayed a dose-dependent increase in proliferation (BrdU assay). Furthermore, ImP induced cardiac fibrosis via p38γ activation, resulting in elevated collagen type I alpha 1 (COL1A1) and α-smooth muscle actin (αSMA) protein expression and enhanced collagen deposition detected by Picrosirius Red staining. These pro-fibrotic effects were abolished with pirfenidone (PFD), an anti-fibrotic and p38γ-inhibiting compound. Consistently, p38γ knockout (KO) mice were protected from ImP-induced cardiac dysfunction and fibrosis, confirming p38γ signaling as a central mediator of ImP-driven cardiac remodeling.
Conclusion:
The microbial metabolite ImP promotes cardiac remodeling and HF progression through p38γ-dependent fibroblast activation and fibrosis, identifying a potential therapeutic target for HF.
