Host-Microbe-Diet Interactions in Ageing

Lead Research Organisation: MRC London Institute of Medical Sciences

Abstract

Centenarians are the fastest growing age group in the UK. The major burden of disability and ill-health in developed countries falls on older people as medical advances are not sufficient to maintain people healthier for longer. This incurs important medical, economic and social costs to societies barely coping with an ageing demographic. Ageing is modulated by genetics and its constant evolving environment. It has been found that body health during ageing is strongly affected by the symbiotic microbes that inhabit the gut. However, the understanding of how microbes affect the functions of the host biology is still in its infancy. This is where the use of model organisms such as nematode worms come into play. These models allow us to tease apart the complex interactions between host genetics, gut microbes and nutrition in a way that no other models can. They also provide a platform to prove mechanistic causation between interventions, such as nutrients or drugs, and allow scientists to build mathematical and computational models that can be used for the translation of this information to application in humans. Ultimately, the findings of this programme will inform on how to harness gut microbes to improve late life health.

Technical Summary

Animals rarely live in isolation, but rather exist in intimate association with other species, particularly microorganisms. The microbiota and its genes play key roles in human health and disease. Recently, several reports have linked the role of microbiota with organismal ageing. Not only the composition and function of the microbiota changes over time within an ageing organism but also the function of the microbiota can modulate organismal ageing. Yet, the causal mechanisms regulating this intertwined and complex communication remain widely unexplored and ill-defined. Despite great advances in our understanding of ageing biology from a genomic-centric approach, we do not fully comprehend why similar mutations or treatments lead to a wide-range of host phenotypes in a context-dependent manner. Nutrition and the microbiome are two key environmental factors regulating host physiology. Chemical elements originating from these exogenous sources are the cornerstone of life as they offer a source of energy, the building blocks for cellular construction and the micronutrients which are essential for the adequate functioning of cells. Importantly, the microbiome is significantly enriched for genes involved in the metabolism of dietary compounds to produce molecules of biological relevance. These metabolites may explain the present gaps in our knowledge coupling the gut microbiota to biological host mechanisms in health and disease throughout life. The overarching goal of this programme is to unravel the molecular basis of microbial and dietary-induced host metabolic-rewiring during ageing. Here, we integrate novel experimental designs to build mechanistic in silico models through systems biology approaches in order to predictively understand the contribution of diet in the regulation of host biology through or independently of the microbiome. The underlying mechanisms will be studied using the powerful genetic, microbiota and ageing model Caenorhabditis elegans, which mirrors many conserved human metabolic pathways and allows for a well-defined control of environmental cues. This interdisciplinary programme will combine state-of-the-art high-throughput screening host- microbe- diet approaches developed in the Cabreiro lab and combined omics approaches at the host and microbial level to identify and characterize: microbially-regulated host metabolic pathways regulating ageing (Aim 1); identify dietary and microbial metabolites critical for healthy ageing (Aim 2); and microbial-diet -interactions regulating metabolism and host ageing (Aim 3). Ultimately, we aim at demonstrating the power of interspecies predictive models and the possibility of creating precise genetic interventions in bacteria for discovering and harnessing new metabolites with important implications in regulating healthy ageing.
 
Description Investigating the role of the metformin resistome on host health
Amount £1,747,775 (GBP)
Funding ID 102531/Z/13/A 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2018 
End 02/2022
 
Title 4-way high-throughput screening approaches 
Description We have developed a novel high-throughput method that allows us to investigate the role of nutrients on the mode of action of diverse therapeutic drugs on host physiology in a microbiome dependent manner 
Type Of Material Model of mechanisms or symptoms - non-mammalian in vivo 
Year Produced 2019 
Provided To Others? Yes  
Impact High impact publication: Host-Microbe-Drug-Nutrient Screen Identifies Bacterial Effectors of Metformin Therapy. Pryor R, Norvaisas P, Marinos G, Best L, Thingholm LB, Quintaneiro LM, De Haes W, Esser D, Waschina S, Lujan C, Smith RL, Scott TA, Martinez-Martinez D, Woodward O, Bryson K, Laudes M, Lieb W, Houtkooper RH, Franke A, Temmerman L, Bjedov I, Cochemé HM, Kaleta C, Cabreiro F. Cell. 2019 Sep 5;178(6):1299-1312.e29. doi: 10.1016/j.cell.2019.08.003. Epub 2019 Aug 29. 
URL https://www.cell.com/cell/fulltext/S0092-8674(19)30891-8
 
Title Atomic force microscopy in ageing C. elegans 
Description We have adapted atomic force microscopy to investigate ageing biomarkers in a model organism 
Type Of Material Model of mechanisms or symptoms - non-mammalian in vivo 
Year Produced 2020 
Provided To Others? Yes  
Impact We have discovered genetic, pharmacological and nutritional interventions that improve healthy ageing. 
URL https://www.nature.com/articles/s41467-020-14785-0
 
Title Live microbiome biosensors 
Description We have developed in vivo microbiome biosensors 
Type Of Material Biological samples 
Year Produced 2019 
Provided To Others? Yes  
Impact We have shown that we can use bacteria as sensors of the metabolic environment in the gut. 
URL http://pubs.acs.org/doi/10.1021/acssynbio.9b00166
 
Description Alexis Barr 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Discovery of novel prokaryotic metabolite regulating cancer therapy
Collaborator Contribution Validation of a prokaryotic metabolite on human cancer cell lines
Impact The is a multi-disciplinary collaboration between a model organism lab (ours) and a human cell cycle lab (Alexis Barr)
Start Year 2019
 
Description Christoph Kaletta 
Organisation University of Kiel
Country Germany 
Sector Academic/University 
PI Contribution We are the leading lab studying the role of microbes on the effect of the antidiabetic drug metformin on host physiology
Collaborator Contribution The partner provided computational expertise and analysed human patient microbiome data to investigate whether the gut microbiota in humans is rewired to produce a metabolite by metformin.
Impact Publications: Rosina Pryor *,1,2,3, Povilas Norvaisas *,3, Christoph Kaleta*,4, Leonor Quintaneiro 1,2,3, Wouter De Haes 5, Celia Lujan 6, Reuben L. Smith 7, Timothy Scott 3, Daniel Martinez-Martinez, 1,2, Orla Woodward 3, Kevin Bryson 8, Riekelt H. Houtkooper 6, Liesbet Temmerman 4, Ivana Bjedov 5, Helena M. Cochemé 1,2 and Filipe Cabreiro. In revision at Cell
Start Year 2018
 
Description Helena Cocheme 
Organisation Medical Research Council (MRC)
Department MRC Clinical Sciences Centre (CSC)
Country United Kingdom 
Sector Public 
PI Contribution Leading lab studying the role of anti-diabetic drugs, microbiota and host regulation
Collaborator Contribution The partner provided support by studying evolutionarily conserved mechanisms found in our lab in another model organism- Drosophila melanogaster
Impact Publications: Rosina Pryor *,1,2,3, Povilas Norvaisas *,3, Christoph Kaleta*,4, Leonor Quintaneiro 1,2,3, Wouter De Haes 5, Celia Lujan 6, Reuben L. Smith 7, Timothy Scott 3, Daniel Martinez-Martinez, 1,2, Orla Woodward 3, Kevin Bryson 8, Riekelt H. Houtkooper 6, Liesbet Temmerman 4, Ivana Bjedov 5, Helena M. Cochemé 1,2 and Filipe Cabreiro. In revision at Cell
Start Year 2016
 
Description Ivana Bjedov 
Organisation University College London
Department UCL Cancer Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Leading lab studying the role of antidiabetic drugs on microbes and host physiology
Collaborator Contribution The partner provided expertise on drosophila and performed experimental work to validate some of our findings
Impact Publications: Rosina Pryor *,1,2,3, Povilas Norvaisas *,3, Christoph Kaleta*,4, Leonor Quintaneiro 1,2,3, Wouter De Haes 5, Celia Lujan 6, Reuben L. Smith 7, Timothy Scott 3, Daniel Martinez-Martinez, 1,2, Orla Woodward 3, Kevin Bryson 8, Riekelt H. Houtkooper 6, Liesbet Temmerman 4, Ivana Bjedov 5, Helena M. Cochemé 1,2 and Filipe Cabreiro. In revision at Cell
Start Year 2015
 
Description Microbiome talk for the general public 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact 50 General practitioners/lay public attended a public engagement event that focused on the role of the microbiome in health and disease. It generated questions and discussion.
Year(s) Of Engagement Activity 2019