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De-mystifying the microbiome and MND

The microbiome has become an important topic of research for scientists because of its links to human health. Dr Derik Steyn, from the University of Queensland, explains what the study of the microbiome means for MND.

What is the microbiome and why is this relevant in MND?
You are home to trillions of micro-organisms, your ‘microbiota’; eukarya, bacteria and archaea – exceptionally small organisms that colonise all parts of your body including your gut and skin. Most of these micro-organisms live in harmony with you, with many performing critical tasks that are central to your everyday life. In exchange, your body provides shelter, nutrients, and all other essential elements that these micro-organisms need.

Recently, there has been a revolution in our understanding of the importance of microbiota. The micro-organisms help to maintain our overall health, and also play a role in our exposure and response to disease. The gut microbiota – or the microbiome of the digestive tract – has emerged as being able to play a role as a friend or foe.

And as our understanding grows of the role gut microbiota play in heath in general, so too will our knowledge of MND-gut microbiota links. Importantly, more studies on the role of the microbiome in the development and progression of MND are beginning to emerge, which are already generating valuable insights into what may help stop the disease.
  
Making sense of gut-microbiota
Your digestive system is home to up to 100 trillion microbes. Of these, approximately 95% are bacteria. The composition or diversity of these bacterial colonies varies considerably between people. It changes with age, diet, and your genetic makeup.

Your microbiome is a dynamic, evolving “organism” that is as unique to you as your fingerprints. The diversity and complexity of the gut microbiota can be explained, in part, through understanding its major function – these bacteria exist to help us digest and release nutrients from food.

The bacteria in our digestive tract also produce by-products or substances. These factors contribute to a range of processes in the body, and may also impact the function and health of the brain (via a system called the gut-brain axis).

Some of the earliest studies on the gut microbiota and the brain found that bacteria in the digestive system could contribute to the build-up of a specific protein (alpha-synuclein) in the specialised nervous system that is part of the gut. This protein is involved in the development of Parkinson's disease, and it is thought that this protein spreads from the gut to the brain.

Additionally, bacteria in the gut can modify a person’s immune system, and in particular, a person's inflammatory response to certain conditions. The inflammatory response, in turn, can impact the brain, possibly contributing to the development of Parkinson’s disease.

The evidence, however, is not conclusive. While studies provide strong evidence to suggest a link between the gut microbiota and diseases of the brain, there is a still a lot we don’t know. More intensive and focussed research is necessary before we can fully understand the role of the gut-microbiota, and how this information can be used to help people with Parkinson’s disease. The initial studies in Parkinson’s disease have been critical though as they have paved the way for studies into other brain diseases, including MND.
 
The gut-microbiota and MND
The earliest study on the gut microbiota and MND emerged in 2015. In the study, researchers reported that they found a difference in the composition of gut bacteria in the faecal matter of mice with MND when compared to mice that did not have MND.

It is important to note here that direct measurements of the microbiota of the stomach or the rest of the gut is difficult to obtain, and so many studies rely on data that is collected from samples that leave our bodies as we eliminate waste. While this is not a very glamorous job, it is convenient, and provides critical information.

The initial study was very small (very few animals were included), and although the data generated was interesting and showed differences, it was by no means conclusive.

A larger follow-up study in 2017 again found differences in the gut-microbiome between MND mice and mice without MND, and proposed that these differences could alter the progression of disease. Interestingly, targeted treatment to reverse these differences was found to alter the progression of disease in MND mice.

It was only this year that more compelling evidence was found for the role of the microbiome in the progression of disease in mouse models of MND. In this study, researchers found that different bacteria contributed differently to the progression of disease, and that by-products of gut-microbiota could advance or slow the progression of disease.

Similar findings were reported in another study involving a small cohort of patients with MND, however these results should be approached with caution due to the small study size. The researchers acknowledge that more evidence is needed. The call for more evidence is in part due to the fact that other existing studies on the gut-microbiota in patients with MND have not produced the same results across studies.

Generally, studies in patients are not well-controlled, and there is risk that selection and enrolment of patients with underlying conditions that directly impact the microbiome could mask actual results.

Studies where enrolment was carefully considered found no real evidence for a difference in the microbiome between people living with MND and those who don’t have MND. This is not entirely surprising though, as studies generally only include a small number of patients – this is a problem when looking for differences in the microbiome between individuals, especially when everyone has a unique “gut fingerprint”.

Compunding the problem of small patient numbers is the fact that MND is highly variable. The progression between patients is so unpredictable. Simply put, research has yet to overcome the challenge of studying a complex system within the context of a complex and variable disease – this is very important if we are to provide evidence for a role of the gut microbiota in the onset and progression of MND.
 
So, where to next and is the gut-microbiota relevant to those living with MND?
With each discovery, we have raised more questions, and there is currently no consensus on how the gut microbiota is involved in MND. However, because of the importance of the gut microbiota in human health, and given the increasing knowledge of its importance in other neurodegenerative diseases, we must continue to look for links.

One of the most promising outcomes has been the development of credible theories that link possible roles for the microbiome relative to factors that are known to impact the health of a person living with MND.

There is indirect evidence that the gut microbiota could impact mechanisms that are confirmed to impact quality of life and disease progression – this includes processes that underlie inflammation, metabolism and the production of by-products that could directly impact the brain.
 
In the absence of data, should we target the microbiome in MND?
Many “bacteriotherapies” have emerged. The use of post- pre-, and pro-biotics are now commonplace, and experimental therapies such as faecal transplant has become more popular.

With all of this activity, it is natural to wonder if some of these therapies might help those living with MND. More critically, we have to ask ourselves if it is safe.

Our gut microbiota is a fragile “organism” that adapts as we experience life. In the absence of strong data to suggest disruption of the gut microbiota in MND, there is a risk that attempts to modify its composition may indeed disrupt a system that is already well-balanced. The resulting “dysbiosis” could in fact be detrimental. Such a risk suggests the need for caution.

Much more credible advice is required. To help improve the evidence base, our research community must come together and conduct large well-controlled international studies. Moreover, clinical trials are needed to determine if there is a benefit of therapies targeting the gut microbiota.

With higher quality evidence, and a more sound understanding of the relationship between microbiota and MND, we may have another important option for determining what may help stop this dreadful disease.

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