Project 2: Gut microbial choline metabolites in cardiometabolic disease

项目2：心脏代谢疾病中的肠道微生物胆碱代谢物

• 批准号: 10447070
• 负责人: Jonathan Mark Brown
• 金额: $ 52.33万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10447070
• 关键词: Adipose tissue; Amines; Anaerobic Bacteria; Atherosclerosis; Bile Acid Biosynthesis Pathway; Bile Acids; Bile fluid; Biliary; Cardiometabolic Disease; Choline; Communities; Data; Development; Diabetes Mellitus; Environmental Risk Factor; Enzymes; FMO3; Fatty acid glycerol esters; Flavins; Food; G-Protein-Coupled Receptors; Genetic Transcription; Genome; Germ-Free; Goals; Hepatobiliary; High Fat Diet; Homeostasis; Homo sapiens; Hormones; Human; Human body; Intake; Intestines; Kinetics; Lecithin; Levocarnitine; Link; Liver; Lyase; Mediating; Metabolic; Metabolism; Mitochondria; Mixed Function Oxygenases; Molecular; Multienzyme Complexes; Mus; Nutrient; Obesity; Operon; Oxidants; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Predisposition; Production; Publishing; Receptor Signaling; Research Personnel; Respiration; Signal Transduction; Sterols; Structure; System; Testing; Therapeutic; Thermogenesis; Thrombosis; Tissue Expansion; Tissues; Transplantation; Up-Regulation; Work; cardiometabolism; commensal bacteria; diet-induced obesity; dietary; disorder risk; feeding; gut microbes; gut microbiome; gut microbiota; host microbiota; in vivo; inhibitor; insight; integrated circuit; member; microbial; microbiome; mutant; receptor; reverse cholesterol transport; small molecule; symbiont; targeted treatment; therapeutic target; trimethylamine; trimethyloxamine

Abstract: Recent evidence has emerged that microbes resident in the human intestine represent a key transmissible environmental factor contributing to obesity-associated cardiometabolic disease. However, mechanisms by which gut microbial-derived factors signal to the host to promote obesity are largely unknown. We have recently discovered a meta-organismal pathway where nutrients present in high fat foods (phosphatidylcholine, choline, and L-carnitine) can be metabolized by the gut microbial enzymes to generate trimethylamine (TMA), which is then further metabolized by the host enzyme flavin-containing monooxygenase 3 (FMO3) to produce trimethylamine-N- oxide (TMAO). With Dr. Hazen's group (Project 1) we discovered that pharmacologic inhibition of gut microbial choline TMA lyase activity (CutC/D) protects mice against in vivo thrombosis and high fat diet-driven obesity. Interestingly, dietary provision of TMA, but not TMAO, reverses the anti-obesity effects of TMA lyase inhibitors. Whereas, the prothrombotic effects of this pathway are initiated by TMAO. We have also found that gut microbial TMAO is abundantly secreted into bile, and the hepatobiliary secretion of TMAO is transcriptionally controlled by the bile acid receptor farnesoid X receptor (FXR). Collectively, our data support the following central hypothesis: The gut microbial co- metabolites TMA and TMAO are unique hormone-like contributors to developing obesity, thrombosis, and atherosclerosis. Our specific aims are: Aim 1. Testing the hypothesis that gut microbial choline TMA lyase activity enhances susceptibility for high fat diet- driven obesity via a host TMA - Taar5 receptor signaling axis. and Aim 2. We will test the hypothesis that FXR-driven hepatobiliary secretion of TMAO initiates an enterohepatic signaling axis that regulates gut microbiome community structure and host bile acid and sterol metabolism. We anticipate our studies to reveal new molecular mechanisms linking gut microbe-derived metabolites TMA and TMAO to cardiometabolic diseases, which will ultimately be leveraged into to the first ever gut microbe-targeted therapeutics targeting the metaorganismal TMAO pathway. !

抽象的： 最近有证据表明，驻留在人类肠中的微生物代表 关键的可传播环境因素有助于肥胖相关 心脏代谢疾病。但是，肠道微生物衍生因子的机制 向宿主促进肥胖的信号在很大程度上是未知的。我们最近发现了 一种荟萃生物途径，在高脂肪食物中存在营养 （磷脂酰胆碱，胆碱和L-肉碱）可以通过肠道微生物代谢 酶产生三甲胺（TMA），然后由该酶进一步代谢 宿主酶黄素单加氧酶3（FMO3）产生三甲胺-N- 氧化物（TMAO）。在Hazen博士的小组（项目1）中，我们发现了药理学 抑制肠道微生物胆碱TMA裂解酶活性（CUTC/D）可保护小鼠免受IN的影响 体内血栓形成和高脂肪饮食驱动的肥胖症。有趣的是，TMA的饮食提供， 但不是TMAO，可以逆转TMA裂解酶抑制剂的抗肥胖作用。而， TMAO启动了该途径的促栓性作用。我们还发现肠道 微生物tmao大量分泌到胆汁中，并分泌 TMAO由胆汁酸受体Farnesoid X受体（FXR）进行转录控制。 总的来说，我们的数据支持以下中心假设：肠道微生物共同 代谢物TMA和TMAO是肥胖的独特类似激素样的贡献者， 血栓形成和动脉粥样硬化。我们的具体目的是：目标1。检验假设 肠道微生物胆碱TMA裂解酶的活性增强了对高脂饮食的敏感性 - 通过宿主TMA -TAAR5受体信号轴驱动的肥胖。和目标2。我们将测试 FXR驱动的TMAO分泌的假设启动了 调节肠道微生物组社区结构和主机的肠肝信号传导轴 胆汁酸和固醇代谢。我们预计我们的研究将揭示新的分子 将肠道微生物衍生的代谢物TMA和TMAO连接到心脏代谢的机制 疾病最终将被利用到有史以来第一个肠道微生物靶向的疾病 针对元有机TMAO途径的治疗剂。 呢