Beyond bacteria: a multi-omics view of the gut-brain axis in Parkinson's disease.

INTRODUCTION: Parkinson's disease (PD) is increasingly recognized as a multisystem disorder in which gastrointestinal dysfunction and gut microbial alterations may contribute to disease pathophysiology. Although most microbiome research in PD has focused on bacteria, growing evidence suggests that the gut ecosystem should be considered more broadly to include fungi, viruses, metabolites, and proteins. METHODS: We searched PubMed and SciFinder for human studies published up to October 28, 2025, using domain-specific search strategies for the bacteriome, metabolome, proteome, virome, and mycobiome, and synthesized the eligible evidence using a structured multi-omics evidence-mapping framework. RESULTS: We summarize the most consistent bacterial findings, including enrichment of mucin-degrading taxa and depletion of short-chain fatty acid-producing commensals, and discuss how these changes relate to impaired fermentation, barrier dysfunction, and immune activation. We further examine emerging evidence for virome and mycobiome alterations, highlighting the possibility that PD-related dysbiosis reflects cross-kingdom ecological disruption rather than bacteria-only imbalance. Metabolomic studies provide functional support for this model by demonstrating altered short-chain fatty acid biology and broader host -microbe co-metabolic remodeling. Protein-focused studies, including host proteomic signatures and bacterial functional amyloids, extend the field toward mechanisms linking gut dysfunction to inflammation, proteostatic stress, and α-synuclein pathology. DISCUSSION: Overall, the evidence supports a multi-layer view of the PD gut -brain axis in which microbial ecology, metabolic output, barrier integrity, immune signaling, and protein-centered mechanisms are interconnected. The field remains limited by cross-sectional designs, methodological heterogeneity, and uneven evidence depth across omics layers. Longitudinal, standardized, and integrated multi-omics studies will be essential to determine which microbiome-associated alterations are mechanistically important, clinically informative, and potentially modifiable in PD.