Project 1 Title: Gut microbial metabolites as drivers of ethanol-induced liver injury

项目 1 标题：肠道微生物代谢物作为乙醇引起的肝损伤的驱动因素

• 批准号: 10609540
• 负责人: Jonathan Mark Brown
• 金额: $ 27.42万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609540
• 关键词: Address; Alcohol abuse; Alcohol consumption; Alcoholic Fatty Liver; Alcoholic Liver Diseases; Alcohols; Amines; Cardiovascular Diseases; Carnitine; Choline; Chronic Kidney Failure; Chronotherapy; Circadian Dysregulation; Circadian Rhythms; Communication; Communities; Cues; Data; Development; Diabetes Mellitus; Diet; Disease; Drug Targeting; Environment; Environmental Risk Factor; Enzyme Inhibitor Drugs; Enzymes; Ethanol; FMO3; FRAP1 gene; Fatty acid glycerol esters; Feces; Food; Funding; G-Protein-Coupled Receptors; Genome; Germ-Free; Grant; Hepatic; Homeostasis; Homo sapiens; Human; Human body; Intestines; Knowledge; Lecithin; Levocarnitine; Link; Liver; Liver diseases; Lyase; Malignant Neoplasms; Microbe; Micronutrients; Mus; Muscular Atrophy; Mutate; National Institute on Alcohol Abuse and Alcoholism; Nutrient; Obesity; Organism; Pathogenesis; Pathway interactions; Patients; Peripheral; Production; R24; Research Personnel; Signal Transduction; Testing; Therapeutic; Time; Tissues; Transplantation; biobank; circadian; circadian pacemaker; cohort; fatty liver disease; gut microbes; gut microbiome; host microbiota; human disease; inhibitor; integrated circuit; liver development; liver injury; microbial; mouse model; mutant; non-alcoholic fatty liver; pharmacologic; receptor; sarcopenia; skeletal muscle metabolism; skeletal muscle wasting; small molecule; symbiont; tissue injury; transmission process; 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. 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 alcoholic liver disease. Unexpectedly, this protection is associated with reorganization of the host circadian clock. Our specific aims are: Aim 1. Testing the hypothesis that alcohol-induced circadian disruption depends on gut microbial TMA production, and that TMA lyase inhibitors represent a gut microbe-targeted chronotherapy; and Aim 2. Testing the hypothesis that the microbe-derived metabolite TMA activates the host G protein-coupled receptor trace amine-associated receptor 5 (TAAR5) to Promote Ethanol-Driven Sarcopenia. These studies 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 alcohol-induced tissue injury.

抽象的 最近有证据表明，驻留在人类肠道中的微生物代表了可传播的关键 环境因素导致许多人类疾病。但是，肠道的机制 微生物衍生的因子向宿主发出信号以促进这些疾病是未知的。我们最近有 发现了一种元有机途径，在高脂食物中存在营养（磷脂酰胆碱，胆碱， 和l-肉碱）可以通过肠道微生物酶代谢，以产生三甲胺（TMA），这是 然后由含有含有黄蛋白的单加氧酶3（FMO3）的宿主酶进一步代谢 三甲胺-N-氧化物（TMAO）。在这里我们表明肠道微生物胆碱TMA的药理抑制 裂解酶CUTC/D可保护小鼠免受酒精性肝病的侵害。出乎意料的是，这种保护是相关的 随着主机昼夜节律的重组。我们的具体目的是：目标1。检验以下假设： 酒精引起的昼夜节律破坏取决于肠道微生物TMA的产生，而TMA裂解酶抑制剂 代表肠道微生物靶向的年代疗法；和目标2。测试微生物衍生的假设 代谢物TMA激活宿主G蛋白偶联受体痕量胺相关受体5（TAAR5）至 促进乙醇驱动的肌肉减少症。这些研究将是重要的，因为它们有可能 发现有史以来第一个描述的饮食 - 微生物衍生的Zeitgeber。这个项目的成功完成将是 通过提供旨在特定微生物酶的非抗生素药物的概念证明来进行变革性。 可以用作酒精诱导的组织损伤的治疗策略。