The gut-kidney-heart axis as a driver of cardiovascular disease progression

即使是肾脏功能的适度下降(20%-30%)也不会让患者去肾脏诊所就诊，也会使未来患心脏病的风险增加一倍。例如，在英国，预计到2030年将有超过500万人患有糖尿病。其中，大约40%(200万)会出现肾脏并发症，随着病情的发展，许多人将需要透析。在接下来的10年里，肾脏功能不正常的糖尿病患者死于中风和心脏病发作的可能性是那些肾脏功能不正常的患者的10倍。因此，找到保护肾脏的新方法是很重要的。生活在我们的消化系统中的数以百万计的细菌，特别是肠道，被称为肠道微生物区系，影响我们使用食物的方式。我们肠道中的这些细菌与宿主交流的一种方式是通过产生化学物质(称为代谢物)，我和其他研究人员已经证明，这种化学物质也会影响我们肾脏的工作。在这项研究中，我想通过减少生活在我们肠道中的细菌产生的有害代谢物来找到保护肾脏的新方法。在试点研究中，使用机器学习和来自德国、法国和丹麦的2200名患者的数据，我发现来自氨基酸苯丙氨酸的细菌产生的一种名为苯乙酰谷氨酰胺的化学物质对肾脏有害，而另一种也可以从苯丙氨酸中提取的化学物质称为3-苯丙酸具有保护作用。现在，我将与来自德国、法国、丹麦和加拿大的顶尖科学家和医生合作，利用机器学习和大数据分析，看看血液中这些化学物质的平衡是否可以作为人类未来严重肾脏和心脏并发症的早期预警信号。除了我在中生成试点数据的原始研究(MetaCardis，N=2200)之外，我还将使用两项人体研究的信息，这两项研究跟踪并收集了长达6年的健康人(9,500名参与者的加拿大纵向老龄化研究)或慢性肾脏病早期患者(德国慢性肾脏病患者，5,000名参与者)的数据。在我的这部分工作中，我将使用来自三项独立人体研究的16,700人的丰富信息，这些研究花费了数千万英镑。然后，在我研究的第二部分，在伦敦和牛津，以及我将在这个项目中聘请的一名研究助理，与帝国理工学院国家心肺研究所和MRC Harwell的科学家合作，我将用这些化学物质治疗患有糖尿病和高血压的细胞和老鼠，研究它们如何改变心脏和肾脏的工作方式。通过这种方式，我希望能更好地了解他们的作用方式，以及如何通过利用微生物群来更好地保护心脏和肾脏。最后，在伦敦和牛津帝国理工学院NHLI和MRC-Harwell，并与来自美国斯坦福德大学的细菌苯丙氨酸新陈代谢的领先专家合作，我将与研究助理一起在老鼠身上测试改良细菌、现有药物和益生菌，看看我是否可以恢复这些化学物质之间的平衡，并保护这些老鼠免受心脏和肾脏疾病的影响。通过改变已经可以安全用于患者的干预措施，我希望能够“破解”微生物群，产生一种有益的化学物质，而不是有害的化学物质。总而言之，如果成功，我的研究将引入一个新的风险因素(微生物群苯丙氨酸代谢)，可以帮助医生更好地预测哪个患者更有可能心脏病发作或肾功能衰竭，并优先治疗。此外，我的工作将产生新的信息，以提高我们对肠道细菌如何改变我们肾脏和心脏工作方式的理解。最后，通过找到重新编程微生物组苯丙氨酸代谢的方法，我的工作可以直接导致人类临床试验。

Even a moderate decrease in how well our kidneys work (by 20-30%) at levels that would not refer a patient to the kidney clinic, can double the risk of future heart disease. For example, in the UK, more than 5million people are predicted to have diabetes by 2030. Of those, approximately 40% (2 million) will develop kidney complications and many will require dialysis as their disease progresses. Patients with diabetes whose kidneys do not work well are up to 10 times more likely to die from strokes and heart attacks in the next 10 years than those who do not. It is therefore important to find new ways to protect the kidney.The millions of bugs that live in our digestive system, especially gut; known as the gut microbiota, affect how we use our food. One way that these bugs in our guts can communicate with their host is by producing chemicals (called metabolites) that I and other researchers have shown that can also affect how our kidneys work.In this research, I want to find new ways to protect the kidney by reducing harmful metabolites produced by the bacteria that live in our gut.In pilot studies, using machine learning and data from 2200 patients from Germany, France and Denmark, I discovered that a chemical made by bugs from the amino acid phenylalanine called phenylacetylglutamine can be harmful for the kidney, while another chemical that can also be made from phenylalanine called 3-phenylpropionate is protective. Now, working together with leading scientists and medical doctors from Germany, France, Denmark and Canada I will use machine learning and big data analyses to see if the balance of these chemicals in the blood can be used as an early warning sign of future serious kidney and heart complications in humans. In addition to the original study (MetaCardis, N=2200) I generated my pilot data in, I will also use information from two human studies that followed and collected data from healthy people (Longitudinal Canadian Study of Aging with 9,500 participants) or people at early stages of chronic kidney disease (German CKD with 5,000 participants) for up to 6 years. For this part of my work, I will use a wealth of information from 16,700 individuals from three independent human studies that has costed tens of millions of pounds to be collected.Then, in the second part of my study, in London and Oxford, together with a Research Assistant I will hire as part of this project and in collaborations with scientist from the Imperial College National Heart and Lung Institute and MRC Harwell, I will treat cells and mice that have diabetes and high blood pressure with these chemicals to study how they change the way the heart and kidney works. In this way, I hope to better understand their mode of action and how to better protect the heart and the kidney by harnessing the microbiome. Finally, in London and Oxford at the Imperial College NHLI and MRC-Harwell and in collaboration with the leading expert of bacterial phenylalanine metabolism from the University of Stamford in the USA, I together with the Research Assistant will test modified bacteria, existing drugs and probiotics in mice to see if I can restore the balance between these chemicals and protect these mice from heart and kidney disease. By re-purposing interventions already safe for use in patients I hope to be able to "hack" the microbiome to produce a beneficial chemical instead of a harmful one. In summary, if successful, my research will introduce a new risk factor (microbiota phenylalanine metabolism) that can help medical doctors better predict which patient is more at risk of heart attack or kidney failure and prioritise treatment. Additionally, my work will generate new information to improve our understanding of how the bacteria in our gut change the way our kidneys and heart works. Finally, by finding ways to re-program microbiome phenylalanine metabolism, my work can directly lead to human clinical trials.