Project 2: Gut microbial choline metabolites in cardiometabolic disease

摘要： 最近有证据表明，居住在人体肠道中的微生物代表一种 与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的机制 向宿主发出的促进肥胖的信号在很大程度上是未知的。我们最近发现 营养物质存在于高脂肪食物中的一种代谢途径 (磷脂酰胆碱、胆碱和L肉碱)可被肠道微生物代谢 产生三甲胺(TMA)的酶，然后进一步由 宿主酶含黄素的单加氧酶3(FMO3)产生三甲胺-N- 氧化物(TMAO)。在黑曾博士的团队(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)保护小鼠免受 体内血栓形成和高脂饮食导致的肥胖。有趣的是，TMA的饮食供应， 但不是TMAO，逆转了TMA裂解酶抑制剂的减肥效果。鉴于， 这一途径的血栓前效应是由TMAO启动的。我们还发现了那个肠子 微生物TMAO大量分泌到胆汁中，肝胆分泌物 TMAO受胆汁酸受体法尼醇X受体(FXR)转录调控。 总的来说，我们的数据支持以下中心假设：肠道微生物共同作用 代谢物TMA和TMAO是导致肥胖的独特的激素样贡献者， 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裂解酶活性增加了对高脂肪饮食的易感性- 通过宿主TMA-Taar5受体信号轴驱动肥胖。目标2。我们将测试 FXR驱动的TMAO肝胆分泌启动AFP的假说 调节肠道微生物群落结构和宿主的肠-肝信号轴 胆汁酸和甾醇代谢。我们期待我们的研究能揭示新的分子。 肠道微生物代谢产物TMA和TMAO与心脏代谢的关系 疾病，这些疾病最终将被利用成有史以来第一个以肠道微生物为靶标的 以超生物TMAO途径为靶点的治疗。 好了！

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. !