This review argues that a "body-first" subtype of Parkinson's may begin in the GI tract—driven by environmental insults, α-synuclein misfolding, oxidative stress and enteric glial activation—that propagates retrogradely via the vagus to the brain and discusses implications for early gut-targeted…

By synthesizing evidence for enteric oxidative stress, glial activation, and α-synuclein propagation as early, potentially druggable events, the paper points to biomarkers and gut-directed or repurposed therapies that could enable earlier, disease-modifying interventions in PD.

Parkinson's disease, characterized by the motor deficits that result from the loss of dopaminergic neurons in the Substantia Nigra pars compacta, is the second most common neurodegenerative disorder worldwide. Parkinson's disease is also commonly associated with severe non-motor symptoms, including hyposmia and sleep disorders, as well as gastrointestinal dysfunction and dysregulation of the brain-gut axis. Increasing evidence indicates that pathology in the "body-first" subtype of Parkinson's disease may originate in the gastrointestinal (GI) tract and then spread to the brain via the vagus nerve. GI dysfunction may also arise, however, from "top-down" or "brain-first" mechanisms, reflecting bidirectional brain-gut interactions. Systemic environmental factors, such as exposure to pesticides and heavy metals, are hypothesized to initiate this pathology and promote α-synuclein (α-syn) misfolding and the formation of Lewy Bodies. A growing body of evidence suggests, however, that oxidative stress and glial activation may emerge in the enteric nervous system and the dorsal motor nucleus of the vagus long before the onset of neurodegeneration, and that these early changes may be sufficient to drive the retrograde spread of pathology to higher brain regions. The purpose of this review is to discuss the progression of PD pathology across the brain-gut axis, providing insights into the contribution of oxidative stress and glial activation to neuronal loss, and highlighting the importance of these mechanisms for potential therapeutic intervention at the earliest stages of PD.