Brain-first versus Body-first: Exploring aspects of gut microbiota in Parkinson’s disease
Date
2025-01-08
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Abstract
Parkinson’s disease (PD) is pathologically characterized by the irreversible aggregation of misfolded α-synuclein protein, forming what is known as Lewy Pathology, which is observed in multiple regions of the brain and gut. The “brain-first” and “body-first” hypothesis proposes distinct patterns of Lewy pathology distribution in the early stages of the disease, which categorizes clinical sub-phenotypes of PD. The “brain-first” sub-phenotype is thought to have predominant involvement of the amygdala, while the “body-first” sub-phenotype involves the enteric nervous system. In mouse models, the microbiota has been shown to be involved in promoting α-synuclein pathology and characteristic motor features in PD. This study aims to investigate whether microbiota from PD patients characterized as “brain-first” or “body-first” sub-phenotypes will induce divergent gastrointestinal functions and motor deficits in human microbiome-associated mice. Human PD microbiome-associated mice were generated by performing fecal microbial transfers from “brain-first” and “body-first” PD donors into germ-free C57BL/6 and dbl-PAC-Tg(SNCAA53T)Snca-/- recipient mice. FMT recipient mice were bred and gastrointestinal and motor functions in these offspring were analyzed. In dbl-PAC-Tg(SNCAA53T)Snca-/- mice, slow intestinal transit, indicative of decreased intestine motility, and increased gastrointestinal permeability were observed in “body-first” group compared to “brain-first” sub-phenotype. No significant motor function differences were detected between the two PD sub-phenotypes in these mouse models. Additionally, male dbl-PAC-Tg(SNCAA53T)Snca-/- “body-first” mice demonstrated a better ability to differentiate preferred odors in the olfactory preference test, whereas those colonized with microbiota from "brain-first" PD patients showed more olfactory dysfunction. Together, these results suggest that gut microbiota from PD patients may influence non-motor impairments associated with PD sub-phenotypes.
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Keywords
Microbiome, Parkinson's disease, Gut microbiota, Mice, Neurodegenerative diseases
Citation
Kiani, P. (2025). Brain-first versus body-first: exploring aspects of gut microbiota in Parkinson’s disease (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.