Feeding microbes to protect the brain: does the gut microbiota mediate the risk-reducing effects of a healthy diet on Alzheimer’s disease?

Background: Ways of reducing the risk of developing Alzheimer’s disease (AD) and other dementias are critically needed, given the almost total lack of truly effective therapeutic options, even despite newer anti-amyloid drugs¹. We have a reasonable idea of the lifestyle features that can reduce AD risk, such as regular exercise, education, and diet, but it is much less clear why these interventions are beneficial. Gaining insights into the molecular mechanisms through which preventative factors reduce AD risk will allow their optimisation and has the potential to identify novel therapeutically exploitable targets. 

One of the most well studied ways of reducing AD risk is eating a healthy diet, i.e., one rich in seafood, wholegrain fibre, fruit and vegetables², with evidence showing this diet to bolster the protective structures of the brain, notably including its blood supply and the blood-brain barrier. Exactly how this effect is brought about is unclear though, holding us back from truly exploiting dietary approaches to support brain resilience and health.

An increasingly important aspect of diet-health interactions is the role of the gut microbiota, and the novel possibilities its manipulation holds for exploitation. Gut microbes, mainly found in the colon, act upon ingested food to produce a wide range of bioactive metabolites, many of which we and others have shown to impact on the brain^3-6 , for example, by protecting memory function, bolstering blood-brain barrier integrity, and limiting neuroinflammatory damage. Notably, gut microbes digest the group of nutrients termed polyphenols found in many foods associated with brain vascular health (e.g., green tea, cocoa, berries), producing a range of small molecules including benzoate, hippurate and the γ-valerolactones. While many polyphenols are beneficial in vitro, these effects are commonly seen at concentrations far greater than occur in vivo, suggesting that direct effects of the polyphenols are unlikely. In line with this, we have data showing some of these microbe-derived polyphenol metabolites to be bioactive and capable of modulating blood-brain barrier function in vivo. We now wish to explore these effects further, aiming to identify new pharmacological/nutraceutical tools that can promote cerebrovascular health, and potentially modify AD risk.

The primary goal of this PhD project will be to investigate the biological effects of microbe-derived polyphenol metabolites, studying both their molecular mechanism(s) and their effects on neuroinflammation and cognition in wild-type animals and in models of AD. Through this work, we will provide critical new information on how microbial fermentation of plant-derived dietary constituents can promote cerebrovascular and neural health, and will identify biological pathways with potential as novel prophylactic targets in AD. 

Research Aims:

1)    To screen different microbe-derived plant polyphenol metabolites for their activity upon blood-brain barrier properties in vitro.

2)    To select promising metabolites and explore their activity upon the brain in vivo, monitoring the blood-brain barrier, cognition, and the response to neuroinflammatory damage in adult mice.

3)    To test the ability of identified beneficial metabolites to slow/halt progression of AD in a mouse model of the condition, in readiness for future therapeutic development.

Admissions Requirements  

Applicants are usually expected to hold a good first BSc honors degree of at least 2:1, or equivalent, to be eligible to apply for admission to research degrees. The exact entry requirements for each PhD will vary depending on the nature of the project. A neuroscience background would be helpful, but not required.

If English is not your first language, the standard requirement for English is an IELTS score of 6.5 overall for non-clinical projects and 7 overall for clinical projects (or equivalent). More details about language requirements can be found here.

For more information on the project, please contact Dr Simon McArthur.  

For information on the application process, please contact [Email Address Removed]