Metaorganismal Endocrinology in Cardiometabolic Disease

心血管代谢疾病的代谢内分泌学

基本信息

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
项目类别：
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

项目摘要

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：最近的证据表明，居住在人类肠道中的微生物代表了导致多种人类疾病的关键传染性环境因素包括肥胖、糖尿病、心血管疾病和癌症。然而，机制肠道微生物衍生因子向宿主发出信号以促进这些疾病的发生很大程度上不为人知。我们最近发现了一种代谢途径高脂肪食物中的营养物质（磷脂酰胆碱、胆碱和左旋肉碱）可以经肠道微生物酶代谢产生三甲胺（TMA），然后进一步被宿主酶含黄素单加氧酶3代谢 (FMO3) 生成三甲胺-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 可保护小鼠免受与高脂肪饮食相关的代谢紊乱。没想到这个保护与宿主对磷脂酰胆碱的昼夜节律控制的重组有关和能量代谢。本提案中描述的这些研究将具有重要意义因为他们有潜力发现有史以来第一个描述的源自饮食的微生物时间。通过提供证明，该项目的成功完成将带来变革概念是针对特定微生物酶的非抗生素药物可以作为与昼夜节律紊乱相关的疾病的治疗策略。