What’s the gut got to do with Parkinson’s?

Quick summary if you’re in a hurry:

• A toxic protein that contributes to the loss of brain cells in Parkinson’s might originate in the gut and travel to the brain.
• Gut bacteria differs in people with and without Parkinson’s. Bacteria in the gut may play a role in the development and progression of Parkinson’s.
• Researchers are looking to identify which bacteria are involved in contributing to Parkinson’s. This will help accelerate the search for better treatments, and a cure for Parkinson’s.
• The latest results from Dr Maria Doitsidou’s team suggest a protective role for a type of bacteria found in probiotics.

Researchers are not exactly sure what causes Parkinson’s and why dopamine-producing brain cells are lost over time. Evidence suggests that Parkinson’s tends to develop gradually and changes in the body may occur years before someone receives a diagnosis. One part of the body where these changes might be occurring is in the gut.

There are a few clues as to what might be causing the death of these vital brain cells. One clue is that toxic proteins are clogging up brain cells, causing problems in Parkinson’s. This toxic protein has also been shown to be present in the gut, leading to the theory that Parkinson’s may originate there.

What do we mean by 'toxic proteins'?

Proteins carry out most of the jobs that happen inside our cells. There are lots of different types of proteins, with many different roles. To function properly, proteins have to be the correct shape and this depends on them folding properly. You could think of this like a paper aeroplane. When the paper is folded in a specific way it forms the correct shape needed to fly.

Misfolded proteins can clog up cells, stopping them from working. In conditions like Alzheimer’s and Parkinson’s, we know that misfolded proteins become a big problem for brain cells.

In Parkinson’s, the main protein that misfolds is alpha-synuclein. And researchers believe that this protein might be responsible for the spread of the condition.

No one is quite sure what causes alpha-synuclein to start clumping in brain cells in Parkinson’s. The trouble starts when alpha-synuclein loses its usual tightly wound shape and becomes more 'sticky' and more likely to clump.

Does Parkinson’s start in the gut?

The brain isn’t the only place where the spread of toxic alpha-synuclein may be happening. Recent research has also found misfolded alpha-synuclein in the gut of those in the early stages of the condition. This finding has led some researchers to believe that Parkinson’s may, for some, start in the gut and travel to the brain.

There is evidence that alpha-synuclein might be travelling via the vagus nerve, which connects the gut to the brain.

The vagus nerve connects our brain via the brain stem to all of our organs, including the gut. It allows the body to monitor and receive information from our organs to allow our body to function.

One theory is that toxic alpha-synuclein may move from the gut, up the vagus nerve, to the brain. Studies have found clumps of alpha-synuclein in the vagus nerve, further supporting the idea that the clumps may not originate in the brain.

Additional evidence of the involvement of the gut in Parkinson’s comes from a procedure for treating ulcers. This procedure was common in the 1970s and 80s, and involved cutting the information flow between the gut and the brain by severing the vagus nerve. Research has since shown this procedure has been linked to a reduced risk of Parkinson’s, suggesting it may have inadvertently stopped alpha-synuclein clumps making the journey from the gut to the brain, and ultimately causing the loss of brain cells. Read more about gut research and Parkinson's on The Science of Parkinson's website.

These findings have caused researchers to rethink where Parkinson’s actually starts. It could mean, for some, the condition may start in the gut or elsewhere in the body, and travel up the vagus nerve towards areas of the brain affected in Parkinson’s.

Researchers don’t fully understand how alpha-synuclein spreads, or what causes these toxic clumps of protein to form in the first place. Understanding this may help shine a light on how we could stop the spread of the condition, or if it does start in the gut, how we could stop it from reaching the brain at all.

Gut bacteria and Parkinson’s

As well as the evidence for the role of alpha-synuclein in the origins and progression of Parkinson’s, there is evidence that gut bacteria also play a role.

Up to a trillion microbes live in our gut, where many are beneficial 'good bacteria'. They help us digest food, make vitamins and fight bad bacteria and infection. Our gut bacteria interact with the rest of the body by releasing chemicals. The vagus nerve is able to send information from the gut to our brain where it influences our unconscious or otherwise involuntary behaviours.

The makeup of gut bacteria will vary from person to person and can change over time. As well as these individual differences, there is evidence that gut bacteria may change in different health conditions and this may be the case in Parkinson’s. Recent research has shown that gut bacteria in individuals with Parkinson’s differs from that of people without Parkinson’s. Scientists now believe that harmful gut bacteria may produce chemicals that are important in the development of the condition.

Further to this, research has shown that keeping mice in a germ-free environment, therefore reducing bacteria in the gut, protected these mice from developing Parkinson’s. Researchers also took bacteria from people with Parkinson’s, which resulted in making movement symptoms worse in the mice. This suggests there are changes occurring in the gut that may affect the progression of the condition.

Read more about Professor Spillantini's research on whether Parkinson's starts in the gut.

Improving gut health

Overall we don’t understand which bacteria are linked to Parkinson’s. But if we did, perhaps we could pinpoint those that are harmful and develop a treatment that could target the damaging bacteria while leaving the beneficial ones unharmed, or develop treatments that help the best bacteria flourish.

It sounds simple, and understanding the effects of different bacteria could form the basis of new treatments. But when you consider there are hundreds of different species in the gut, it becomes a little harder to figure out which bacteria are good, bad or somewhere in the middle.

There are ongoing clinical trials looking at whether a probiotic, aiming to boost 'good' bacteria in the gut of people with Parkinson’s, can help people manage their symptoms. We’ll keep an eye on the progress of this research.

But what about research that’s helping unpick the role of specific gut bacteria in the progression of Parkinson’s?

Researchers like Dr Doitsidou and her team, funded by Parkinson’s UK, are systematically studying the various types of bacteria to identify those that play an important role in Parkinson’s.

The team are using a microscopic and transparent type of C. elegans worm to study the effects of individual types of bacteria on the clumping of a toxic protein involved in Parkinson’s. These worms happily eat bacteria, so the researchers simply feed a different type of bacteria to each group of worms. The worms have been engineered so that the alpha-synuclein protein glows green under the microscope.

From the hundreds of bacteria that may play a role, the team hopes to identify the key ones to look at in more detail. They will then try to discover the mechanisms by which these bacteria have either protective or damaging properties, knowledge which could pave the way for new treatments.

Let’s hear from Dr Maria Doitsidou, from the University of Edinburgh, to tell us more about her research and share an exciting update.

Do you think that specific bacteria are impacting the build up of toxic alpha-synuclein in the gut?

"The evidence so far points in that direction. A previous study compared mice with and without gut bacteria and found that the presence of bacteria in the gut impacts the build-up of alpha-synuclein.

"However, the gut bacteria (microbiome) of humans and mice is very complex, therefore it is very difficult to tease apart harmful from beneficial bacteria. Simpler animals like the worm can be very useful in helping to understand which bacteria may be having an impact."

Why is a treatment that targets the gut instead of the brain attractive?

"First, because the gut may be the origin of the problem. Thus, finding ways to stop alpha-synuclein buildup in the gastrointestinal tract may be an important approach for targeting the root cause of the problem.

"Second, the brain and the gut are much more closely linked than one might think. The bacteria that live in the gastrointestinal tract have multiple ways to communicate with the brain and affect its function. This makes our gut microbiome a very attractive target.

"Another advantage is that targeting the gut is much easier. It is very difficult to deliver drugs to the brain at effective doses. But it is very easy to deliver live bacteria to the intestine."

What are the aims of your research?

"Our research focuses on the bacteria that live in our gut (the gut microbiome) and their effects in Parkinson’s.

"We are looking to identify specific types of bacteria that play a role, positive or negative, in the development of Parkinson’s symptoms. We do this using the microscopic and transparent nematode worm, C. elegans.

"We are looking into probiotic bacteria that are available commercially, as well as bacteria that are either more or less common in the gut of people with Parkinson’s compared to healthy controls. In the case of probiotics, we test bacteria that we find in marketed yoghurts, kefir and probiotic supplements in our worm model for their effect on alpha-synuclein aggregation."

What has your research found so far?

"Our most exciting finding is the discovery that the probiotic bacterium Bacillus subtilis protects against aggregation of alpha-synuclein in our worm model of Parkinson’s. We found that when we feed these probiotic bacteria to the worms, they not only slow the accumulation of alpha-synuclein but also help to clear some of the already formed protein clumps."

Read the full research paper on the Cell Reports website.

What are the next steps?

"Our next steps are to progress to studies with mouse models of Parkinson’s and fast-track human clinical trials to confirm the ability of Bacillus subtilis to inhibit the formation of alpha-synuclein aggregates. Another good thing regarding this bacterium is that it is already commercially available for human use.

"We are now systematically studying the link between the different types of bacteria in the human gut and Parkinson’s. We are specifically focusing on types of bacteria that are over- or underrepresented in the gut of people who live with Parkinson’s. Our investigations are still ongoing, but we already have some indications that certain types of gut bacteria may have positive effects whereas others act negatively on alpha-synuclein accumulation.

"Understanding which bacteria in the human gut microbiome may improve or worsen aspects of Parkinson’s means that we can try and boost certain 'good' bacteria to fight Parkinson’s progression, perhaps using probiotic supplements. Conversely, we could try to eliminate the 'bad' bacteria in a targeted way, to slow the condition."

It’s early days as scientists are only just starting to learn about how the gut may be linked to conditions like Parkinson’s, but this project will give us invaluable insight and potentially lead to new treatments. And while there will still be many questions to answer, the hope is that research projects like this, which aim to better understand the gut, will be key to treating many health conditions.

This blog is not meant as health advice. You should always consult a qualified health professional or specialist before making any changes to treatments or lifestyle.