Highlights from the World Parkinson Congress: the gut and Parkinson’s
The World Parkinson Congress takes place every 3 years in a different place around the world, and provides an opportunity for the whole Parkinson’s community to get together. In 2023, the congress was held in Barcelona between 4 and 7 July. This blog is part of a series that brings you some of the research highlights from the congress.
Parkinson’s is primarily thought of as a condition that’s to do with the brain. It is often diagnosed after symptoms have developed due to a reduction in a vital brain chemical called dopamine, made by brain cells to control things such as movement. However, it is becoming increasingly apparent that, for some, there are early signs of Parkinson’s that predate movement symptoms, such as digestive problems.
This has led to researchers investigating the links between the gut and the brain in Parkinson’s. This blog summarises some of the research to date and touches on new evidence shared at the World Parkinson Congress 2023.
What is the gut-brain axis?
The gut-brain axis is a 2-way communication system where our gut (stomach and intestines) and our brain can send messages to each other. The nervous system is not just made up of cells in the brain but an intricate network that spans the whole body to control the flow of information and actions. It is the vagus nerve that connects the brain to all of our organs, including the gut.
Why are researchers interested in the gut-brain axis in Parkinson’s?
A protein called alpha-synuclein, which is known to stick together and form troublesome clumps in brain cells of people with Parkinson’s, might actually originate in the gut. The vagus nerve is thought to offer the route for alpha-synuclein to travel around the body and ultimately cause problems in the brain. In this case, researchers would call this body-first Parkinson’s.
There are a few key pieces of evidence to support the spread of alpha-synuclein from the gut to the brain:
- Toxic clumps of alpha-synuclein have been observed in the gut of some people up to 20 years before a Parkinson’s diagnosis.
- Alpha-synuclein has been found in the vagus nerve that links the gut and the brain.
- A procedure from the 1970s and 80s to treat ulcers, where they cut the vagus nerve, was linked to a reduced risk of Parkinson’s.
Researchers believe not everyone’s Parkinson’s will have started in the gut. And this explains why you may have seen reference to the idea of body-first or brain-first Parkinson’s.
Brain-first Parkinson’s theory
- Troublesome alpha-synuclein clumps start to form in the brain.
- This can result in someone experiencing motor symptoms.
- Alpha-synuclein spreads within and outside of the brain and causes more widespread symptoms.
Body-first Parkinson’s theory
- Troublesome alpha-synuclein clumps start outside of the brain, specifically the gut.
- Early symptoms might be related to the digestive system or the control of things like blood pressure.
- Alpha-synuclein clumps spread to the brain. This can result in someone experiencing motor symptoms.
New research presented at the World Parkinson's Congress
More insights into body-first and brain-first Parkinson’s
At the World Parkinson Congress (WPC), Dr Nathalie Van Den Berge from Aarhus University in Denmark presented evidence to build on the understanding of how alpha-synuclein might spread in body-first and brain-first rat models of Parkinson’s.
Nathalie and her team used rats that had been modified to mimic symptoms of Parkinson’s. The researchers injected some of the rats with alpha-synuclein in the duodenum, a part of the small intestine, and some of the rats with alpha-synuclein in the brain. After 4 months, the researchers studied the rats to see how the alpha-synuclein had spread.
The body-first Parkinson’s rats, that had the alpha-synuclein injected into their guts, experienced the death of dopamine-producing neurons on both sides of the brain. This suggests that the alpha-synuclein travelled from the gut to both sides of the brain. These rats also showed a loss of nerve cells in the heart and the gut. This could offer a reason why some people experience problems with controlling blood pressure and digestion ahead of experiencing motor symptoms.
After 4 months, the brain-first Parkinson’s rats, which had the alpha-synuclein injected into their brains, still only had alpha-synuclein on the same side of the brain, which is where the nerve cells died. This might explain why some people experience motor symptoms on just one side of the body. These rats did not experience a loss of nerves elsewhere.
They also found that depending on where the alpha-synuclein was injected, it affected the structure of the alpha-synuclein clumps that formed. These structures could potentially be used to predict how severe the symptoms might be.
What makes the spread of alpha-synuclein clumps worse?
Dr Ulusoy from the German Center for Neurodegenerative Diseases in Germany presented research results to show that the travel of alpha-synuclein between the gut and the brain and vice versa is different to the travel of other proteins. So how does alpha-synuclein spread from one neuron to another when other proteins can’t do this?
The researchers showed that the spread of alpha-synuclein increased when a process called oxidative stress was increased. This is when harmful products build up within cells impacting their function and can ultimately lead to cell death.
Oxidative stress can be caused by environmental toxins but also through the energy production in cells not working as it should. This has a role to play in the development of neurodegenerative conditions such as Parkinson’s. These results suggest it also increases the accumulation of alpha-synuclein and its spread, creating a harmful loop.
The role of gut microbes in clumping of alpha-synuclein
The gut microbiome, also known as the microbiota, is all of the microorganisms present in the gut. Each person’s gut microbiome is slightly different and plays an important role in general health.
Several neurological conditions, including Parkinson’s, have been linked to certain changes in the gut microbiome. Changes and imbalances in the gut microbiome is called dysbiosis. Research has shown that imbalances in certain gut bacteria are evident in people with Parkinson’s compared to people without the condition. There’s ongoing work to pinpoint exactly what bacteria might be helpful or harmful in Parkinson’s.
A specific type of cell in the gastrointestinal tract called enteroendocrine cells are thought to be the only cells in the intestinal epithelium that make alpha-synuclein. These cells are in contact with gut microbes, form connections with the vagus nerve and are important for gut health. This means that these cells can detect imbalances in the gut microbiome which might contribute to the accumulation and spread of alpha-synuclein.
Dr Samspon from Emory University School of Medicine, Atlanta, USA shared their latest research results on this topic.
Dr Sampson’s team ran an analysis of the microbiomes of many people with Parkinson’s and identified individual microorganisms that appeared to be imbalanced. His team took each of these one by one, and studied the impact of each of the individual microorganisms on the nervous systems in mice.
Some of the microorganisms associated with Parkinson’s caused these mice to become more constipated, an early symptom of Parkinson’s that people can experience. He also saw that some of the microorganisms were capable of increasing the clumping of alpha-synuclein.
Carroll Siu, who has Parkinson’s and works alongside researchers to help shape their studies, shared her thoughts on the sessions:
"I was attracted to this session on the gut-brain axis and its role in the spread of alpha-synuclein because of my work with the Michael J. Fox Foundation (MJFF) last year, investigating new ideas of staging Parkinson’s. The new method of staging is based on the identification of aggregated alpha-synuclein threads.
"In this presentation, there were 3 international speakers, all of whom are specialists in the field of cell biology related to neurodegenerative conditions. The key takeaway messages that were significant for me were that the spread of the alpha-synuclein aggregates can be in both directions (gut to brain and vice versa) where the vagus nerve offers a route for the spread of these aggregates that can be the main contributor to non-motor symptoms in Parkinson’s, long before motor symptoms appear. This was, in my case, the loss of smell, which occurred 10 to 15 years before my tremors.
"One speaker highlighted some of the causative factors of the spread of alpha-synuclein. She mentioned environmental and metabolic triggering factors, which give rise to oxidative stress and inflammatory processes within the neurons (particularly the mitochondria, sometimes described as cell batteries). Again, this resonated with me, as in my nursing career, I dealt with phenolic agents and I frequently inhaled the airborne fumes. So, I would guess that the entry into my body was via the olfactory bulb (brain to gut route). One speaker pointed to the fact that 'brain-first' formation of alpha-synuclein is more likely to trigger effects on one side of the brain, whereas 'gut-first' formation of alpha-synuclein causes neurodegeneration on both sides. Interestingly, my tremors have been on one side for all these years since my diagnosis.
"The last speaker focused on the changes in the balance of gut microbiome (called dysbiosis), which has been proven to be evident in people with Parkinson’s. He explained that there are entero-endocrine cells in the intestinal wall that interact with the vagus nerve. Dysbiosis of the gut microbiome triggers the spread of alpha-synuclein. Therefore, people with Parkinson’s who experience spread of the alpha-synuclein threads from the gut to the brain, are more likely to suffer from constipation."
What does this mean for people with Parkinson’s?
The more we understand how the brain and the gut are linked, the more likely we are to find ways to intervene and slow the progression of the condition, or maybe even stop it in the first place. The fastest impact perhaps will come from pinpointing the specific microbes that are imbalanced in the condition. This could lead to recommendations for existing diets and supplements to redress the balance and help people live well with Parkinson’s.
Carroll shares what it means to her:
"Understanding these biological changes and causal factors has enabled me to appreciate that lifestyle changes, such as good gut health and avoidance of harmful agents (either inhaled or ingested), could play a role in the progression of my Parkinson’s."
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