The microbiome and its influence on cognition, brain health and neurodegeneration

Lead Research Organisation: Imperial College London

Abstract

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Technical Summary

The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019.

Increased life expectancy in many societies has contributed to the growing social and financial burden of dementia diseases. The aetiology of many of these diseases is unknown, but there is strong evidence that gene-environment interactions play important roles. Evidence suggests that environmental factors such as diet1, physical activity, stress, sleep deprivation2, obesity3 and other lifestyle factors impact on cognitive deterioration. Analytical platforms for deep phenotyping of biofluids such as plasma, urine and CSF based on nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) can generate metabolic “fingerprints” that contain latent information relating to physiological or pathological status, informing on
disease mechanisms, diagnosis and prognosis. This technology has been applied to various preclinical and clinical studies of neurodegenerative diseases such as Alzheimers Disease (AD) Huntington’s Disease and vascular dementia. Specifically, metabolic profiling studies on AD and other dementias4,5 have highlighted alterations in a variety of biochemical pathways, including those involving nucleotides, tricarboxylic acid cycle intermediates, energy transfer substrates, carbohydrates, neurotransmitters, phospholipids and amino acids using gas chromatography–MS (GC-MS)6, NMR spectroscopy7 and liquidchromatography- MS (UPLC-MS)8. However, to date, metabolomic studies on dementias have focused on patients with fully developed mild cognitive impairment (MCI) and have been limited to small study groups or, in the case of animal models, only partially reflect disease phenotype. Thus further validation of proposed biomarkers in large cohort studies of prodromal rather than incident dementia is critical to promote mechanistic understanding of the pathological processes and to validate biomarkers for disease
risk.

Publications

10 25 50
 
Title Tryptophan Method 
Description Targeted LC-MS method for the quantitative analysis in biofluids of metabolites in the kynurinine and tryptophan metabolic pathway (key gut microbial metabolites). 
Type Of Material Technology assay or reagent 
Year Produced 2019 
Provided To Others? Yes  
Impact This method has now been published. The method will be applied to research studies. 
URL https://www.ncbi.nlm.nih.gov/pubmed/30848589
 
Description Association of cardiovascular disease risk factors with cognitive decline 
Organisation University of North Carolina at Chapel Hill
Department UNC Nutrition Research Institute
Country United States 
Sector Academic/University 
PI Contribution We are conducting the metabolic phenotyping component of the collaboration
Collaborator Contribution Provision of cognitive scores for a population study.
Impact multidisciplinary metabonomics microbiomics cognitivw measures
Start Year 2018
 
Description Cardia Collaboration - Katie Meyer 
Organisation University of North Carolina at Chapel Hill
Country United States 
Sector Academic/University 
PI Contribution Metabolite profiling of human samples for markers of cardiovascular health as a direct risk factor for Dementia.
Collaborator Contribution The collaborator has provided human samples for this study.
Impact No outputs or outcomes yet.
Start Year 2017
 
Description Metabolic Phenotyping for Alzheimer's research 
Organisation University of Oxford
Department Department of Psychiatry
Country United Kingdom 
Sector Academic/University 
PI Contribution Previous collaborative studies between the Holmes group at Imperial College London and the Lovestone group at the University of Oxford has lead to important research outcomes and key publication to contribute to the field. Metabolic Phenotyping methods have been applied to biofluid samples from Alzheimer's Patients. It is hoped that this collaborative effort will continue under the UK-DRI, with a specific interest in collaborating in order to apply the recently developed Tryptophan method (Whiley L et al 2019) to the Alzheimer's patient cohort.
Collaborator Contribution The collaborator will provide human samples for this study.
Impact This Collaboration has been on-going for many years with the outcomes of the research contributing to the information to further our knowledge in this field. The collaborative effort relevant to this funding is yet to start. It is hoped that there will be much to report on the application of the new Tryptophan method on this cohort.
Start Year 2019
 
Description Peters & Smitth CARDIFF-DRI 
Organisation Cardiff University
Country United Kingdom 
Sector Academic/University 
PI Contribution carry out metabolic phenotyping analysis
Collaborator Contribution provide the samples for analysis
Impact We have identified metabolic signatures that associate with risk genes. As a result of this we now want to understand the underlying mechanisms of disease. This has lead to the holmes group collaborating with Drs Owen Peters and Gaynor Smith, from the Cardiff Centre of the DRI. The Smith and Peters programs have been set up to develop drosophila models of dementia. They will develop model systems by knocking out genes associated with dementia. The knockout fly colonies will be investigated by the Holmes theme using metabolic phenotyping analysis. This will enable researchers to identify specific pathways that are disrupted, which may explain the disease pathogenesis and uncover mechanistic insight into the effect of the causative gene.
Start Year 2018
 
Description Sven Petterson Group 
Organisation Karolinska Institute
Department Department of Microbiology, Tumour and Cell Biology
Country Sweden 
Sector Academic/University 
PI Contribution We applied a 1H nuclear magnetic resonance (NMR) spectroscopy-based metabolic phenotyping approach to investigate whether the gut microbiome modulates the neurobiochemical signature of the frontal cortex and hippocampus in two rodent germ-free models compared to their conventional equivalents. These regions have been selected due to their role in executive functions, particularly working memory, a function modulated by the gut microbiome.
Collaborator Contribution Sven Petterson Group have provided extracts from the frontal cortex and hippocampal regions of germ free and normal mice and rats for the metabonomic study of gut microbial influence on host brain metabolism.
Impact Application of 1H NMR spectroscopy to the metabolic phenotyping of rodent brain extracts: A metabonomic study of gut microbial influence on host brain metabolism J.R. Swanna, I. Garcia-Perez, V. Branistec, I.D. Wilsona, J.E. Sidawayc, J.K. Nicholsona, S. Pettersson, E. Holmes. Journal of Pharmaceutical and Biomedical Analysis 143 (2017) 141-146.
Start Year 2016
 
Description Beavers Visit 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Manuja Kaluarachchi organised and delivered a science session to a Beaver (primary school age children) in Buckinghamshire. The 2 hour workshop included making brain hats. This sparked questions relating to brain structure and function. The children were amazed to know that our brains are structured the way it is. The children were engaged with making the brain hats, wore them throughout the session and were able to take them home.

As the science session took place on Darwin day, a fossil making session was included- which the children really enjoyed as it involved a lot of messy mixing of flour, coffee grounds and water. The children made fossils with small items (such as toy dinosaurs, cars and figures) brought from home. The children took pride in what they had made and took them home to dry.

The children also carried out a 'test the beak' activity in which they used different items (tweezers, pegs, spoons and scissors) to represents birds beaks to pick up different foods (twiglets, marshmallows, crisps, skittles and raisins). The children recorded their results on sheets to decide which item suited which food the best.
Year(s) Of Engagement Activity 2019
 
Description Invited Talk (Quees Mary University of London) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other audiences
Results and Impact Luke Whiley was invited to give a talk about his current research and the work of the Holmes group (Imperial UK-DRI) to researchers in the Neuroscience Department, OMUL on Wednesday 6th March 2019.

The researchers at QMUL were very interested in the research. There are discussions surrounding future collaborations.
Year(s) Of Engagement Activity 2019
 
Description Plenary Lecture (14th International Conference of the Metabolomics Society) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Prof Holmes gave a Plenary Lecture entitled 'The role of metabolic profiling in 21st century medicine' at The 14th International Conference of the Metabolomics Society in Seattle, June 25th 2018.

The conference has an overall goal of Making Connections, with major scientific themes of systems biology, big data, technology advances, precision medicine and translational science, plant metabolomics, the microbiome, and the exposome, including environmental and nutritional metabolomics. In addition, the conference provided a number of networking opportunities to help establish connections for early career scientists, metabolomics scientists across the Pacific Rim as well as globally.
Year(s) Of Engagement Activity 2018
URL http://metabolomics2018.org/program/plenary-speakers
 
Description Plenary Lecture (The 3rd Latin American Metabolic Profiling Society Meeting) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Prof Holmes gave a Plenary Lecture entitled 'Metabolic Profiling Pipelines' at The 3rd Latin American Metabolic Profiling Society Meeting, Rio de Janeiro, October 22nd 2018.

The organizing committee is committed to providing an appropriate atmosphere for the scientific discussion of various aspects of Metabolomics such as Metabolomics in Health and Human Disease, in Plants and Food among other aspects of technology advances and precision medicine. LAMPS will provide excellent opportunities for collaboration and networking for scientists and students.

Rio de Janeiro is an exciting city and an important center of science in Brazil.
Year(s) Of Engagement Activity 2018
URL http://lamps2018.com.br/lecturers/
 
Description Research Talk (Cardiff DRI) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other audiences
Results and Impact To develop understanding and the theme for what is now a new collaborative project between the Holmes group and the Cardiff-DRI, Luke Whiley presented his current research related to metabolic phenotyping in Cognition to the research group in Cardiff.

The researchers were excited to hear about the use of metabolic phenotyping as a tool to identify metabolic signatures of the disease to develop a better understanding of disease and further the development of disease prediction, prevention and/or treatment. The teams are actively discussing the collaboration and work will soon start.
Year(s) Of Engagement Activity 2018
 
Description Research Talk (Kings College London) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other audiences
Results and Impact Luke Whiley delivered a research talk on his current research surrounding metabolic phenotyping and Cognition.

The researchers were excited to hear about the use of metabolic phenotyping as a tool to identify metabolic signatures of the disease to develop a better understanding of disease and further the development of disease prediction, prevention and/or treatment.
Year(s) Of Engagement Activity 2018
 
Description Training Course Tutor (Imperial International Phenome Training Centre) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Luke Whiley is one of the dedicated tutors for the IIPTC and has been teaching on the LC-MS metabolomics phenotyping course.

This week long course aims to cover how to perform a metabolic profiling experiment, from start to finish. It will cover study design, sample preparation, the use of mass spectrometry for global profiling and targeted methodologies and data analysis.
Year(s) Of Engagement Activity 2019
URL http://www.imperial.ac.uk/imperial-international-phenome-training-centre/courses/hands-on-lc-ms-for-...