Investigating the influence of gut microbial metabolism on normal age-related cognitive decline

Cognition is a mental process for gaining knowledge and understanding of the world around us, and it usually gets worse with age. This deterioration often coincides with structural and functional changes in the brain. While healthy lifestyles can reduce the rate of age-associated cognitive decline, obesity has been implicated in its acceleration. This is important as obesity rates continue to rise in the UK, peaking in adults aged 45-54 years (36% obese) and remain high in older groups (33.5%, 55-74 years).

A vast population of microorganisms are present in the human gut, collectively referred to as the gut microbiota. We, and others have shown that these microorganisms are able to produce chemicals in the gut that can modify processes occurring in the brain with implications for cognition and overall well-being. Importantly, the types of microbes present in the gut and their overall activities change with age and obesity, and we now have preliminary data suggesting that the intestinal microbiota and their chemical output is related to normal age-related cognitive decline.

To further investigate this, we will measure the chemicals produced by the gut microbiota in humans of different ages and body mass index (BMI; a measure of obesity) and explore relationships between these signals and brain structure and function. Using different analytical chemistry techniques, we will measure microbial-related molecules in blood and stool samples collected from over 1,000 people (aged 50-98 years). These participants have had their brain structure and function measured as well as the microorganisms present in their stools (reflective of their gut microbiota). This data will allow us to identify microbial metabolites that are associated with brain function, the microorganisms responsible for their production, and the influence of age and obesity on their production and effects.

To confirm these findings, we will measure these same chemical messengers in blood and stool samples from a second set of individuals (181 in total; aged 23-66 years) whose brain function and gut microbiota has also been determined. These individuals have provided two samples one year apart with some samples provided by obese participants before and after weight loss. This data will allow us to confirm our initial findings in a separate group of people, assess the stability of microbial signals within the same individual, and the impact of obesity and weight loss on their production.

Finally, the processes through which these microbial metabolites affect brain structure and function will be studied in rodents. Here, rats will receive these chemicals and their cognitive functions will be assessed and specific brain processes will be measured. This will provide detailed information that will advance our understanding of how intestinal microorganisms can influence normal age-related cognitive decline. This will guide the development of strategies aimed at preserving a healthy microbiota (for example, high-fibre diets, prebiotics and probiotics) during ageing and in the presence of obesity to help reduce this decline.

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.