"We search for the key metabolic interactions between our genetics, lifestyle and environment that cause dementia. Greater understanding of these mechanisms will lead to new therapeutic targets and improve the treatment of dementia." Elaine Holmes
UK DRI Group Leader
Prof Elaine Holmes is a pioneer in the search for metabolic biomarkers of disease, using mathematical modelling and personalised medicine to find molecular ‘fingerprints’ in an individual. Obtaining her PhD in Analytical Chemistry from Birkbeck College, she went on to Imperial College London, becoming Head of Division of Computational and Systems Medicine in 2010. Elected Fellow of the Academy of Medical Sciences in 2018, she now works internationally, bringing her expertise in the role of the microbiome in neurodegenerative disease to the UK DRI at Imperial.
1. At a glance
Gut instinct: How bacteria may be impacting our risk of developing dementia
The research of Prof Elaine Holmes investigates the underlying physiological process of how and why certain people get Dementia. They look at how both genetics and lifestyle factors interact together to initiate the processes that lead to dementia.
For example, a key area of research involves looking at the health of our gut and the diversity of bacteria that normally live there. Current estimates suggest that there are more bacterial cells in our gut than there are of our own cells in our entire body, and interactions with these microbes will influence our health across our lifetime. Gut bacteria can release chemicals that can provoke a response in the brain, and changes in gut bacteria diversity have been reported in individuals with dementia. Therefore, the group are investigating these specific chemicals released by bacteria to see how they could affect the brain and if they alter processes that lead to dementia.
2. Scientific goals
Metabolic phenotyping of population cohorts provides a systems-level overview of the phenotypic status of individuals and provides mechanistic insight into health and disease. However, to date, metabolomic studies into dementia have typically been underpowered and have focused on identifying metabolic signatures associated with dementia in case-control cohorts, with varying methods and quality control.
A number of environmental factors have been associated with dementia risk including diet, lifestyle, stress, sleep deprivation and exposure to pollutants and toxins. Recently, it has been recognised that inflammation in the brain is an important contributor to Alzheimer’s Disease (AD). Additionally, increasing credence is given to the role of the gut microbiome in neurodegenerative diseases and pro-inflammatory gut bacterial taxa have been shown to be associated with brain amyloidosis and peripheral inflammation in cognitively impaired elderly. Gut bacteria have been shown to influence brain function, not only via the chemicals that they synthesize, but also by interacting with the immune system to control inflammation around the body including the brain; depletion of gut bacteria has been shown to reduce microglial activation.
This programme of work will identify candidate biomarkers of dementia risk and early-stage dementia. By characterising the metabolic phenotypes associated with specific dementia risk factors (genetic predisposition, high cardiovascular risk, sleep deprivation, adverse gut microbial environments), Elaine’s team aims to improve understanding of the molecular origins of the pathology and of the pathway shifts that occur in dementia and cognitive decline.
Main objectives and research goals:
The overarching goal is to identify metabolic pathways implicated in the onset of dementia through large-scale population phenotyping and to progress understanding of how modulation of these pathways can alter disease risk with the aim of i) identifying early biomarkers of dementia or dementia risk; ii) identifying molecular targets for prevention or early treatment of dementia. Specific objectives are to:
1. Identify metabolites and pathways associated risk factors for AD, Parkinson’s disease and vascular dementias using well-characterised population cohorts.
2. Explore the mechanism of molecular pathways uncovered in objective one in models of disease.
3. Assess the metabolic consequences of sleep deprivation and alteration of circadian rhythms in dementia.
4. Explore the role of the gut microbiome in dementia aetiology and progression by using metabolic phenotyping to map pathways of microbe-derived molecules and investigate the impact of these on the gut-brain-axis.
3. Team members
Dr Luke Whiley (Postdoctoral Researcher)
Dr Brenan Durainayagam (Postdoctoral Researcher)
Parisa Mottaghi (PhD Student)
Adesola Bello (Research Assistant)
Within UK DRI:
- Prof Paul Elliott, UK DRI at Imperial
- Prof Julie Williams, UK DRI at Cardiff
- Dr Gaynor Ann Smith, UK DRI at Cardiff
- Dr Owen Peters, UK DRI at Cardiff
- Dr Marco Brancaccio, UK DRI at Imperial
- Prof William Wisden, UK DRI at Imperial
- Prof Bart De Strooper, UCL
Beyond UK DRI:
- Prof Sven Pettersson, National Technological University, Singapore
- Dr Anna Martinez Muriana, KU Leuven
Population metabolic phenotyping, metabolome, microbiome, gut-brain axis, biomarkers
Metabolomics, computational modelling, mouse models, spectral profiling techniques, next-generation sequencing, mass spectrometry, DESI imaging, NMR spectroscopy
7. Key publications
Whiley L, Nye LC, Grant I, Andreas NJ, Chappell K, Sarafian MH, Misra R, Plumb R, Lewis MR, Nicholson JK, Holmes E. UHPLC-ESI-MS/MS quantification of tryptophan metabolites and markers of gut health in serum and plasma–Application to clinical and epidemiology cohorts. Analytical chemistry. 2019 Mar 8.
Andreas NJ, Al‐Khalidi A, Jaiteh M, Clarke E, Hyde MJ, Modi N, Holmes E, Kampmann B, Mehring Le Doare K. Role of human milk oligosaccharides in Group B Streptococcus colonisation. Clinical & translational immunology. 2016 Aug;5(8):e99.
Dona AC, Jiménez B, Schäfer H, Humpfer E, Spraul M, Lewis MR, Pearce JT, Holmes E, Lindon JC, Nicholson JK. Precision high-throughput proton NMR spectroscopy of human urine, serum, and plasma for large-scale metabolic phenotyping. Analytical chemistry. 2014 Sep 16;86(19):9887-94.
Nicholson JK, Holmes E, Kinross J, Burcelin R, Gibson G, Jia W, Pettersson S. Host-gut microbiota metabolic interactions. Science. 2012 Jun 8;336(6086):1262-7.
Holmes E, Kinross J, Gibson GR, Burcelin R, Jia W, Pettersson S, Nicholson JK. Therapeutic modulation of microbiota-host metabolic interactions. Science translational medicine. 2012 Jun 6;4(137):137rv6-.