Journal Excerpt: Parkinson Disease and the Microbiome

Abstract

Parkinson disease (PD) is one of the fastest-growing neurodegenerative diseases, with gastrointestinal symptoms often preceding motor symptoms by several decades. As such, there has been an interest in understanding the potential role of the microbiome and how it relates to PD and what clinical implications this may have for patient management. 

The aim of this review was to conceptualize current understandings of the crosstalk between neurological and gastrointestinal systems as they relate to PD pathogenesis. 

It is now understood that gut factors play a role in both initiating and promoting neurodegeneration in a subset of PD patients. Some of the major mechanisms underpinning these factors include intestinal dysbiosis, intestinal hyperpermeability, inflammation, and enteric alpha-synuclein aggregation. An integrative approach to the assessment of PD patients encompasses understanding such mechanisms and how they may be contributing to PD progression. Gut-specific treatments should focus on targeting pathogens that may enhance disease progression or interfere with medication efficacy, improving microbial diversity and gastrointestinal-related symptoms, targeting alpha-synuclein aggregation and neuronal inflammation, and promoting antioxidative function. 

The gut microbiome offers potential opportunities to enhance care and promote patient outcomes for those with PD. While naturopathic and integrative medicine does not offer a cure, it may play a role in slowing disease progression and enhancing quality of life for these patients.

Introduction

Parkinson disease is a progressive neurodegenerative disorder affecting over 10 million individuals worldwide.¹ Second only to Alzheimer disease in prevalence, PD is the fastest-growing neurodegenerative disease, with rates of prevalence continuing to accelerate. ² In those aged 45 years and more, the overall prevalence of PD has been reported as 572 per 100,000 people in North America.³ Nearly 90,000 Americans are diagnosed with the condition each year, and some studies predict both prevalence and incidence will rise 30% by the year 2030.⁴ 

PD results from the loss and degeneration of dopaminergic neurons in the basal ganglia and an aggregation of Lewy bodies.⁵ While motor features remain the hallmark of establishing a diagnosis, gastrointestinal symptoms can precede them by several decades and have led to an increased interest in the potential role of the microbiome in PD pathogenesis.⁶ Novel strategies are needed to support clinical outcomes, as traditional approaches have thus far failed to encompass the entire spectrum of disease presentation. 

Background

While the pathological signatures of PD have been well-documented, its pathomechanisms remain somewhat elusive.⁷ A progressive loss of dopaminergic neurons in both the substantia nigra (a component of the basal ganglia) and the locus coeruleus lead to dopamine deficiency in striatum receptors, causing interrupted transmission to the thalamus and motor cortex. This has consequences for motor functioning and results in the motor disturbances seen in individuals affected by the disease.⁸

Lewy bodies composed of alpha-synuclein aggregates and other proteins are another neuropathological hallmark of PD.⁹ Alpha-synuclein proteins are abundant in dopamine-producing neuronal cells and are involved in the regulation of vesicular transport and neurotransmitter release; thus, they play an important role in the regulation of synaptic function.¹⁰ In PD, there is a mismatch between the production and degradation of alpha-synuclein proteins, and this appears to play a central role in disease pathogenesis.¹¹ Under physiological circumstances, alpha-synuclein is produced and degraded in a balanced manner, but in PD there appears to be both increased production of alpha-synuclein as well as decreased clearance rates, allowing for accumulation in the form of Lewy bodies.¹²

There are a few theories on why these processes may occur. A possible explanation includes disruptions to normal cellular mechanisms regulating alpha-synuclein turnover, including impaired lysosomal function, a process responsible for degrading and recycling cellular waste.¹² Genetic mutations are another potential mechanism in which several factors may increase the expression of alpha-synuclein or interfere with its degradation pathways.¹²

Additional external factors may also play a role in alpha-synuclein misfolding and the subsequent aggregation observed in PD. Oxidative stress, a process that occurs via an imbalance between the production of reactive oxygen species (ROS) and the host’s antioxidant defenses, has been shown to promote alpha-synuclein misfolding and aggregation.^13–15 Via similar mechanisms, chronic inflammation,¹⁶ environmental toxin exposure,^17,18 and traumatic brain injuries^19,20 are also thought to contribute to PD development due to associations between such factors and increased disease risk. Some evidence also suggests that certain microbial infections, which may promote inflammation and oxidative stress, contribute to Lewy-body formation as well and, thus, PD pathogenesis.²¹ 

Most alpha-synuclein aggregates are found in the brainstem, substantia nigra, and cortex. Interestingly, they have also been discovered in other areas, including the spinal cord, peripheral nervous system, cardiac plexus, and the enteric nervous system.²² These aggregates found outside of the central nervous system have been identified as a potential marker, or even a contributing factor, in developing PD pathophysiology. 

Both genetic and environmental factors are thought to play a role in PD pathogenesis. However, studies suggest that only 3% to 5% PD cases occur due to mutations in a single gene, while 16% to 36% of cases can be explained by influenced by variations in multiple genes.²³ Therefore, most PD cases remain idiopathic.²³ 

Editor's Note: To read the full Natural Medicine Journal peer-reviewed article, click here.

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