Investigating the influence of gut microbial metabolism on normal age-related cognitive decline
Lead Research Organisation:
University of Oxford
Department Name: Psychiatry
Abstract
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Technical Summary
We aim to determine the influence of gut microbial metabolism on normal age-related cognitive decline. Our recent preliminary work in humans identified gut microbial species, processes and metabolites related to cognitive functions that were negatively correlated with age and BMI. We have shown that several microbial metabolites that change with age and obesity are involved in the gut-brain axis. However, the role of gut microbial metabolism in normal age-related cognitive decline has not been comprehensively studied in humans and causality has not yet been established. The influence of obesity on this relationship also remains to be defined.
To investigate this, an initial discovery phase will leverage banked plasma and faecal samples from a large cross-sectional human study where cognition has been found to be inversely correlated with age and BMI (>1,000 participants [50-98 years]). A combination of high-resolution untargeted (NMR spectroscopy-based) and targeted (mass spectrometry-based) metabolomic approaches will be used to measure a broad range of metabolic features associated with gut microbial metabolism. Integrative multivariate data analysis techniques will be used to combine this metabolic data with existing shotgun metagenomic, brain structure and function data to identify microorganism-function-metabolite relationships related to cognitive decline. Candidate microbial metabolites will be validated using samples from an independent longitudinal study (181 individuals; 23-66 years) with accompanying metagenome, brain structure and function data. The longitudinal nature of this study also enables the stability of microbial metabolites to be evaluated over a one-year period, including in obese individuals before and after weight loss. Finally, rodent models will be used to demonstrate causality and understand the biomolecular mechanisms contributing to cognitive decline. This work will comprehensively address the research question posed.
To investigate this, an initial discovery phase will leverage banked plasma and faecal samples from a large cross-sectional human study where cognition has been found to be inversely correlated with age and BMI (>1,000 participants [50-98 years]). A combination of high-resolution untargeted (NMR spectroscopy-based) and targeted (mass spectrometry-based) metabolomic approaches will be used to measure a broad range of metabolic features associated with gut microbial metabolism. Integrative multivariate data analysis techniques will be used to combine this metabolic data with existing shotgun metagenomic, brain structure and function data to identify microorganism-function-metabolite relationships related to cognitive decline. Candidate microbial metabolites will be validated using samples from an independent longitudinal study (181 individuals; 23-66 years) with accompanying metagenome, brain structure and function data. The longitudinal nature of this study also enables the stability of microbial metabolites to be evaluated over a one-year period, including in obese individuals before and after weight loss. Finally, rodent models will be used to demonstrate causality and understand the biomolecular mechanisms contributing to cognitive decline. This work will comprehensively address the research question posed.
Organisations
People |
ORCID iD |
| Philip Burnet (Principal Investigator) |
Publications
Costa CFFA
(2024)
Importance of good hosting: reviewing the bi-directionality of the microbiome-gut-brain-axis.
in Frontiers in neuroscience
| Description | An analysis of a human database by the lead PI (Southampton) revealed that the concentration of certain bile acids increased with age and was negatively associated with cognitive ratings. Bile acids are like detergents that help digest fats in our diet, and are initially produced in the liver from cholesterol. However these 'primary' bile acids are secreted into the gut and converted by resident gut microbes to 'secondary' bile acids, which then assist with the digestion of our food. These bile acids are found in the circulation and can penetrate the brain. Initially, the bile acids deoxycholic acid (DCA), glycodexoycholic acid (GDCA) and hyo-deoxycholic acid (HDCA) were identified in the database. In Oxford, therefore, we tested the hypothesis that when these bile acids are fed to mice, cognitive function will be reduced. Mice were orally administered DCA, GDCA or HDCA at concentrations (30mg/kg) slightly lower than in the current literature which use high doses to induce liver pathology. We found that: 1) GDCA impaired recognition memory in the Novel Object Recognition (NOR) task in both male and female mice, but did not affect spatial memory. 2) HDCA reduced a component of spatial reference memory in male and female mice, but not spatial working memory in the Y-maze. Performance in the NOR task was not affected by HDCA. 3) All bile acids reduced bile acid receptors in the brain, which indicates brain penetrance. 4) GDCA and HDCA reduced the expression of glutamate NMDA receptors in different brain regions 5) These effects were independent of animal weight and, in a pilot study, these effects were not observed in young mice. 6) The effect of these bile acids on the gut microbiota themselves are currently being explored, to test if an elevation of these molecules reduce the abundance of beneficial bacteria. The latter have been shown to decrease with age. Together these data show that gut microbiota-derived bile acids affect different components of cognitive function. Recognition memory (recall of images, places, people) and spatial reference memory (using visual cues in the environment to confirm location of self or an item in that environment), are reported to decrease with age. We conclude, therefore that an accumulation of bile acids during the natural aging process may affect brain function. NB: since these findings, a more stringent analysis of the human database revealed only HDCA negatively correlated with cognitive performance. However, since an elevation of GDCA with age has been reported in human subjects, we plan to publish the HDCA and GDCA findings in two separate papers: 1) HDCA behavioural effects with the findings from the human data-base and 2) GDCA behavioural and molecular effects in mice. In this paper the effect of DCA on bile acids will be reported together with its null effect on other genes and behaviour. |
| Exploitation Route | The influence of bile acids on brain gene expression specifically involved the bile acid receptors, FXR and TG5R, as expected, but also the NMDA receptor subunit, GluN2A. Given that the latter is a crucial mediator of optimal cognitive function, in vitro neuronal cell cultures can now be used to explore the interactive signalling pathway between these receptors. Human neural cultures derived form stem cells from donors of different ages, could be used to examine age-related changes in these pathways that may underlie susceptibility to age-related cognitive decline. We hope to seek further BBSRC funding to conduct such experiments. Overall, our findings demonstrate another mediator of the microbiome-gut-brain axis: the current canonical mediators of microbiome-modulated brain function are the vagus nerve, immune system and microbial short-chain fatty acids. In the latter instance, bile acids can be added to the list of microbial metabolites directly affecting the brain which, although has been recognised, remains under-explored. |
| Sectors | Agriculture Food and Drink Education Healthcare Pharmaceuticals and Medical Biotechnology |
| Description | Public engagement lecture on consciousness and the microbiome for New Scientist magazine |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | The activity (a "one-day master class") involved speakers from Universities around the UK giving an overview of their research/opinions on the elements of human and animal consciousness. The lectures were delivered under specific themes which were then followed by questions and a discussion forum. The event organised by New Scientist was intended to provide their readers with an overview on what we know about the consciousness in general, which the magazine has found to be a topic of interest to the general public. I was invited as the 'microbiome' is also a very popular topic which was evident after my talk: I was approached by several members of the public who wanted to share their experiences and views that were relevant to the subject. |
| Year(s) Of Engagement Activity | 2024 |
| URL | https://www.newscientist.com/science-events/conscious-mind/ |