MICA: Host-microbial co-metabolite hippurate inhibits Mnk1 and regulates mRNA translation in metabolic diseases

我们肠道中的细菌在塑造我们的新陈代谢和健康方面起着至关重要的作用。我们的肠道细菌帮助我们将原本无法消化的食物，如纤维，分解成我们可以吸收的小分子。微生物群是由2000万个基因组成的肠道微生物携带的所有遗传物质，是我们肠道中制造化合物的小型制药厂，其中一些化合物的作用类似于药物。这些化合物被称为代谢物，不仅是生命的组成部分，也是必不可少的化学信使。然而，影响人类健康的关键微生物信号仍然难以捉摸。这个新的研究项目汇集了来自英国各地伦敦、剑桥和邓迪的顶尖专家以及来自加拿大蒙特雷亚尔的一位国际合作者，专注于了解我们的肠道细菌如何通过这些微生物化学物质与我们的器官交谈，以及它们如何结合细胞中特定类型的效应器，这种效应器就像分子开关一样，称为激酶，它调节我们的细胞如何对不断变化的环境做出反应。这个研究项目的重点是我们的肠道细菌产生的一种名为马尿酸的化学物质如何调节一种名为Mnk1的激酶。这种激酶控制着信使RNA的翻译，信使RNA是DNA蓝图的副本，它转化为蛋白质，在体内执行各种工作。这些工作包括糖和脂的新陈代谢，激素的产生或炎症，就像患有代谢性疾病的患者一样。我们的初步数据显示，马尿酸盐通过阻断Mnk1，阻止特定蛋白质的mRNA翻译和合成，这已经被证明对代谢性疾病是有益的。如果我们能证明这一机制，这意味着我们可以利用微生物群来改善患有2型糖尿病和肥胖症等代谢疾病的患者的健康。在这项研究拨款中，我们有三个主要目标：第一，我们将在剑桥和蒙特雷亚尔研究马尿酸盐对肠道、肝脏和脂肪细胞的影响，以及在喂食高脂饮食的小鼠中引发代谢性疾病的效果。我们将与专门从事芯片上器官的英国生物技术初创公司CN Bio Innovation合作，模拟马尿酸对肠道屏障和肝功能的影响，以及它如何使我们的肠道和肝脏更健康。第二，我们将识别对马尿酸做出反应的mRNA和蛋白质，以了解马尿酸盐如何改善健康。这将通过使用RNA-Seq和蛋白质组学等技术来实现，帝国理工学院、剑桥大学和邓迪大学的共同申请者掌握了这些技术。这将使我们能够准确地绘制出人类细胞中马尿酸的机制。最后，我们将分析几项对患有代谢性疾病的人群的研究数据，以找到更多证据表明马尿酸盐对患有代谢性疾病的人有益。我们将确定马尿酸影响的临床条件和风险因素，以确定马尿酸对人类的直接作用。总之，这项研究将帮助我们发现肠道细菌如何将营养物质转化为化学信使，调节肥胖和代谢性疾病中的人体新陈代谢。我们将特别放大马尿酸，以更好地了解微生物群控制人类生理的一个重要机制。这将使我们更好地了解微生物组如何有益地侵入宿主细胞机械，以塑造新陈代谢、健康和疾病。

The bacteria in our guts play a crucial role in shaping our metabolism and health. Our gut bacteria help us break down otherwise indigestible foods, such as fibres, into smaller molecules we can absorb. The microbiome, all the genetic material carried by our gut microbes made of 20 million genes, is a tiny pharmaceutical factory in our guts making compounds, some of which act like drugs. These compounds, called metabolites, not only are the building blocks of life but are also essential chemical messengers. However, the critical microbial signals influencing human health remain elusive. Bringing together leading experts from across the UK in London, Cambridge and Dundee and an international collaborator from Montréal in Canada, this new Research Project focusses on understanding how our gut bacteria talk to our organs through these microbial chemicals and how they bind a certain type of effector in the cell acting like molecular switches, called kinases, which regulate how our cells react to a changing environment. This Research Project focuses on how a chemical produced by our gut bacteria called hippurate regulates a kinase called Mnk1. This kinase controls the translation of messenger RNAs, the copy of the DNA blueprint, into proteins, which carry out various jobs in the body. These jobs include metabolism of sugar and lipids, hormone production or inflammation, as this is the case for patients living with metabolic diseases.Our pilot data show that hippurate, by blocking Mnk1, stops mRNA translation and synthesis of particular proteins, which has already been shown to be beneficial in metabolic diseases. If we can demonstrate this mechanism, this means we could harness the microbiome to improve the health of patients with metabolic conditions such as type 2 diabetes and obesity. In this Research Grant, we have three major aims:First, we will study in Cambridge and Montréal the effect of hippurate on gut, liver and fat cells and in mice fed a high-fat diet to trigger metabolic diseases. Partnering with UK biotech start-up CN Bio Innovations specialised in Organs-on-Chip, we will model the effect of hippurate on gut barrier and liver function which are both important in metabolic diseases, and how it can make our gut and liver healthier.Second, we will identify the mRNAs and proteins responding to hippurate to understand how hippurate improves health. This will be achieved by using technologies such as RNA-Seq and proteomics, which are mastered by our co-applicants at Imperial, Cambridge and Dundee. This will allow us to precisely map the hippurate mechanism in human cells.Finally, we will analyse data from several studies of human populations with metabolic diseases to find more evidence about hippurate's beneficial roles for people living with metabolic diseases. We will identify the clinical conditions and risk factors affected by hippurate, to define hippurate's direct role in humans.In conclusion, this research will help us discover how gut bacteria turn nutrients into chemical messengers regulating human metabolism in obesity and metabolic diseases. We will zoom in on hippurate in particular to better understand an important mechanism by which the microbiome controls human physiology. This will allow us to understand better how the microbiome beneficially hacks the host cellular machinery to shape metabolic health and disease.