Gut-microbial metabolism of aromatic amino acids and cardiovascular disease

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A novel gut microbial pathway has been clinically and mechanistically linked to cardiovascular disease (CVD) via generation of phenylacetylglutamine (PAGln), a compound we show to modulate adrenergic receptor signaling. PAGln is the product of a meta-organismal pathway that begins with gut microbial catabolism of dietary phenylalanine into phenylacetic acid followed by conjugation of glutamine by the host liver enzymes. PAGln is just one of a dozen possible microbial metabolites derived from aromatic amino acids. Using untargeted and targeted metabolomics, we have identified multiple gut-microbe metabolites derived from phenylalanine and tyrosine in clinical study samples that are associated (or not) with incident CVD risk. The overall goals of this application are to define gut microbial pathways of aromatic amino acid metabolism that impact host CVD. This is a critical initial step for improved understanding of gut microbiota contributions to CVD, and in the development of therapeutic strategies to leverage this information. In Aim 1 we will identify specific gut microbial metabolites derived from aromatic amino acids that can impact CVD phenotypes. In Aim 2, by combining microbial transplantation studies using genetically engineered human commensals (gain and loss of function mutants), we will test causal contribution of defined microbial enzymes to specific candidate metabolites linked to CVD.