Gut-microbial metabolism of aromatic amino acids and cardiovascular disease

一种新的肠道微生物途径在临床上和机制上与心血管疾病有关。 通过产生苯乙酰谷氨酰胺（PAGln）来治疗CVD疾病，我们发现这种化合物 调节肾上腺素能受体信号传导。PAGln是一种代谢途径的产物 首先是肠道微生物将食物中的苯丙氨酸转化为苯乙酸 随后通过宿主肝酶缀合谷氨酰胺。PAGln只是一打 来源于芳香族氨基酸的可能的微生物代谢物。使用无目标和 有针对性的代谢组学，我们已经确定了多种肠道微生物代谢物来源于 临床研究样本中的苯丙氨酸和酪氨酸与事件相关（或不相关） CVD风险。本申请的总体目标是确定芳香族化合物的肠道微生物途径。 影响宿主CVD的氨基酸代谢。这是改善的关键第一步。 了解肠道微生物群对CVD的贡献，并在开发治疗 策略来利用这些信息。在目标1中，我们将确定特定的肠道微生物代谢产物 源自芳香族氨基酸，可影响CVD表型。在目标2中， 使用基因工程人类胚胎的微生物移植研究（gain和 功能丧失突变体），我们将测试确定的微生物酶的因果贡献， 与CVD相关的特定候选代谢物。

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.