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Cirstea, Mihai Serban

University of British Columbia

Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world. Gastrointestinal comorbidities, especially constipation and slow colonic transit time, affect most patients and can manifest decades before motor symptom onset, leading to speculation that the gut microbiota may be involved in disease etiology and pathophysiology. Leveraging clinical cohorts and in vitro models, I investigated the microbiota’s role in PD. Bacterial (16S) and fungal (ITS2) amplicon sequencing elucidated the composition of the microbiota in PD patients and controls, and paired serum metabolomics helped infer microbial function. I showed that the PD microbiota had a reduced abundance of several co-abundant short-chain fatty acid producing bacteria, including well-known butyrate producing genera such as Faecalibacterium and Roseburia. The butyrate production capacity of the PD microbiota was inversely associated with colonic transit time as estimated by Bristol Stool Scale score. Conversely, the PD microbiota had a higher abundance of several co-abundant bacteria with diverse metabolic capacities, including the mucin-degrading Akkermansia muciniphila. PD-enriched microbes were strongly associated with increased colonic transit time and serum concentrations of the proteolytic microbial metabolites p-cresol and phenylacetylglutamine. These findings generated mechanistic hypotheses that were carried into in vitro experiments. Regarding PD-relevant microbial metabolites, I showed that butyrate dampened cytokine production and immune cell attachment in a blood brain barrier endothelial cell line, while p-cresol caused inflammation and downregulated genes involved in gut peptide and serotonin biosynthesis in an enteroendocrine cell line. A final clinically-informed mechanistic insight came from the observation that the abundance of the PD-enriched genus Bifidobacterium was correlated with levodopa (L-DOPA) dose in patients. L-DOPA is the primary treatment for PD. It is taken orally, absorbed in the intestines, and must reach the brain intact to exert its clinical effect. Peripheral breakdown of L-DOPA is an ongoing clinical concern, including metabolism by gut microbes. Through in vitro assays, a pathway was discovered whereby certain Bifidobacterium species can metabolize L-DOPA into its equivalent lactic acid using existing tyrosine metabolism genes. In conclusion, in this thesis I demonstrate compositional and functional alterations in the PD microbiota with important downstream consequences on gut function and therapeutic management.

Text

2024-01-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/83591

Microbiology and Immunology

University of British Columbia

UBCV

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