Metaorganismal Endocrinology in Cardiometabolic Disease

摘要： 最近的证据表明，人类肠道中的微生物代表了 导致一些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通过该途径向宿主发出信号以促进这些疾病， 大部分未知。我们最近发现了一种超生物途径， 存在于高脂肪食物中的营养素（磷脂酰胆碱、胆碱和L-肉毒碱）可以是 由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 （FMO 3）以产生三甲基胺-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可保护小鼠免受 与高脂肪饮食有关的代谢紊乱出乎意料的是，这种保护 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。本提案中所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描述的饮食微生物来源的 时代精神。该项目的成功完成将通过提供证明变革 一种针对特定微生物酶的非抗生素药物可以作为 与昼夜节律紊乱有关的疾病的治疗策略。

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 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.