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Gut-microbial metabolism of aromatic amino acids and cardiovascular disease

芳香氨基酸的肠道微生物代谢与心血管疾病

基本信息

批准号：
10338499
负责人：
Ina Nemet
金额：
$ 55.81万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-15 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10338499
关键词：
Acids Adrenergic Receptor Agonist Animals Antibiotics Aromatic Amino Acids Atherosclerosis Award Benzoic Acids Binding Proteins Blood Platelets Bypass Cardiac Cardiovascular Diseases Catabolism Clinical Clinical Pathways Clinical Research Coagulation Process Cohort Studies Cresol Data Development Diet Habits Dietary Proteins Disease susceptibility Enzymes Event Funding Future Generations Genes Genetic Engineering Germ-Free Glutamine Goals Health Healthy Eating Human Human Engineering In Vitro Individual Lead Link Lipoproteins Liver Maps Metabolic Metabolism Mus Output Pathway interactions Phenotype Phenylalanine Phenylalanine Metabolism Pathway Physiology Plasma Production Receptor Signaling Research Risk Role Sampling Studies Stroke Sulfate Testing Therapeutic Thrombosis Tracer Transplantation Tyrosine Validation amino acid metabolism base cardiovascular disorder prevention cardiovascular disorder risk defined contribution dietary disease phenotype gut microbes gut microbiota improved in vivo loss of function metabolomics microbial microbial community microbiome mortality risk mutant novel phenylacetic acid platelet function prevent stable isotope therapeutic development thrombotic tyrosine analog vascular inflammation

项目摘要

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.

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。