Abstract :
[en] The human gut microbiome, which includes a diverse array of microorganisms such as bacteria, archaea, and viruses, plays a crucial role in maintaining overall health and influencing disease outcomes. This microbiome integrates environmental, genetic, and immune signals to support various physiological functions, including digestion, immune regulation, and detoxification. Dysregulation of the gut microbiome has been implicated in several diseases, including Parkinson’s Disease (PD). Although PD is not traditionally associated with gut disorders, emerging evidence links microbial imbalances in the gut to disease onset and progression. This connection is supported by the observation that PD-related protein aggregations and gastrointestinal symptoms often precede motor symptoms. In PD, there is an elevated abundance of pro-inflammatory bacteria and a reduction in beneficial bacterial species. Furthermore, an increased presence of methanogenic archaea, particularly Methanobrevibacter smithii, has been observed, indicating a potential involvement in the gut-related symptoms frequently associated with PD. These findings underscore the importance of the gut-brain axis and highlight the need for further research into how gut microbiota may contribute to neurodegenerative diseases like PD.
This thesis investigates the role of the gut microbiome in PD through a range of computational and analytical methods. The primary objective of this work is to elucidate the complex interactions between microbial functions and PD using advanced meta-omics and network-based techniques. A key finding of this research is the alteration in microbial structure and function associated with PD, particularly the elevated levels of β-glutamate linked to specific microbial genera. This study identifies glutamate metabolism as a central process within the PD-associated microbiome, highlighting disruptions that correlate with decreased transcript abundances in chemotaxis and flagellar assembly among PD-related taxa. The reduction in flagellin transcription by certain bacteria in PD indicates intricate interactions between microbial changes and host immune responses. Further analysis utilizing Weighted Gene Co-Expression Network Analysis (WGCNA) revealed significant differences in co-expression patterns in PD. Notably, modules of co-expressed genes in healthy controls (HC) demonstrated greater functional diversity, while PD was characterized by reduced gene diversity and specific metabolic alterations, including glycerolipid metabolism, peptidoglycan biosynthesis, lipoic acid metabolism, and valine degradation. The network-based approach confirmed significant enrichment in flagellar assembly among HC, alongside the identification of secondary bile acid biosynthesis as an enriched process. Additionally, our study revealed significant alterations in bacterial microcompartments (BMCs) within certain commensal bacteria, exhibiting a strong correlation with flagellar assembly genes, further underscoring their interconnected roles in PD. To our knowledge, this work is the first to establish a link between BMCs and flagellar assembly in the context of PD, revealing essential microbiome functions that are disrupted in this disease. These findings offer valuable insights into the microbial mechanisms contributing to PD pathogenesis and lay the groundwork for future experimental validation.
The study also explored the role of intestinal archaea, particularly Methanobrevibacter smithii, in PD. This archaeon, known for its involvement in gastrointestinal disorders, was found to have significant interactions with gut microbiome functions, with implications for gastrointestinal symptoms commonly seen in PD. Advanced protein structure prediction identified gut-specific archaeal proteins potentially involved in defense mechanisms, virulence, adhesion, and the degradation of toxic substances. Preliminary evidence also suggested interdomain horizontal gene transfer between Clostridia species and M. smithii, based on structure-based protein annotation.
In conclusion, this thesis underscores the significant role of the gut microbiome in the pathogenesis of PD. Through comprehensive computational and analytical methods, the research highlights critical alterations in microbial structure and function, particularly in glutamate metabolism and microbial diversity. The study also brings to light the involvement of intestinal archaea, such as Methanobrevibacter smithii, in microbiome function. These insights pave the way for future research aimed at understanding the gut-brain axis and developing microbiome-based interventions for neurodegenerative diseases like PD.
