What lies behind the causal impact of body mass index level and change on human health? Added value from complementary study design and deep metabolom

Lead Research Organisation: University of Bristol
Department Name: Sch of Medical Sciences

Abstract

This project aims to better understand how body mass index (BMI) exerts an effect on human health and disease using metabolomics in complementary study designs and through applied genetic epidemiology.

Rationale
There is strong evidence that BMI causally influences a wide range of health outcomes, but there is little understanding of the mechanisms driving BMI effects and at the level of the population we are limited in our ability to alter BMI.

Targeted lifestyle and pharmaceutical interventions have failed to deliver large reductions in BMI and the only effective intervention is surgery.

The proposal here is that metabolomic measurements can be used to understand the mechanisms by which BMI contributes to disease.

Circulating metabolites are the product of genetic and non-genetic factors and are a useful read-out of physiological function. Despite the similarity of metabolites to complex health outcomes, it remains possible to map metabolites to genotypes and translatable biological pathways. Consequently, identifying metabolites important in the link between BMI and disease is a promising approach to further understanding BMI as a risk factor.

Aims and Objectives
To better understand how BMI exerts an effect on human health and disease using metabolomics in complementary study designs and through applied genetic epidemiology.

This PhD will be coodrinated with a Wellcome Trust funded programme of research that explicitly seeks to use the most contemporary and powerful study designs, metabolic data capture and analytical techniques to explore BMI as a risk factor.

Methods
We will address five key research questions by testing the hypotheses that:
1. Specific circulating metabolites are affected by BMI change
2. BMI has a causal effect on the human metabolite response to feeding
3. BMI has a causal effect on the on the human faecal microbiome
4. It is possible to causally map the human faecal microbiome onto the metabolome to extend the study of the microbiome
5. Metabolites identified through population based causal analysis of BMI, intervention studies of BMI change, the effect of BMI on metabolic response and investigation of the microbiome ("BMI-metabolites") have a causal effect on disease risk.

Research summary
BMI, a measure of adiposity, is observationally associated with health outcomes including all-cause mortality, CVD, T2D, and cancer. We do not yet know the full story of why BMI is a risk factor, and altering BMI at the population level is challenging.

Metabolic differences are present across BMI levels and this is reflected in circulating metabolites. The result of genetic and non-genetic factors, circulating metabolites provide information on physiological function and can be used to identify links between BMI and disease.

Publications

10 25 50
 
Title Creative Reactions Bristol 
Description Creative Reactions Bristol pairs artists and researchers together to produce artistic responses to research. These artworks are put on display and audiences are drawn in through ancillary events such as talks and performance art. I organise this event and have had my research turned into artistic works. Specifically, I worked with Phil Young (https://www.dendrophile.co.uk/). 
Type Of Art Artistic/Creative Exhibition 
Year Produced 2019 
Impact This is a unique way to communicate my research with different audiences. The collaboration helped develop my communication skills and has positively influenced the my research. 
URL https://www.instagram.com/creativereactionsbristol/
 
Description Alumni Foundation, University of Bristol
Amount £1,000 (GBP)
Organisation University of Bristol 
Sector Academic/University
Country United Kingdom
Start 01/2019 
End 12/2019
 
Description EPSRC Impact Acceleration Account
Amount £14,985 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 01/2019 
End 12/2019
 
Description EPSRC Impact Acceleration Account
Amount £27,522 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 03/2020 
End 07/2021
 
Description GW4 Flexible Funding Supplement
Amount £8,661 (GBP)
Organisation GW4 
Sector Academic/University
Country United Kingdom
Start 04/2021 
End 07/2021
 
Description Outreach, University of Bristol
Amount £1,000 (GBP)
Organisation University of Bristol 
Sector Academic/University
Country United Kingdom
Start 01/2019 
End 12/2019
 
Description Public Engagement Seed Corn Funding
Amount £5,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2018 
End 12/2018
 
Description Widening Participation, University of Bristol
Amount £1,000 (GBP)
Organisation University of Bristol 
Sector Academic/University
Country United Kingdom
Start 12/2019 
End 07/2020
 
Description Widening Participation, University of Bristol
Amount £1,000 (GBP)
Organisation University of Bristol 
Sector Academic/University
Country United Kingdom
Start 01/2019 
End 01/2019
 
Description Widening Participation, University of Bristol
Amount £2,000 (GBP)
Organisation University of Bristol 
Sector Academic/University
Country United Kingdom
Start 12/2019 
End 07/2020
 
Title EpiViz: an implementation of Circos plots for epidemiologists 
Description Circos plots enable visualisation of large amounts of data but can be cumbersome to produce. EpiViz is intended to streamline and enable the efficient creation of Circos plots for a range of data typicaly used by epidemiologists. EpiViz was designed with metabolite association analyses in mind. These analyses involve hundreds of metabolites which can be grouped together in different combinations. Of particular interest in these studies is how groups of metabolites behave rather than individual metabolites. In this instance we use the sections of the Circos plot to plot individual groups of metabolites and look at the overall picture for that group of metabolites. 
Type Of Technology Webtool/Application 
Year Produced 2020 
Open Source License? Yes  
Impact Used by colleagues to visualise large epidemiology analyses. Visualisations have been used in posters, presentations and publications. 
URL https://github.com/mattlee821/EpiViz