Project 2: Gut microbial choline metabolites in cardiometabolic disease

摘要： 最近的证据表明，人类肠道中的微生物代表了 导致肥胖相关的关键可传播环境因素 心脏代谢疾病然而，肠道微生物衍生因子 向宿主发出促进肥胖的信号在很大程度上是未知的。我们最近发现 高脂肪食物中的营养物质 （磷脂酰胆碱，胆碱和L-肉毒碱）可以通过肠道微生物代谢， 酶产生三甲胺（TMA），然后进一步代谢的 宿主酶含黄素单加氧酶3（FMO 3）产生三甲胺-N- 氧化物（TMAO）。在哈岑博士的小组（项目1）中，我们发现药理学 抑制肠道微生物胆碱TMA裂解酶活性（CutC/D）可保护小鼠免受 体内血栓形成和高脂肪饮食导致的肥胖。有趣的是，TMA的饮食供应， 而不是TMAO逆转TMA裂解酶抑制剂的抗肥胖作用。鉴于 该途径的促血栓形成作用由TMAO引发。我们还发现， 微生物TMAO大量分泌到胆汁中， TMAO由胆汁酸受体法尼醇X受体（FXR）转录控制。 总的来说，我们的数据支持以下中心假设：肠道微生物共- 代谢物TMA和TMAO是发展肥胖症的独特的类似脂肪的贡献者， 血栓形成和动脉粥样硬化。我们的具体目标是：目标1。检验假设 肠道微生物胆碱TMA裂解酶活性增强了对高脂肪饮食的易感性- 通过宿主TMA-Taar 5受体信号传导轴驱动肥胖。目标2我们将测试 FXR驱动的TMAO的肝胆分泌启动了一种 调节肠道微生物群落结构和宿主的肝肠信号传导轴 胆汁酸和固醇代谢。我们希望我们的研究能揭示新的分子 肠道微生物衍生的代谢物TMA和TMAO与心脏代谢相关的机制 疾病，这将最终被利用到有史以来第一个肠道微生物为目标， 靶向代谢生物体TMAO途径的治疗剂。 !

Abstract: Recent evidence has emerged that microbes resident in the human intestine represent a key transmissible environmental factor contributing to obesity-associated cardiometabolic disease. However, mechanisms by which gut microbial-derived factors signal to the host to promote obesity are largely unknown. We have recently discovered a meta-organismal 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). With Dr. Hazen's group (Project 1) we discovered that pharmacologic inhibition of gut microbial choline TMA lyase activity (CutC/D) protects mice against in vivo thrombosis and high fat diet-driven obesity. Interestingly, dietary provision of TMA, but not TMAO, reverses the anti-obesity effects of TMA lyase inhibitors. Whereas, the prothrombotic effects of this pathway are initiated by TMAO. We have also found that gut microbial TMAO is abundantly secreted into bile, and the hepatobiliary secretion of TMAO is transcriptionally controlled by the bile acid receptor farnesoid X receptor (FXR). Collectively, our data support the following central hypothesis: The gut microbial co- metabolites TMA and TMAO are unique hormone-like contributors to developing obesity, thrombosis, and atherosclerosis. Our specific aims are: Aim 1. Testing the hypothesis that gut microbial choline TMA lyase activity enhances susceptibility for high fat diet- driven obesity via a host TMA - Taar5 receptor signaling axis. and Aim 2. We will test the hypothesis that FXR-driven hepatobiliary secretion of TMAO initiates an enterohepatic signaling axis that regulates gut microbiome community structure and host bile acid and sterol metabolism. We anticipate our studies to reveal new molecular mechanisms linking gut microbe-derived metabolites TMA and TMAO to cardiometabolic diseases, which will ultimately be leveraged into to the first ever gut microbe-targeted therapeutics targeting the metaorganismal TMAO pathway. !