Investigating the causal associations of diet and gut microbiome in the development of metabolic disease.

Lead Research Organisation: Imperial College London
Department Name: School of Public Health

Abstract

Increased body weight (i.e. obesity) is prevalent not only in the UK but worldwide: 1.9 billion people suffer from overweight and obesity. Obesity often brings along other health conditions like diabetes (422 million people) and heart disease that are responsible for taking the lives of 17.7 million people worldwide every year. Often we think of bad diet and lack of exercise as the main drivers of obesity. But research indicates that other factors like our genes, hormones, immune factors and even the microbes in our gut (i.e. gut microbiome) determine our susceptibility to these conditions by affecting how our body responds to what we eat and how we live. If we can understand how these factors work with each other, we can find ways to prevent and cure obesity and its health consequences. In this project, I will study how our diet and gut microbes are related to obesity, diabetes and heart disease. Using genetic methods applied to population cohorts, I will study if diet can change our gut microbes. I will also look at how our gut microbiome changes with obesity, diabetes and heart disease and finally, I will develop mathematical models to predict whether we can use diet to fix our gut microbes such that we can cure or prevent these conditions. I will also find ways to apply my findings for improving the health of general public at-large.

Technical Summary

Obesity and its related conditions are leading public health concerns worldwide. Besides diet and physical activity, gut microbiota is a modifiable factor that can be targeted to prevent and treat these conditions. Indeed, alterations in gut microbiome (i.e. gut dysbiosis) have been reported in obesity and diabetes. Gut microbiome itself is affected by diet, however, the causal role of diet in gut dysbiosis, and in turn, a causal role for gut dysbiosis in the development of metabolic disease remains to be determined. Causality is difficult to assess as observational studies are subject to reverse causation and confounding bias. Mendelian Randomization (MR) is an approach that can assess causality using genetic variants, as they are randomly inherited and remain constant over life. In this project, I will begin by identifying genetic variants associated with dietary variables through genome-wide association studies (GWAS) using the UK Biobank. Next, MetaCardis cohort will be utilized to investigate the relationship between diet and gut microbial profiles during metabolic disease development. Finally, 2 sample MR will be applied using the genetic variants for dietary variables identified in step1 to the metagenomic data in step 2 to investigate whether diet causes metabolic disease via changes in the gut microbiome. These observations will also be utilized for developing health policy-related research questions in order to enhance the translational impact of the proposed work.

Planned Impact

The proposed project involves components of nutrition, genomics, gut microbiome and heath policy as they relate to the development and management of obesity, type 2 diabetes and cardiovascular disease. My work, thus, has the potential of having a direct impact on each of the respective research communities. To begin with, my work would lead to the identification of genetic instruments associated with dietary variables that can be utilized by others and us for investigating causal relationships in approaches like Mendelian Randomization. In addition, we have set out to characterize the gut microbiome under novel disease conditions like coronary heart disease including heart failure, tease out mechanistic networks and most importantly identify the dietary factors that are causal in the development of gut dysbiosis associated with obesity, type 2 diabetes and heart disease. Indeed, recognition of these dietary factors can allow for the development of personalized nutrition for targeting gut microbiota both for prevention and treatment. Moreover, the microbial profiles can be utilized for risk prediction in otherwise healthy individuals. Gut microbial profiles in combination with metabolomic data (urinary and serum metabolites data available for MetaCardis cohort) can further be utilized for the development of biomarkers of disease progression. Thus, my observations can have a direct impact on the industry and product development as well as health care and public health bodies. Diet, genetics, gut metabolites are also increasingly becoming part of the 'exposome' (i.e. complex set of biological, environmental and economic factors) that increases one's risk to the development of metabolic disease. Indeed, biological information is already being utilized to develop policy-relevant causal pathways and tools that can be utilized for investigating the relationship among obesogenic environments such as food systems, community environments and socioeconomic status as well as for monitoring and evaluating policy interventions in Horizon 2020 Project like STOP targeting childhood obesity in Europe led by Dr. Franco Sassi. Indeed, the observations out of my project can be utilized to develop such public health policy-relevant research questions and directly affect policy development and community as well as food environment design eventually.
 
Description Co-PI on the grant entitled "Evaluating Microbiome Causality in the Gut-Liver Axis and Impact on Insulin Resistance".
Amount £397,774 (GBP)
Funding ID 19/0006059 
Organisation Diabetes UK 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2020 
End 02/2024
 
Description Institutional Strategic Support Fund
Amount £3,000,000 (GBP)
Funding ID 204834/Z/16/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2017 
End 03/2023
 
Description Microbiome and Kinome in Metabolic Disease 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution I will be contributing to the Mendelian Randomization aspect of a programme grant focusing on the role of microbial metabolites in metabolic disease via their respective impact on the kinome.
Collaborator Contribution Professor Marc Emmanuel Dumas is the principal applicant of this programme grant. He brought multiple experts together and have conceived this multi-disciplinary project to address an important question of the mechanistic basis of the associations among gut microbial metabolites and metabolic diseases.
Impact A programme grant is submitted. Significant research related output in terms of publications, talks and future grants is anticipated.
Start Year 2021
 
Description Participation in ISARIC consortium 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution I am contributing to the data analysis as it relates to the plasma and urinary metabolomics of the individuals with covid-19 with the objective of finding causal associations using Mendelian Randomization.
Collaborator Contribution The partners have collected the clinical samples and other clinical data/records whereas other colleagues within Imperial performed the metabolomics analytical experiments.
Impact The following publications as a consortium collaborator: 10.1016/S0140-6736(21)00799-6 10.1136/heartjnl-2021-320047 10.1016/j.isci.2021.103353 10.1016/j.cell.2021.12.046 10.1038/s41586-021-03767-x
Start Year 2021
 
Description The role of the gut microbiome - kidney axis as a driver of cardiovascular complications in kidney failure. 
Organisation Imperial College London
Department National Heart & Lung Institute (NHLI)
Country United Kingdom 
Sector Academic/University 
PI Contribution I will be providing analytical (data analysis and systems biology approaches) and expert subject matter support to this collaboration with Dr. Petros Andrikopoulos. Our collaboration is aimed at submission of a project grant to British Heart Foundation in addition to conducting the project and disseminating research outcomes in the form of publications and conference presentations eventually.
Collaborator Contribution Dr. Petros Andrikopoulos conceived the project and designed the experimental and analytical aspects of this work with expert input from all his collaborators. He will be leading this project.
Impact Potential outcomes include a project grant submission and research publications.
Start Year 2020
 
Description Mendelian Randomization in action: Identification of a gut-microbiome-kidney-heart axis in human populations 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Nearly 40 students and researchers from MDR Bioinformatics joined the session where I was one of the invited speaker. Idea was to introduce the students and researchers to one of the epidemiological method for causal inference called Mendelian Randomization and discuss its practical use. Stimulated discussion took place after the talks which could potentially inspire students to incorporate this method in their own research.
Year(s) Of Engagement Activity 2021
URL https://www.imperial.ac.uk/events/129438/mdr-bioinformatics-meetup-mendelian-randomization-verena-zu...
 
Description Microbiome causality assessment using mendelian randomisation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Other audiences
Results and Impact I presented my research findings at the first annual meeting of the Imperial's Microbiome network held on 5th March 2020. The audiences inlcuded researchers and graduate students working across multi-disciplinary spectrum of microbiome research at Imperial. My presentation led to discussions and conversations around the potential for future collaborations.
Year(s) Of Engagement Activity 2020
URL https://www.imperial.ac.uk/microbiome-network/news-and-events/