Gut Microbiome–Parkinson’s Disease Interactions: Mechanistic Insights from Caenorhabditis elegans and Translational Perspectives

Parkinson’s disease is a neurodegenerative disorder marked by dopaminergic neuron loss and α-synuclein aggregation. Non-motor symptoms, like gastrointestinal disturbances, often precede motor issues, implicating the gut–brain axis. The gut microbiome, influencing host metabolism, immunity, and barrier function, may drive neuroinflammation, α-synuclein aggregation, and neurodegeneration through metabolic, immune, and neural pathways. Caenorhabditis elegans is a powerful model for studying these interactions due to its genetic tractability, short lifecycle, and well-defined nervous system. Studies show that specific bacterial taxa, microbial metabolites (e.g., short-chain fatty acids, lipopolysaccharides), and bacterial amyloids (e.g., curli) directly impact α-synuclein aggregation, dopaminergic neuron degeneration, and locomotor deficits. Host genetics and transgenerational epigenetic effects further modulate these interactions. However, Caenorhabditis elegans lacks a blood–brain barrier and has a simplified immune system and microbiome, requiring validation in complex models and human studies. Future research should integrate multi-omics, AI, and synthetic microbiome engineering to bridge this gap. Microbiome-based therapies, like probiotics and fecal transplants, show potential but need clinical validation. A multi-model pipeline combining Caenorhabditis elegans, mammalian, and human data is essential to clarify the microbiome’s role in Parkinson’s disease and develop targeted interventions.