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起着至关重要的作用。我们的肠道细菌有助于我们分解诸如纤维等食物，例如我们可以吸收的较小分子。微生物组是由我们的肠道微生物携带的所有遗传物质，由2000万个基因制成，是我们肠道中的小型药物工厂，制作化合物，其中一些像药物一样起作用。这些化合物，称为代谢产物，不仅是生命的基础，而且是必不可少的化学信使。但是，关键的微生物信号会影响人类健康仍然弹性。该新的研究项目汇集了来自伦敦，剑桥和邓迪的英国，剑桥和邓迪的领先专家，以及来自加拿大蒙特利尔的国际合作者，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器官与我们的器官交谈，以及它们如何粘结在细胞作用中的某种类型的效应器，例如分子开关，称为Kinass，称为Kinases，称为Kinass，它调节环境如何改变环境。该研究项目的重点是我们的肠道细菌（称为Hippurate）如何调节称为MNK1的激酶。这种激酶控制了Messenger RNA的翻译，即DNA蓝图的副本，将其在体内从事各种工作。这些工作包括糖和脂质的代谢，hors烯的产生或注射，因为对于患有代谢疾病的患者就是这种情况。我们的飞行员数据表明​​，通过阻断MNK1，Hippurate停止mRNA翻译并合成特定蛋白质，这已经证明是在代谢疾病中有益的。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具有2型糖尿病和肥胖症等代谢状况的患者的健康状况。在这项研究赠款中，我们有三个主要目的：首先，我们将在剑桥和蒙特利尔学习嬉皮士对肠道，肝脏和脂肪细胞的影响，以及在喂养高脂饮食以触发代谢疾病的小鼠中。 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.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，剑桥和邓迪的共同申请者掌握。这将使我们能够准确地绘制人类细胞中的嬉皮机制。在本文中，我们将分析几项有关人群的代谢性疾病的研究的数据，以找到更多有关嬉皮士对代谢疾病患者的有益作用的证据。我们将确定受嬉皮士影响的临床状况和危险因素，以定义Hippurate在人类中的直接作用。总而言，这项研究将帮助我们发现肠道细菌如何将养分转化为在肥胖和代谢性疾病中进行人类代谢的化学信使。我们将缩小搭档，特别是更好地理解微生物组控制人类生理的重要机制。这将使我们能够更好地了解微生物组如何有益地破解宿主细胞机制以塑造代谢健康和疾病。