Unravelling Gut microbial integrative transcriptomics and host gene expression in Parkinson’s disease through computational RNA-Seq Analysis

Parkinson's disease (PD) is a multi-factorial, progressive neurodegenerative disorder with the primary feature, i.e., degeneration of dopaminergic neurons of the substantia nigra and the formation of pathological aggregates of misfolded 4-synuclein in the Lewy bodies. Although historically viewed as a brain-based illness, mounting evidence has set PD into a new perspective as a systemic disease with initial involvement of peripheral systems, more so the gut. Such a shift in perception has been driven to a large degree by the growing awareness of the gut-brain nexus. Microbial dysbiosis is characterized by the imbalance in the normal composition of the gut microbiota, linked to the development and progression of PD more often. Porphyromonas gingivalis and Collinsella aerofaciens , to neurodegeneration in terms of inflammation, barrier dysfunction, and the pathology of alpha-synuclein. By using high-throughput RNA-Seq data retrieved via public repositories (e.g., NCBI GEO), we developed a computational analysis pipeline enclosing quality control, mapping differential gene expression, pathway enrichment, and network-based interpretation. Transcriptomic data of these microbes and associated tissues with hosts were used to elucidate the interactions on a gene level and possible mechanistic pathways operating in the pathophysiology of PD. The results have shown that periodontal pathogen (P. gingivalis) induces virulence factors such as gingipains and LPS, impairing the integrity of the epithelial and blood-brain barrier and provoking the neuroinflammatory process. Similarly, another commensal, C. aerofaciens , which can act as a pathobiont, showed impaired expression of Th17-related cytokines and reduced levels of tight junction markers, demonstrating that C. aerofaciens was associated with impaired intestinal permeability and overall activation of the immune system. These microbial signatures were associated with changes in transcriptomic patterns of their hosts, which indicated mitochondrial glitch, increased oxidative pressure, TNF-alpha pathway, and immune imbalance, which further support the hypothesis that microbial metabolites and inflammatory mediators contribute to dopaminergic neurodegeneration.