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Review
. 2022;12(8):2339-2352.
doi: 10.3233/JPD-223461.

Exploring the Connection Between the Gut Microbiome and Parkinson's Disease Symptom Progression and Pathology: Implications for Supplementary Treatment Options

Dennis G Chan  1 , Katelyn Ventura  1 , Ally Villeneuve  1 , Paul Du Bois  1 , Matthew R Holahan  1
Affiliations
Review

Exploring the Connection Between the Gut Microbiome and Parkinson's Disease Symptom Progression and Pathology: Implications for Supplementary Treatment Options

Dennis G Chan et al. J Parkinsons Dis. 2022.

Abstract

The contribution of the microbiota to induce gastrointestinal inflammation is hypothesized to be a key component of alpha-synuclein (aSyn) aggregation within the gastrointestinal (GI) tract in the pathological progression of Parkinson's disease (PD). The function of the GI tract is governed by a system of neurons that form part of the enteric nervous system (ENS). The ENS hosts 100-500 million nerve cells within two thin layers lining the GI tract. The gut-brain axis (GBA) is the major communication pathway between the ENS and the central nervous system. It has become increasingly clear that the microbiota in the gut are key regulators of GBA function and help to maintain homeostasis in the immune and endocrine systems. The GBA may act as a possible etiological launching pad for the pathogenesis of age-related neurodegenerative diseases, such as PD, because of an imbalance in the gut microbiota. PD is a multi-faceted illness with multiple biological, immunological, and environmental factors contributing to its pathological progression. Interestingly, individuals with PD have an altered gut microbiota compared to healthy individuals. However, there is a lack of literature describing the relationship between microbiota composition in the gut and symptom progression in PD patients. This review article examines how the pathology and symptomology of PD may originate from dysregulated signaling in the ENS. We then discuss by targeting the imbalance within the gut microbiota such as prebiotics and probiotics, some of the prodromal symptoms might be alleviated, possibly curtailing the pathological spread of aSyn and ensuing debilitating motor symptoms.

Keywords: Microbiome; Parkinson’s disease; alpha-synuclein; fecal microbiota transplantation; gastrointestinal tract; prebiotics; probiotics; prodromal symptoms.

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Conflict of interest statement

The authors have no conflict of interest to report.

Figures

Fig. 1
Fig. 1
The aggregation process of aSyn protein. aSyn protein is normally found in natively unfolded monomeric structures but can also be found in α-helical tetramers when binding to lipid compounds. Aggregation of misfolded aSyn protein can either form oligomers that are rich in β-sheet formations (off-pathway) or oligomers that are not rich in β-sheet formations (on-pathway). Oligomers that are not rich in β-sheet conformations aggregate into fibrils, ultimately leading to the formation of LBs. These pathologic aSyn fibrils can act as a template for aSyn monomers and induce misfolding, creating a cycle of misfolding and aggregation of aSyn. Created with BioRender.com.
Fig. 2
Fig. 2
Progression of non-motor and motor symptoms in Parkinson’s disease. In the Braak Model of PD, it is hypothesized that the origin of PD originates in the PNS such as the olfactory bulbs and the ENS (Stage I). Non-motor symptoms can start to appear months or years prior to the onset of motor symptoms. Transmission of pathogenic forms of aSyn is thought to spread throughout the body in a prion-like manner, where aggregated aSyn can travel from the ENS to the brain via the vagus nerve. The diagnosis of PD is made once motor symptoms become apparent (Stage III). Long-term progression of PD causes a decrease in dopamine levels in the brain and an increase in the severity of motor and non-motor symptoms such as postural instability and cognitive disturbances, resulting in a dramatic decline in the quality of life of PD patients. Created with BioRender.com.
Fig. 3
Fig. 3
Schematic representation of the gut-brain axis in Parkinson’s disease. Alternations of the microbiota composition can be caused by various factors such as genetics and environmental risks. Dysbiosis of the microbiome can contribute to PD pathology in the gut before spreading to the brain via the vagus nerve. This results in a decrease in abundance of beneficial bacteria and a reduction of their metabolites, SCFAs, which have been shown to lower inflammation and gut permeability. Meanwhile, the abundance of harmful bacteria increases, along with the release of endotoxins like LPS. It is hypothesized that these endotoxins can increase inflammatory cytokine expression and cause the gut to become permeable for bacteria and endotoxins to enter the CNS and induce aSyn misfolding. Consequently, aSyn pathology can develop in the gut and travel up the vagus nerve where pathogenic aSyn can spread to brain regions in a prion-like manner. Created with BioRender.com.
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