Glycopeptide vancomycin reshapes gut microbiota to mediate cardioprotective effects via microRNA-204 - SUMMARY Left ventricular (LV) pressure overload caused by conditions such as chronic hypertension or aortic stenosis is a significant risk factor for the development of heart failure. A decline in microbial diversity caused by certain antibiotics also increases the risk of heart failure, suggesting that the gut harbors cardioprotective microbes. However, our current knowledge of which microbes are cardioprotective and which have deleterious cardiac effects is inadequate, not allowing us to leverage gut microbial manipulation with antibiotics to treat or mitigate heart failure. microRNA-204-5p (miR-204) is a noncoding RNA well-expressed in mouse and human hearts. We recently reported that the miR-204 inhibits mouse myocardial hypertrophy induced by experimental pressure overload, and its expression in many tissues, including the heart, is sensitive to changes in the gut microbiome. Our preliminary data show that glycopeptide antibiotic vancomycin alters the mouse gut microbial landscape, leading to the enrichment of Lactobacillus sp that confers protection from pressure overload-induced myocardial hypertrophy and LV dysfunction. Moreover, vancomycin increases the abundance of the bacterial metabolite tryptamine in the feces and serum, which inhibits myocardial hypertrophy and LV dysfunction. Both, vancomycin and tryptamine stimulate cardiac miR-204 expression, which is essential for their cardioprotective effects. Based on these data, we hypothesize that vancomycin-induced reshaping of the gut microbiome enriches Lactobacillus sp. that promotes tryptophan's metabolism to tryptamine, leading to upregulation of cardiac miR-204 that inhibits pressure overload-induced myocardial dysfunction. This application will leverage unique reagents and tools to connect vancomycin-induced reshaping of the gut microbiome to cardiac miR-204-regulated cardioprotection. The application will determine whether vancomycin-induced enrichment of Lactobacillus sp. in the gut stimulates bacterial tryptophan metabolism to confer protection from myocardial hypertrophy and LV dysfunction. Next, we will explore the role of cardiac miR-204 in mediating the cardioprotective effect of vancomycin on pressure overload-induced myocardial hypertrophy and LV dysfunction. We expect our study to identify specific microbes (e.g., Lactobacillus murinus), metabolites (e.g., tryptamine), and signaling intermediaries (e.g., miR-204) that mediate the cardioprotective effects of vancomycin. There is a crucial knowledge gap in our understanding of how the gut microbiome modulates cardiac contractile function. This gap is a hurdle to using gut microbiome manipulation as a therapeutic strategy for heart failure. This application will narrow this gap by exploring a novel nexus between gut bacteria, bacterial metabolites, and cardiac miR-204.
