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Radisavljevic, Nina

University of British Columbia

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor dysfunction. Non-motor symptoms including gastrointestinal (GI) dysfunction and mood disorders (such as depression) are also particularly common. GI symptoms include constipation, and PD patients display altered gut microbiota composition. Evidence in animal models points towards a potential causal role for the microbiota in mediating PD pathology. However, the constipation, medication use, and lifestyle habits of PD patients can also be expected to change microbiota composition. In this thesis, I explore the role of the gut microbiota in PD, in terms of the degree that it is shaped by the disease state and its ability to mediate disease symptoms. Using a transgenic mouse model of PD that displays motor deficits, GI dysfunction, and behavioral alterations, I assessed how broad alterations to the gut microbiota impacted the motor and non-motor phenotype. I found that both depletion of the microbiota through antibiotics, and a shift towards a healthy wild-type mouse microbiota, had a minimal impact on the PD-like symptoms. This suggested that the PD-like transgenic state of this model may drive the disease phenotype to a greater extent than the microbiota. Similarly, I demonstrated that the decreased abundance of Lachnospiraceae and decreased abundance of Ruminococcaceae and Oscillospira observed in PD patients may be a result of constipation by treating PD mice with laxatives that reversed these shifts. Lachnospiraceae abundance was also found to be decreased by treatment of this model with the PD medications L-DOPA and carbidopa. Conversely, different antibiotic treatment regimens were able to shift the microbial community and alter GI transit time in PD mice. Specific bacterial taxa, such as Lachnospiraceae (Ruminococcus), were associated with transit time – indicating a potential to treat PD constipation via the microbiota. Furthermore, treatment of PD mice with PD medications had a beneficial effect on constipation and depression-like behavior, potentially through increasing the abundance of Turicibacter and promoting butyrate production. This thesis demonstrates that certain PD-associated microbiota alterations may be a result of slowed GI transit or the presence of medications. However, specific shifts to the gut microbiota may in turn mediate non-motor symptoms in PD.

Text

2023-09-19

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/85966

Biochemistry and Molecular Biology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/