Metaorganismal Endocrinology in Cardiometabolic Disease

心血管代谢疾病的代谢内分泌学

• 批准号: 10311272
• 负责人: Jonathan Mark Brown
• 金额: $ 53.17万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-13 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10311272
• 关键词: Address; Adipose tissue; Amines; Bile Acids; Biological; Cardiometabolic Disease; Cardiovascular Diseases; Carnitine; Choline; Chronic; Chronotherapy; Circadian Dysregulation; Circadian Rhythms; Communities; Cues; Data; Development; Diabetes Mellitus; Diet; Disease; Drug Targeting; Endocrinology; Energy Metabolism; Environment; Environmental Risk Factor; Enzymes; FMO3; Fatty acid glycerol esters; Feedback; Food; G-Protein-Coupled Receptors; Genome; Germ-Free; Glucose; Hepatic; High Fat Diet; Homeostasis; Homo sapiens; Human; Human body; Ingestion; Insulin; Insulin Resistance; Intestines; Kidney; Lecithin; Levocarnitine; Light; Link; Lipids; Liver; Lyase; Malignant Neoplasms; Metabolic; Metabolic Diseases; Metabolism; Microbe; Micronutrients; Molecular; Mus; Nutrient; Obesity; Pathogenesis; Pathway interactions; Peripheral; Pharmacology; Phase; Phosphatidylcholine Biosynthesis; Phospholipid Metabolism; Predisposition; Production; Publishing; Regulation; Signal Transduction; Skeletal Muscle; TPD52L1 gene; Testing; Therapeutic; Transplantation; Volatile Fatty Acids; Work; cardiometabolism; circadian; circadian pacemaker; gut microbes; gut microbiome; hormonal signals; host microbiota; human disease; improved; inhibitor/antagonist; insight; microbial; mutant; novel; prevent; public health relevance; receptor; response; small molecule; symbiont; trimethylamine; trimethyloxamine

Abstract: Recent evidence has emerged that microbes resident in the human intestine represent a key transmissible environmental factor contributing to a number of human diseases including obesity, diabetes, cardiovascular disease, and cancer. However, mechanisms by which gut microbial-derived factors signal to the host to promote these diseases are largely unknown. We have recently discovered a metaorganismal 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). Here we show that pharmacologic inhibition of the gut microbial choline TMA lyase enzyme CutC/D protects mice against the metabolic disturbances associated with a high fat diet. Unexpectedly, this protection is associated with reorganization of host circadian control of both phosphatidylcholine and energy metabolism. These studies described in this proposal will be significant because they have the potential to uncover the first ever described diet-microbe-derived zeitgeber. Successful completion of this project will be transformative by providing proof of concept that a non-antibiotic drug targeting a specific microbial enzyme can serve as a therapeutic strategy for diseases associated with circadian disruption.

抽象的： 最近有证据表明，驻留在人类肠中的微生物代表 关键可传播环境因素导致许多人类疾病 包括肥胖，糖尿病，心血管疾病和癌症。但是，机制 肠道微生物衍生的因子向宿主发出信号以促进这些疾病是 在很大程度上未知。我们最近发现了一种元有机途径 高脂食品（磷脂酰胆碱，胆碱和L-肉碱）中存在的营养可能是 由肠道微生物酶代谢以产生三甲胺（TMA），这是 然后由含有含含黄蛋白的单加氧酶3的宿主酶代谢 （FMO3）产生三甲胺-N-氧化物（TMAO）。在这里，我们证明了药理学 抑制肠道微生物胆碱TMA裂解酶CUTC/D可保护小鼠免受 与高脂饮食有关的代谢障碍。出乎意料的是，这种保护 与两种磷脂酰胆碱的宿主昼夜节律控制的重组有关 和能量代谢。这些提案中描述的这些研究将是重要的 因为他们有可能发现有史以来第一个描述的饮食 - 微生物衍生的 Zeitgeber。通过提供证据，成功完成该项目将具有变革性 旨在靶向特定微生物酶的非抗生素药物可以用作的概念 与昼夜节律中断相关的疾病的治疗策略。