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

摘要 最近的证据表明，人类肠道中的微生物是一种关键的传染性疾病， 环境因素导致了许多人类疾病。然而，肠道 微生物衍生因子向宿主发出信号以促进这些疾病在很大程度上是未知的。我们最近 发现了一种代谢途径，其中存在于高脂肪食物中的营养物质（磷脂酰胆碱，胆碱， 和L-肉毒碱）可以被肠道微生物酶代谢产生三甲胺（TMA）， 然后由宿主酶含黄素单加氧酶3（FMO 3）进一步代谢， 三甲基胺-N-氧化物（TMAO）。在这里，我们表明，药理学抑制肠道微生物胆碱TMA 裂解酶CutC/D保护小鼠免受酒精性肝病。出乎意料的是，这种保护与 宿主生物钟的重组。我们的具体目标是：目标1。测试假设， 酒精诱导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时间疗法;和目标2.检验微生物来源的 代谢物TMA激活宿主G蛋白偶联受体痕量胺相关受体5（TAAR 5）， 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 发现了第一个被描述的饮食微生物来源的时间表。该项目的成功完成将是 通过提供一种针对特定微生物酶的非抗生素药物的概念证明， 可以作为酒精诱导的组织损伤的治疗策略。

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.