Metaorganismal Endocrinology in Cardiometabolic Disease

心血管代谢疾病的代谢内分泌学

• 批准号: 10468993
• 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/10468993
• 关键词: Address; Adipose tissue; Amines; Bile Acids; 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; insight; integrated circuit; 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.

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