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

MICA：宿主微生物共代谢物马尿酸抑制 Mnk1 并调节代谢疾病中的 mRNA 翻译

• 批准号: MR/X010155/1
• 负责人: Marc-Emmanuel Dumas
• 金额: $ 105.72万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX010155%2F1
• 关键词: MICA; Host; microbial; co; metabolite

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.

我们肠道中的细菌在塑造我们的新陈代谢和健康方面发挥着至关重要的作用。我们的肠道细菌帮助我们将纤维等不易消化的食物分解成我们可以吸收的微生物组，即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微型制药工厂，生产化合物，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，也是重要的化学信使。影响人类健康的微生物信号仍然难以捉摸，这个新的研究项目合作者汇集了来自英国伦敦、剑桥和邓迪的顶尖专家以及来自加拿大蒙特利尔的国际专家，重点研究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进行对话。以及它们如何结合细胞中某种类型的效应器，其作用类似于分子开关，称为激酶，调节我们的细胞对不断变化的环境的反应。该研究项目重点研究肠道细菌产生的一种称为马尿酸的化学物质如何调节一种称为激酶的激酶。 Mnk1。这种激酶控制着信使 RNA（DNA 蓝图的副本）翻译成蛋白质，这些蛋白质在体内执行各种工作，包括糖和脂质的代谢、激素的产生或炎症。我们的试验数据表明，马尿酸通过阻断 Mnk1 来阻止 mRNA 翻译和特定蛋白质的合成，这已被证明对代谢疾病有益。如果我们能够证明这种机制，这意味着我们可以利用这一机制。微生物组以改善健康在这项研究资助中，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对肠道、肝脏和脂肪细胞的影响，以及对喂食高剂量马尿酸的小鼠的影响。脂肪饮食引发代谢疾病。我们将与专门从事器官芯片研究的英国生物技术初创公司 CN Bio Innovations 合作，模拟马尿酸对代谢疾病中很重要的肠道屏障和肝功能的影响，以及它如何发挥作用。让我们的直觉和其次，我们将鉴定对马尿酸有反应的 mRNA 和蛋白质，以了解马尿酸如何改善健康。这将通过使用 RNA 测序和蛋白质组学等技术来实现，这些技术由我们在帝国理工学院、剑桥大学和剑桥大学的共同申请人掌握。邓迪。这将使我们能够精确地绘制人类细胞中的马尿酸机制。最后，我们将分析来自患有代谢疾病的人群的多项研究的数据，以找到有关马尿酸对人体有益作用的更多证据。我们将确定受马尿酸影响的临床状况和危险因素，以确定马尿酸对人类的直接作用。总而言之，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调节人体新陈代谢的化学信使。我们将特别关注马尿酸，以更好地了解微生物组控制人类生理学的重要机制，这将使我们更好地了解微生物组如何有益地破坏宿主细胞机制以塑造代谢健康和疾病。