Part 1: Unraveling the Connection
A progressive neurodegenerative disorder with devastating clinical symptoms, Parkinson’s disease (PD) afflicts an estimated 8.5 million people worldwide. Because age is a major risk factor, numbers are expected to soar as populations trend older.
Tremors, muscle rigidity, and slow movement are hallmark symptoms of PD. Notably, many patients also experience gastrointestinal symptoms particularly constipation, which can manifest years, or even decades, before the onset of motor symptoms. The intriguing correlation has prompted much research into the complex relationship between the gut microbiome and PD.
After an introduction to PD, this blog will delve into the research regarding gut microbial changes in PD and then explore the underlying mechanisms through which the gut microbiota may mediate PD.
Due to length considerations, a second blog will review the latest research on microbial therapies for PD.
Parkinson’s Disease, in brief
Parkinson’s disease is the second most common neurological disorder worldwide. While the exact cause remains largely unknown, the pathogenesis entails the degeneration of neurons in the basal ganglia which are located deep in the brain where they play a role in, among others, motor control, learning and habit formation. Their degeneration leads to reduced dopamine levels, disrupting their function and contributing to the characteristic movement problems in PD.
Besides motor dysfunction, patients often experience non-motor symptoms like cognitive or behavioral issues, anxiety, depression, sleep disturbances, a disordered sense of smell, and gastrointestinal problems.
Gastrointestinal dysfunction is one of the earliest non-motor symptoms, affecting up to 80% of PD patients. Extensive evidence has prompted the International Movement Disorders Society to recognize constipation as a clinical biomarker for PD in its diagnostic criteria for the prodromal phase (latent period of years or decades before classic motor symptoms appear). Early recognition of developing PD may allow early neuroprotective therapies.
Currently, PD is clinically diagnosed when disease progression is already advanced. Studies estimate a 40–60% loss of dopaminergic cells and a reduction of synaptic function by up to 80% before the appearance of motor symptoms.
While there is no cure, current treatments primarily focus on managing symptoms, though they tend to lose effectiveness over time. The most common treatment is levodopa, a drug that helps replenish dopamine levels in the brain. However, its effectiveness may diminish as the disease progresses, often leading to fluctuations in symptom control and the development of motor complications like dyskinesia (involuntary movements). This is because, over time, the brain’s ability to convert levodopa to dopamine becomes less efficient, and the underlying neurodegeneration continues.
Only 5–10% of PD cases are attributed to genetic factors. The most common form, sporadic PD, involves the buildup of misfolded α-synuclein proteins (Lewy bodies) in neurons of both the central and enteric nervous systems.
Notably, this accumulation happens not only in the basal ganglia but also in the gut. According to the groundbreaking Braak hypothesis, α-synuclein misfolding may start in the gut and spread in a “prion-like” manner through the vagus nerve to the lower brainstem, eventually reaching the midbrain. Dysbiosis may lead to α-synuclein misfolding and PD pathology.
Gut microbiota & Parkinson’s Disease
Researchers know that gut problems, including constipation, dysphagia, changes in gut microbiota, and leaky gut, may occur in some PD patients years before they are diagnosed. After a 2015 study kicked off the research into the relationship between gut dysbiosis and PD, dozens more have explored alterations related to PD.
Although there is no agreement on the ideal gut microbiome composition in healthy individuals, distinct changes are observed in the gut microbiota of PD patients.
For example, small intestinal bacterial overgrowth (SIBO) occurs at a significantly higher rate in PD patients than in healthy adults, with as many as 14% to 67% struggling with SIBO depending on the study.
Advances in genome sequencing have facilitated the identification of specific microbial shifts associated with PD. However, according to one review, several factors contribute to inconsistencies and variations in microbial profiles of PD patients, including disease stage, patient characteristics (ethnicity, age, diet), sampling methods, and medication usage, all of which complicate the identification of a consistent microbial signature and the development of microbiota-targeted therapies.
Nevertheless, gene-sequencing analysis of the microbiome revealed consistent patterns such as increased levels of genus Akkermansia and decreased abundances of genera Faecalibacterium and Roseburia in PD patients compared to healthy controls.
Akkermansia plays a vital role in maintaining intestinal barrier homeostasis; however, its overgrowth can erode the mucous barrier, leading to increased intestinal permeability and heightened exposure to oxidative stress or toxins. This may trigger α-synuclein aggregation, Lewy body formation, and neuroinflammation, potentially increasing the risk or progression of PD.
The decreased abundance of Faecalibacterium and Roseburia is troublesome because of their short-chain fatty acid (SCFA) production capabilities.
SCFAs play a crucial role in maintaining the integrity of the intestinal barrier and promoting gut homeostasis. Reduced levels of fecal SCFAs, particularly butyric acid, have been associated with the breakdown of intestinal tight junctions, leading to a leaky gut and increased intestinal inflammation. This disruption is believed to exacerbate the progression of PD. Recent studies have shown that the microbiota responsible for producing SCFAs are less abundant in individuals with more severe PD, correlating with faster deterioration of motor and cognitive functions. Additionally, lower fecal butyric acid levels have been specifically linked to cognitive decline in PD patients.
Thus, compositional shifts to dysbiosis may contribute to PD.
Mechanisms
A 2024 review concluded that gut microbial dysbiosis is linked to PD pathology through a multitude of possible mechanisms. Below are the key mechanisms the authors highlighted because “they can potentially be corrected by microbiome-targeting therapies.”
Many of these mechanisms involve disruptions in the gut-brain axis, a bidirectional communication system between the gut and brain regulated by the gut microbiome.
- Intestinal barrier damage: Gut dysbiosis weakens the intestinal barrier, leading to increased permeability, which allows harmful substances to enter the bloodstream and reach the brain, causing inflammation in both the gut and central nervous system (CNS).
- Inflammation: Changes in gut bacteria composition increase levels of pro-inflammatory substances, such as lipopolysaccharides (LPS), which trigger neuroinflammation, neuronal death, and alpha-synuclein release, contributing to PD progression.
- Oxidative stress: A reduction in beneficial gut microbes leads to oxidative stress in the gut, which spreads to the brain, causing protein misfolding, neuroinflammation, and damage to dopaminergic neurons.
- Pathogenic bacteria overgrowth: Overgrowth of harmful bacteria in the gut increases inflammation and neurotoxic effects, worsening motor symptoms and accelerating disease progression in PD patients.
- Small intestinal bacterial overgrowth (SIBO): Overcolonization of bacteria in the small intestine causes local inflammation and increased gut permeability, which can facilitate the movement of harmful substances and proteins into the brain, triggering neurodegeneration.
- Metabolome depletion: A reduction in beneficial microbial metabolites, such as SCFAs, leads to increased gut and brain inflammation, weakening the intestinal and blood-brain barriers, and increasing susceptibility to alpha-synuclein aggregation.
- Protein misfolding: Dysbiosis promotes the production of bacterial proteins that interact with human proteins, leading to misfolding of alpha-synuclein in the brain, which exacerbates neuroinflammation and motor symptoms.
- Changes in neurotransmitter signaling: Altered gut microbiota disrupts the production of key neurotransmitters, such as GABA and dopamine, which worsens gut-brain communication and contributes to motor symptoms in PD patients.
Takeaway
Parkinson’s disease (PD) is a progressive neurodegenerative disorder primarily known for its motor symptoms but often preceded by gastrointestinal issues like constipation, which may occur decades before diagnosis. Emerging research highlights the complex relationship between gut dysbiosis and PD, showing that alterations in the gut microbiome can contribute to PD progression through mechanisms such as increased intestinal permeability, neuroinflammation, oxidative stress, and neurotransmitter disruption.
Though inconsistencies remain in identifying a specific microbial signature, common patterns of dysbiosis, including reduced short-chain fatty acid-producing bacteria and increased pro-inflammatory microbes, suggest that gut health may play a crucial role in the development and progression of PD. Be sure to read the second part of this topic coming next month— Parkinson’s Disease and Gut Microbiota/ Part 2: Targeted Strategies—where IPA explores emerging approaches targeting the gut microbiome to address PD.
Image by Gerd Altmann from Pixabay
Key references
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Chandra, Rashmi et al. “α-Synuclein in gut endocrine cells and its implications for Parkinson’s disease.” JCI insight vol. 2,12 e92295. 15 Jun. 2017, doi:10.1172/jci.insight.92295
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