The Brain‐Gut Axis in Parkinson's Disease Pathology

TL;DR

This review explores how Parkinson's disease may start in the gut and spread to the brain, highlighting the role of the brain-gut axis in disease progression.

Contribution

The paper provides a comprehensive overview of bidirectional brain-gut interactions in Parkinson's disease and their implications for early therapeutic intervention.

Findings

Parkinson's pathology may originate in the gut and spread to the brain via the vagus nerve.

Oxidative stress and glial activation in the gut can precede and drive neurodegeneration in the brain.

Environmental toxins contribute to gut dysbiosis and α-synuclein misfolding, promoting disease progression.

Abstract

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.

Exposure to environmental toxins induces gut dysbiosis, increases intestinal epithelial barrier permeability, immune activation, and oxidative stress, promoting α‐syn misfolding and propagation. Brainstem DMV neurons exhibit α‐syn pathology, dysregulating neuronal excitability and vagal control of GI functions. Dopaminergic SNpc neurons exhibit α‐syn pathology, increased oxidative stress, glial activation, mitochondrial dysfunction, and neurodegeneration. Figure legend: Representative schematic illustrating route of pathology propagation and anatomical connectivity between the GI tract, brainstem (via the vagus nerve) and—the SNpc (via the nigro‐vagal pathway). Vagal afferent fibers relay sensory information from the GI tract to the NTS, which assimilates this information with inputs from brainstem, midbrain, and higher brain regions before relaying the integrated signal to the adjacent DMV. Preganglionic parasympathetic neurons of the DMV innervate postganglionic neurons within the ENS to regulate GI functions. The SNpc modulates DMV neuronal activity, hence parasympathetic output, via dopaminergic inputs to activate D1‐like receptors. The right panels indicate region‐specific pathological changes observed in PD. In the SNpc, (top panel), dopaminergic neurons exhibit α‐syn pathology, increased oxidative stress, glial activation, mitochondrial dysfunction and neurodegeneration, and subsequent loss of neuromelanin. In the DMV, (middle panel) cholinergic neurons exhibit α‐syn pathology, increased oxidative stress, glial activation, mitochondrial dysfunction, leading to increased neuronal excitability and disrupted GI functions (i.e., delayed gastric emptying, altered GI motility). In the ENS, (bottom panel) exposure to environmental toxins and altered gut microbiota increase epithelial barrier permeability, immune activation and oxidative stress, which promotes α‐syn misfolding and propagation. Image created with Biorender under license (KNB).

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