Wednesday, February 5, 2025
2/5/2025
Project Summary This application is entitled “Gut microbial dietary phenylalanine metabolism and heart failure”. There is rapidly growing awareness of the significant role of diet and the gut microbiome to human health and disease. Here we examine how differences in macronutrient metabolism between subjects at risk for heart failure are linked to changes in gut microbial community structure and function, and contribute to disease (heart failure) etiology. Specifically, how alterations in gut microbial phenylalanine metabolism impacts patient risks for development of disease, and multiple pathophysiologic mechanisms linked to heart failure relevant phenotypes. Our studies reveal how altered microbial metabolism of phenylalanine, an essential macronutrient, alters metabolic homeostasis, examined new biomarkers of both heart failure development risk, and how protein diet / nutrient exposure alters susceptibility to disease. The studies explore a meta-organismal pathway (involving both microbes, and host enzymes) for a metabolite linked to cardiovascular disease, with focus on heart failure. We identify in preliminary studies striking clinical associations between microbe dependent metabolites derived from dietary phenylalanine, and heart failure development. And in preliminary animal model studies, observe recapitulation of these clinical observations extending to evidence of a causal link between gut microbial metabolite generation and multiple heart failure related phenotypes. Our studies aim to explore whether nutrient intake (dietary protein), via gut microbe dependent changes in host metabolism (metabolite levels), is linked to adaptive physiological responses, and when in excess, maladaptive effects on myocardial function and remodeling. The studies proposed are multidisciplinary, ranging from human clinical observational studies, to more mechanistic microbial engineering, cellular, and preclinical disease model investigations. Defined microbial contributors to the metaorganismal pathway are examined in model gnotobiotic systems designed to recapitulate the complex microbial community / host integrated network that collectively contribute to the metabolic and physiological effects observed in vivo. Successful completion of the proposed studies will further advance our knowledge of how dietary nutrients, through the filter of our gut microbial community, can impact host metabolism, physiology and disease etiology.
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