Targeting the Gut to Modify Parkinson's Disease: From Mechanisms to Potential Therapeutics

Parkinson's disease (PD) is the second most common neurodegenerative disorder and its prevalence continues to rise with population aging. Its cardinal motor features arise from the loss of dopaminergic neurons in the substantia nigra, accompanied by intraneuronal α-synuclein aggregates known as Lewy bodies. Neuropathological evidence suggests that, in a subset of patients, α-synuclein pathology first appears in the enteric nervous system and ascends to the brain via the gut-brain axis. Consistent with this "body-first" trajectory, a growing body of work has documented distinct alterations in gut microbial composition and microbiota-derived metabolites in people with PD relative to healthy individuals, with some changes detectable in the prodromal phase. Current management, whether dopaminergic pharmacotherapy or deep brain stimulation, alleviates motor symptoms but does not slow neurodegeneration, and long-term treatment is complicated by motor fluctuations and other adverse effects. Therapies directed at the underlying disease process are therefore urgently needed. Because early perturbations of the gut microenvironment appear to contribute to PD pathogenesis, interventions that restore gut homeostasis represent a rational disease-modifying strategy, particularly for patients whose pathology originates in the gut. This review synthesizes current understanding of how the gut microbiota shapes the gut-brain axis in PD, spanning immune, metabolic, neuroendocrine, and neural pathways, and critically appraises the emerging evidence for microbiota-directed interventions, including fecal microbiota transplantation, probiotics, and prebiotics, as candidate disease-modifying therapies.