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.

摘要： 最近有证据表明，居住在人体肠道中的微生物代表一种 导致许多人类疾病的关键可传播环境因素 包括肥胖、糖尿病、心血管疾病和癌症。然而，机制 肠道微生物衍生因子通过哪些信号向宿主传递促进这些疾病的信号 很大程度上是未知的。我们最近发现了一条超生物路径，在那里 高脂肪食物中存在的营养物质(磷脂酰胆碱、胆碱和L肉碱)可以 由肠道微生物酶代谢产生三甲胺(TMA)，这是 然后被宿主酶黄素单加氧酶3进一步代谢 (FMO3)生产三甲胺-N-氧化物(TMAO)。在这里，我们展示了药理学 抑制肠道微生物胆碱TMA裂解酶CutC/D保护小鼠免受 与高脂肪饮食相关的新陈代谢紊乱。出乎意料的是，这种保护 与宿主对卵磷脂的昼夜节律控制的重组有关 和能量新陈代谢。这项提案中描述的这些研究将具有重要意义 因为他们有可能发现有史以来第一个被描述的饮食-微生物来源 Zeitgeber。这个项目的成功完成将是变革性的，通过提供证据 一种针对特定微生物酶的非抗生素药物可以作为 针对与昼夜节律紊乱相关的疾病的治疗策略。