Does Parkinson's Disease start in the gut?

An insight into a rather uncanny connection between Parkinson's Disease and the gut

Theme: Health Issues and Disease

Zuairia Shahrin

DISCLAIMER: The following information provided by Under The Microscope is purely constituent of research findings. This article only aims to educate and inform readers about new research and is provided in good faith. However, this article does not imply the use of these findings in current healthcare faculties. Under The Microscope, therefore, does not take any responsibility concerning the accuracy, adequacy, validity, reliability or completeness of the research data. 

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A few months ago, I was writing a research paper. During one of my all-nighters, I came across this statement that left me spellbound and eager to find out more, “New research by Aarhus University states that Parkinson’s Disease (PD) may begin in the gastrointestinal tract and spread through the vagus nerve to the brain.”[1] The vagus nerve is a nerve made up of parasympathetic fibres, that emerges directly from the brain, going through the face and thorax to reach our abdomens. Isn’t that amazing? If that is true, my friends, Medicine may be a step closer to finding a cure for PD. 

Before we even get on to understanding its origins, we must first understand the disease itself. Named after an English surgeon called James Parkinson, PD is a long-term neurodegenerative disease that predominantly affects our motor system.[2] PD occurs when neurons in the deepest brain chambers (basal ganglia and substantia nigra) that are responsible for the production of dopamine, die. Dopamine is a crucial chemical that drives bodily movements and emotional response. Without the right balance of dopamine, our physical and mental health can be inordinately impacted. PD patients experience shaking, rigidity in muscles and difficulty in movement because of dopamine deficiency. As you can probably tell, it is an immobilizing condition that does not have a cure yet. However, scientists are now becoming very sceptical about the origins of PD.[5] Because it is a degenerative disorder, it would lead us to believe that PD stems from the brain. But, the latest research propounds otherwise. Danish postdoctoral clinician Elisabeth Svensson stated, “Patients with PD are often constipated many years before they receive the diagnosis, which may be an early marker of the link between neurologic and gastroenterologic pathology related to the vagus nerve.”[7]

Often, those who have peptic ulcers encounter a surgical procedure called “vagotomy,” that eases the soreness. This surgical operation removes either all of the vagus nerve or parts of it. It can be done in two ways: one way is called “truncal,” which removes the main and central trunk of the vagus nerve. Another way is called “selective,” which removes specific gastric nerves that are on the front side and the backside of the stomach. The proposed hypothesis is that pathogens (different to gut bacteria) accountable for PD to worsen travel upwards towards the brain via the vagus nerve. Hence, if this nerve did not exist at all, it would not leave any route behind that pathogens can use as a means of moving upwards. Quite instinctually, it was discovered that patients who had dissevered vagus nerves had a 40% lower chance of developing PD compared to those who had this nerve intact in their bodies.[7] But does that mean we should remove our vagus nerves? No. Vagotomy was conducted in the first place to protect patients from peptic ulcers, given that the stomach begins to produce dangerous levels of acid. In reality, the vagus nerve is merely a passage; only a road that takes pathogens from one place to the other in the body. The game-changing element, that causes PD to start is a protein identified as “ɑ-synuclein, which controls the flexibility of dopamine overflow in presynaptic terminals.[3][6]

Researchers have noticed that PD patients frequently report gastroenteric problems 10 years before observing tremors. The Californian Institute of Technology conducted research that examined the spread of ɑ-synuclein fibres. The ɑ-synuclein fibre is small and soluble in healthy neurons, but for PD patients, these molecules misfold, forming clusters that detriment the brain’s neurons. The formation of these clusters happens because of the presence of pathogens. These same pathogens act as a trigger to misfold the protein, leaving large envelopes of dead brain matter, known as Lewy bodies.[3] As a result of the misfolding of this protein, dopamine production is reduced. This causes brain cells to die, taking away a person's ability to move, think or modulate emotions. Interestingly, researchers noticed that PD patients who had the ɑ-synuclein fibre in their brains also had it in their guts. We may wonder, if these molecules are in different locations within the body, are both lots of the ɑ-synuclein fibres the same? Maybe, there is a possibility that the molecules found in the gut are slightly different from those in the brain. Well, the appearance of the ɑ-synuclein molecules in the gut is consistent with some of the early symptoms of PD. Hanseok Ko, PhD associate professor of neurology at the John Hopkins School of Medicine, suspected that the ɑ-synuclein fibres might be using the vagus nerve as a “ladder” to reach the brain.[3][6]

To test this theory, the researchers injected a sample of this very same protein into the guts of dozens of healthy mice. Over 10 months, the researchers noted that the ɑ-synuclein protein began building exactly where the vagus nerve connected to the gut and continued to spread to the brain.[6] They then ran a similar study, but this time included a group of mice with dissevered vagus nerves. Upon injecting this group of mice with the misfolded ɑ-synuclein protein, they observed that the mice showed no signs of cell death, whereas the group with intact vagus nerves had neuronal damages. Ted Dawson, Director of the John Hopkins Institute for Cell Engineering and Professor of Neurology at the John Hopkins School of Medicine, evaluated that the removal of the vagus nerve halted the ɑ-synuclein protein’s advances towards the brain.[3]

Further supporting the same theory was Elisabeth Svensson’s clinical study. Her team organized research on 15,000 vagotomy patients, who had faced either truncal or selective vagotomy in the past. Patients who had experienced truncal vagotomy were more protected against PD, with their risk of developing PD halving.[4][7] However, patients who had encountered selective vagotomy were not protected at all.[1][7] This also fits Dawson’s judgement that the advancement of this disease is reliant on the condition of the vagus nerve (whether it is fully or partially intact) and if it holds the potential to reach the brain. If it does (which is quite possible if selective vagotomy is done), pathogens can use the vagus nerve as a pathway to proceed towards the brain.[3]

Many studies have begun to examine the origins of PD. Quite a few experiments proclaim that PD may have started in the gut, and spread through the vagus nerve to the brain. You might assume that if gastrointestinal problems are treated on time, PD might not emerge at all. Although the data gives us a fundamental link that may indicate possible prevention of PD, we cannot apply this knowledge in real-life healthcare because there is no evidence that PD starts in the gut for all patients. All of us have different bodies with varying chemical reactions inside them; what works for some patients might not work for all. Besides, scientists are yet to find out answers to lots of questions, like - What are the factors that trigger neurodegeneration? Which parts of the brain allow the misfolded ɑ-synuclein to reach the brain, and does a stopping mechanism exist? Nonetheless, scientists speak with certainty that many of our questions will be answered in due course as medical research progresses. Until then, we can take safety measures by consulting with a doctor regularly to identify any health problems in their earliest stages, buying us enough time to combat the disease and arise as healthier and stronger people. 

For more details about how the brain is related to the gut, feel free to read my literature review below:

https://docs.google.com/document/d/13v3VxWjz7gNXON-LYXizqLoLsDgHZWcVfrr5pppssGc/edit?usp=sharing

GLOSSARY:

1. Parkinson’s Disease (PD): A progressive nervous system disorder that affects our movement. This is caused by the death of dopamine-producing neurons, which cannot be replenished. 

2. Neurodegenerative Disease: A term that collectively summarises many diseases and conditions that are caused by the death of neurons. 

3. Motor System: The group of structures found in our central and peripheral nervous systems that aid bodily movement, coordination and balance. 

4. Basal ganglia: A structure at the base of our brains that contributes to coordination in movement.

5. Substantia nigra: A layer of the midbrain that is rich in dopamine-producing neurons, contributing to movement.

6. Dopamine: An organic chemical that is released by neurons that sends signals to other nerve cells. This chemical provides a person with feelings of pleasure and reward. 

7. Degenerative Disorder: A disorder in which the structure or function of the affected tissues only worsens over time rather than improving.

8. Vagus Nerve: A bundle of parasympathetic fibres that runs from the brain to the abdomen. It is the longest and one of the most complex cranial nerves of the body. 

9. Peptic ulcer: Painful sores in the lining of the stomach, small intestine or esophagus. 

10. Vagotomy: A surgical operation where one or more branches of the vagus nerve are cut to minimise the effect of excessive acid production in the body. 

11. Truncal Vagotomy: Severing the main trunk of the vagus nerve that enters the abdomen. This is more commonly done.

12. Selective Vagotomy: Severing only the branches that reach the lower esophagus and stomach. This is rarely done. 

13. Dissevered: To separate or remove 

14. Alpha-synuclein / ɑ-synuclein: A protein of unknown function that is found in the tip of the neurons in presynaptic terminals. 

15. Lewy Bodies: Abnormal aggregations of proteins that develop inside neurons, hence contributing to Parkinson’s Disease. 

REFERENCES:

1. Aarhus University. (23 June 2015). Parkinson’s disease may begin in the gut. Retrieved 12 April 2020. [Online] Available from: <https://medicalxpress.com/news/2015-06-parkinson-disease-gut.html>

2. Kwon, D. (8 May 2018). Does Parkinson’s Begin In The Gut? Scientific American. Retrieved 12 April 2020. [Online] Available from: <https://www.scientificamerican.com/article/does-parkinsons-begin-in-the-gut/>

3. Anonymous. (26 June 2019). New Research Shows Parkinson’s Disease Origins In The Gut. John Hopkins School of Medicine. Retrieved 12 April 2020. [Online] Available from: <https://medicalxpress.com/news/2019-06-parkinson-disease-gut.html>

4. Borghammer, P. (23 September 2019). Does Parkinson's Disease Start In The Gut Or In The Brain? Working Parkinson’s Connections. Retrieved 12 April 2020. [Online] Available from: <https://www.worldpdcongress.org/home/2019/9/10/does-parkinsons-disease-start-in-the-gut-or-in-the-brain>

5. Anonymous. (5 December 2016). New Evidence Suggests Parkinson’s Might Not Start In The Brain. The Cure Parkinson’s Trust. Retrieved 12 April 2020. [Online] Available from: <https://www.cureparkinsons.org.uk/news/parkinsons-starts-in-gut>

6. Sandoiu, A. (11 February 2019). What Role Does The Gut Play In Parkinson’s Disease? Medical News Today. Retrieved 12 April 2020. [Online] Available from: <https://www.medicalnewstoday.com/articles/324402>

7. Nield, D. (17 March 2019). There’s Mounting Evidence That Parkinson’s Starts In The Gut - Not The Brain. Science Alert. Retrieved 12 April 2020. [Online] Available from: <https://www.sciencealert.com/there-s-mounting-evidence-that-parkinson-s-starts-in-the-gut-not-the-brain>