Gut-microbial metabolism of aromatic amino acids and cardiovascular disease

一种新的肠道微生物途径在临床和机制上与心血管疾病有关 疾病(CVD)通过生成苯乙酰谷氨酰胺(PAGln)，我们展示了一种化合物 调节肾上腺素能受体信号。PAGln是一种元生物途径的产物 这始于肠道微生物将饮食中的苯丙氨酸分解为苯乙酸 然后是宿主肝酶与谷氨酰胺的结合。PAGln只是十几个中的一个 芳香族氨基酸可能产生的微生物代谢物。使用非目标和 靶向代谢组学，我们已经鉴定出来自于 与事件相关(或无关)的临床研究样本中的苯丙氨酸和酪氨酸 心血管疾病风险。本应用程序的总体目标是定义芳香族的肠道微生物途径 影响宿主心血管疾病的氨基酸代谢。这是改进的关键的第一步 了解肠道微生物区系在心血管疾病中的作用，以及在治疗方法的发展中的作用 利用这些信息的策略。在目标1中，我们将识别特定的肠道微生物代谢物 来源于芳香氨基酸，可影响心血管疾病的表型。在目标2中，通过结合 使用基因工程人类共生体的微生物移植研究(GAIN和 功能突变丧失)，我们将测试定义的微生物酶对 与心血管疾病有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.