MICA: Host-microbial co-metabolite hippurate inhibits Mnk1 and regulates mRNA translation in metabolic diseases
Lead Research Organisation:
Imperial College London
Department Name: Metabolism, Digestion and Reproduction
Abstract
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.
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.
Technical Summary
We propose unravelling one of the most fundamental mechanisms by which the microbiome communicates and influences the host kinome, central to metabolic diseases (MDs). The human microbiome, consisting of up to 20 million bacterial genes (our "2nd genome"), is now recognised as a critical determinant in MDs. We showed that hippurate is a microbial-host co-metabolite associated with microbiome gene richness and metabolic health in human populations eating a western-style diet rich in saturated fats, which we also confirmed in mice fed a high-fat diet (HFD). However, the underlying mechanism of hippurate action remains to be characterised.
We have discovered that hippurate inhibits MNK1, the kinase regulating eIF4E, which controls the initiation of translation regulation and modulates metabolism in MD contexts. This new Research Project will focus on unravelling these mechanisms through the hippurate-MNK1-eIF4E axis:
1) To study the effect of hippurate on MD phenotypes. We will confirm and refine the IC50 for hippurate. We will then characterise its bioactivities in vitro in gut, liver and adipose cells, and in microfluidic organs-on-chip Gut- and Liver-on-Chip. We will then perform an in-depth in vivo phenotyping in in preclinical models of T2D such as HFD-fed mice, including transgenics (Mnk1 KO, activated eIF4E knock-in).
2) To map the hippurate-responsive mRNAs and proteins, we will perform RNA-Seq and proteomics. This will reveal the signalling and translational control pathways activated by the hippurate-MNK1-eIF4E axis in metabolic cells and tissues.
3) To further characterise the association spectrum and causal pathways involving hippurate, its genetic and environmental influences and MDs in human populations (FLORINASH, METACARDIS, CLSA).
This Project will enable the first in-depth functional characterisation of the hippurate-MN1-eIF4E axis and demonstrate how the microbiome beneficially hacks host mRNA translation in MDs.
We have discovered that hippurate inhibits MNK1, the kinase regulating eIF4E, which controls the initiation of translation regulation and modulates metabolism in MD contexts. This new Research Project will focus on unravelling these mechanisms through the hippurate-MNK1-eIF4E axis:
1) To study the effect of hippurate on MD phenotypes. We will confirm and refine the IC50 for hippurate. We will then characterise its bioactivities in vitro in gut, liver and adipose cells, and in microfluidic organs-on-chip Gut- and Liver-on-Chip. We will then perform an in-depth in vivo phenotyping in in preclinical models of T2D such as HFD-fed mice, including transgenics (Mnk1 KO, activated eIF4E knock-in).
2) To map the hippurate-responsive mRNAs and proteins, we will perform RNA-Seq and proteomics. This will reveal the signalling and translational control pathways activated by the hippurate-MNK1-eIF4E axis in metabolic cells and tissues.
3) To further characterise the association spectrum and causal pathways involving hippurate, its genetic and environmental influences and MDs in human populations (FLORINASH, METACARDIS, CLSA).
This Project will enable the first in-depth functional characterisation of the hippurate-MN1-eIF4E axis and demonstrate how the microbiome beneficially hacks host mRNA translation in MDs.
