Gut bacteria and the brain: the surprising impact of bacteriophages .

Rationale: Changes in the gut microbiome and intestinal permeability are contributing to age-related conditions and may even cause cognitive and motor dysfunction in Parkinson's disease (PD). People with PD report digestive problems up to 10 years before neurological symptoms occur and mice that receive faecal matter from PD mice or patients, show impaired motor function, a--synuclein neuropathology and decreased levels of neurotransmitters (PMID27912057). Increased expression of a-synuclein, within the intrinsic nervous system of the gut, is a normal response to infection, aimed at mobilizing the immune system and fight pathogens (PMID31316206, PMID28651250). However, when the expression of a--synuclein exceeds its clearance, for example as a result of chronic infections, neurotoxic aggregates form, damaging the enteric nervous system, promoting propagation of pathology to the brain. Collectively, these studies strongly link the gut microbiome, the local gut nervous system, and inflammation to the development of PD, but factors determining microbiome composition are incompletely understood. Bacteriophages directly modulate bacterial composition and abundance in the gut and may be an overlooked factor influencing the development of age-related conditions.
Approaches to be used: Faecal samples from PD or control mice (and PD patients) will be used to characterise the composition and function of the gut microbiome using state-of-the-art shotgun metabolomics and metagenomics. The interaction between phages, bacteria and the host, will be studied in gut tissue samples, using in-situ sequencing and block-face Scanning-Electro-Microscopy, followed by computational modelling to identify bacteria and/or phages associated with PD. Finally, we will build phages to target PD-associated bacteria, and test these in mouse models.
Areas of impact: This studentship may provide much needed insight into the mechanisms underpinning neurodegeneration associated with the gut microbiome. Elucidating possible beneficial and detrimental roles of phages in the gut will increase understanding of interbacterial and bacteria-host interactions, and contribute to novel strategies to remodel the gut microbiota for therapeutic purposes.