The Enteric Nervous System as a Mediator of Microbiota-Gut-Brain Interactions in Parkinson's Disease

Parkinson's disease (PD) is a multifactorial neurodegenerative disorder in which gastrointestinal dysfunction is highly prevalent and often precedes motor symptoms. Although research on gut microbiota alterations in PD has expanded rapidly, inconsistent findings and the absence of a reproducible microbial signature reveal the limitations of a microbiota-centered view. The enteric nervous system (ENS), the intrinsic neural network of the gut, has been comparatively overlooked and remains underexplored, yet mounting evidence indicates that it undergoes profound alterations in PD. Pathological changes in enteric neurons and glial cells, including α-synuclein accumulation, disrupted neurotransmission, impaired epithelial barrier regulation, and neuroinflammation, not only contribute to gastrointestinal dysfunction but may also drive disease propagation along the gut-brain axis. In parallel, PD-related dysbiosis alters microbial metabolites and immune signaling, disrupting ENS physiology. This review reframes PD gut pathology by emphasizing the ENS as a central mediator of microbiota-brain communication. We highlight potential key pathways underlying this crosstalk, including short-chain fatty acids (SCFAs), Toll-like receptor (TLR) signaling, and serotonergic circuits, which normally sustain ENS function but, in the context of PD, contribute to barrier impairment, neuroinflammation, and neuronal alterations. By integrating evidence from human studies and experimental models, we argue that investigating ENS-microbiota interactions provides a more comprehensive perspective on PD pathophysiology and may guide the identification of novel biomarkers and therapeutic approaches capable of addressing both gastrointestinal and neurological manifestations of the disease.