PhD Studentship: The Gut-brain-axis: How Does The Gut Microbiota Affect The Function of The Brain?

The gut microbiota is an important contributor to overall health of the central nervous system (CNS), with a bidirectional communication (gut-brain-axis). In humans, there is evidence of association between the gut microbiome and mental health disorders, however, causality and target validation are still needed. Gut microbiota perturbations, specifically a depletion of anti-inflammatory butyrate-producing bacteria and an enrichment of pro-inflammatory bacteria, are associated with depression, bipolar disorder, schizophrenia, and anxiety. A disruption of the gut microbiome, known as dysbiosis, can predispose to mental health disorders whilst diet-mediated changes in the gut microbiota have been associated with poor mental health.

Gut bacteria can produce neurotransmitters such as serotonin, dopamine, noradrenaline and can also modulate tryptophan metabolism. All of these molecules have profound effects on the brain and alter mood, memory, behaviour and more. Inflammation of the gut makes the lining of the gut “leaky” and this is communicated to the brain and can cause several mental illnesses including anxiety and depression. Probiotics have the ability to restore normal microbial balance, and therefore may have a potential role in the treatment and prevention of anxiety and depression. We hypothesise that changes in the gut microbiota in rodents over their lifespan lead to inflammation in the brain that causes mental illness development and that restoring the normal gut microbiota will alleviate inflammation in the brain and subsequent mental illnesses.

In this project we will use rodent models throughout their lifespan to understand the impact of the microbiome on the normal postnatal CNS development and potential changes in the brain over time that may explain the occurrence of mental health problems. In rodents, we will first define the “normal” gut microbiota by analysing stool samples; convenient, inexpensive and can be repeatably sampled. We will then challenge the gut microbiota (e.g. by changing the diet to reduce fibre intake and increase fatty acids and monosaccharides) and determine circulating levels of proinflammatory cytokines and neurotransmitters in blood as fluid biomarkers for potential changes. Brain tissues will then be subjected to analysis by immunohistochemistry (IHC) to determine microglial and astrocyte activation and changes in proinflammatory cytokines, using a panel of specific antibodies. Attention will be paid to proinflammatory cytokines associated with mental illnesses such as interleuikin-6, which is associated with for example, depression and psychosis in general. Blood brain barrier (BBB) permeability will be assessed in depth using Evans Blue dye extravasation into the brain parenchyma and measurement of tight junction proteins such as claudin 5, CCLN and ZO-1. All of these changes will be correlated with behavioural changes in rodents which test for depression, anxiety and aggression amongst others, that are routinely used in the Ahmed lab. Finally, we will perform neuropathological assessments to determine changes in specific regions of the brain associated with mental illnesses

This project will combine the expertise of two world-leading researchers in microbiology & infection and neuroscience to lead to a deeper understanding of the gut-brain-axis and how changes in the gut microbiota may bring about the development of mental illnesses.

Funding Details

Additional Funding Information

This project is funded by MIBTP’s BBSRC Doctoral Training Programme (https://warwick.ac.uk/fac/cross_fac/mibtp/). International students may apply and overseas fees will be waived but visa and health insurance surcharge will need to be paid by the student.

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