Exploring a gut-brain axis when immunity is constitutively active

Thesis

A gut-brain axis influenced by host innate immunity and resident microbiota has been implicated in neurological conditions, including Alzheimer’s disease and Parkinson’s disease. However, the precise connection of innate immunity to neurodegeneration remains unclear. Using Pirk, a negative regulator of the IMD/NF-κB pathway in Drosophila, we investigated the neurological phenotypes induced, when genetically predisposing flies to an over-reactive innate immune response. Pirk mutants exhibited age-dependent neurological phenotypes, exemplified by reduced locomotion activity and altered sleep patterns. Raising flies in axenic conditions showed that, the absence of gut bacteria only partially rescued the neurological and neurodegenerative phenotypes of pirk flies. These results correlate with data obtained by tissue-specific pirk RNAi, where silencing pirk in gut stem cells and glial cells led to earlier onset of the neurological phenotypes. This, alongside dysbiosis of pirk mutants, highlighted a potential early role for the gut-brain axis in the onset of neurodegeneration. These are hallmarks of Alzheimer’s in humans, but do not exist in flies. Our results indicate an evolutionarily conserved path to neurodegeneration linked with a predisposition to overactive innate immunity, even in the absence of beta-amyloid aggregation or tau protein tangles.

Authors: Arora, S

• DOI: 10.5287/ora-jn6xqzzxr
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: Drosophila melanogaster; innate immunity; gut microbiota/dysbiosis; ageing; neuroinflammation; IMD/NF-κB signalling pathway; neurodegeneration; sleep behaviour; Pirk; gut–brain axis
• Subjects: Neuroinflammation; Drosophila melanogaster; Immunology