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纤维等难以消化的食物分解成我们可以吸收的小分子。微生物组，由我们的肠道微生物携带的所有遗传物质由2000万个基因组成，是我们肠道中的一个小型制药厂，制造化合物，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，不仅是生命的基石，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。汇集来自英国各地的领先专家在伦敦，剑桥和邓迪和来自加拿大蒙特利尔的国际合作者，这个新的研究项目的重点是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某种类型的效应器，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化学物质马尿酸盐如何调节一种名为Mnk 1的激酶。这种激酶控制信使RNA（DNA蓝图的拷贝）翻译成蛋白质，蛋白质在体内执行各种工作。这些工作包括糖和脂质的代谢，激素的产生或炎症，因为这是生活在代谢性疾病患者的情况下。我们的初步数据显示，马尿酸盐，通过阻断Mnk 1，停止mRNA翻译和特定蛋白质的合成，这已经被证明是有益的代谢性疾病。如果我们能够证明这种机制，这意味着我们可以利用微生物组来改善患有2型糖尿病和肥胖症等代谢疾病的患者的健康状况。在这项研究资助中，我们有三个主要目标：首先，我们将在剑桥和蒙特利尔研究马尿酸盐对肠道，肝脏和脂肪细胞的影响，以及在高脂肪饮食引发代谢疾病的小鼠中的影响。我们将与专注于芯片器官的英国生物技术初创公司CN Bio Innovations合作，模拟马尿酸盐对肠道屏障和肝功能的影响，这两种作用在代谢疾病中都很重要，以及它如何使我们的肠道和肝脏更健康。其次，我们将鉴定马尿酸盐应答的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，这些技术由我们在帝国大学，剑桥和邓迪的共同申请人掌握。这将使我们能够精确地绘制出人体细胞中马尿酸盐的作用机制。最后，我们将分析几项针对代谢性疾病人群的研究数据，以找到更多关于马尿酸盐对代谢性疾病患者有益作用的证据。我们将确定受马尿酸影响的临床条件和风险因素，以确定马尿酸在人类中的直接作用。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，调节肥胖和代谢疾病的人体代谢。我们将特别放大马尿酸，以更好地了解微生物组控制人体生理的重要机制。这将使我们更好地了解微生物组如何有益地攻击宿主细胞机制，以塑造代谢健康和疾病。

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.