Balancing gut bacteria in Motor Neurone Disease

We are all home to trillions of micro-organisms including eukarya, bacteria and archaea, which are exceptionally small organisms that colonise our bodies. Most of these micro-organisms live in harmony with us and perform critical tasks central to our everyday life. In exchange, we provide them with shelter, nutrients and elements needed for their survival.

In recent years, our understanding of the importance of micro-organisms in maintaining good health, and our exposure and response to disease, has been revolutionised. The gut microbiota – or the microbiome of the digestive tract – has emerged as a particularly valuable friend and, sometimes, foe.

Early microbiome and brain studies have found that bacteria in the digestive system may contribute to the build-up of a specific protein (alpha-synuclein) in the gut’s specialised nervous system. This protein has been associated with the development of Parkinson’s disease, and is thought to spread from the gut to the brain. Researchers also found gut bacteria may modify a person’s immune system, especially their inflammatory response to specific conditions. These studies are compelling, but they are not conclusive, and more research is needed to fully understand the role of gut-microbiota and how it can be targeted as treatments for diseases such as Parkinson’s disease.

These studies have also paved the way for more research into other brain diseases, including motor neurone disease (MND). MND is a disease of the neurons that control our muscles. In MND, these neurons progressively die, resulting in the loss of function of our voluntary muscles (the muscles that we can control). As patients lose control of these muscles they become paralysed. Eventually, MND affects the muscles of breathing, and most patients die within 3 to 5 years after first noticing symptoms.

In 2015 it was first suggested that the composition of gut bacteria in the faecal matter of mice with MND was different to mice without MND. In 2019, researchers found different bacteria contributed differently to the progression of MND in mouse models, and suggested that by-products of gut-microbiota could advance or slow disease progression. While these studies have offered insights into MND progression, none have compared the microbiome of patients relative to their course of disease.

Studies that have considered the gut microbiome of people with MND haven’t all been well controlled, and some have risked enrolling participants with underlying conditions that potentially impacted the microbiome and results. None of them have found overwhelming evidence of microbiome differences between MND patients and those without the disease. This is no surprise when studies have been based on small participant numbers, and every individual has a unique ‘gut fingerprint’. Also, MND is highly variable, and progression between patients is quite different, and nearly impossible to predict. Simply put, research has yet to overcome the challenge of studying a complex system within a variable disease context. This is critical if we are to provide evidence of the gut microbiota’s role in the progression of MND.

University of Queensland researchers have since conducted the first global study that compared the microbiota of MND patients, relative to the progression of their disease.

Commencing in 2016, we enrolled 64 patients with MND and 74 participants without, and compared their microbiome. Of these participants, 100 provided good quality samples, enabling us to conduct a more comprehensive study on the microbiome and MND to date. Our study, the first of its kind, compared the microbiome composition of MND patients, the clinical characteristic of their disease, and disease progression.

We found general microbiome composition didn’t differ between MND patients and those without MND. We also found no considerable microbiome variance between patients at different stages of disease, and different types of disease – for example, there was no difference in the microbiome between patients with a disease type that started in the spinal cord and a disease that started in their bulbar region. Simply put, our results show that the gut microbiome of people with MND was not remarkably different when compared to the very variable microbiome normally found across a range of people that don’t have MND.

However, there was one surprise finding in the research; patients with a microbiome normally considered ‘bad’ -   i.e. low in richness and diversity - lived longer after MND diagnosis. The same survival outcome was observed when Firmicutes and Bacteroidetes bacteria were compared. Patients with a higher proportion of Firmicutes were found to do better than those with a greater proportion of Bacteroidetes. In both examples, this ‘favourable’ microbiome signature was observed in people with diets normally considered bad, and increased the risk of obesity.

On the surface, these findings appear paradoxical and raise the question – why would a microbiome considered “poor” correspond with a favourable outcome? While there was no conclusive answer to the question, we did establish a theory. Unlike other diseases, MND patients are normally encouraged to gain weight. It’s possible, longer survival by patients with an ‘unhealthy’ gut microbiome is secondary to the fact that they ate foods high in fat, making them more likely to maintain their weight or gain weight. We found high fat and high calorie diets were able to slow down MND progression in patients with rapid progressing disease. This enabled these patients to retain weight, which is thought to help slow down disease progression. We still need to be careful in treating MND patients, as this approach may not work for all MND patients, especially those with slower progressing disease.  

Our study suggested behaviours that may help some MND patients, could be bad for diversity and richness of their gut bacteria. While this may be frowned upon in circumstances where poor diversity and imbalanced gut bacteria are considered a bad sign, for people living with MND it could be a good thing.

This paper was published in the journal Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, DOI: 10.1080/21678421.2020.1772825.

Dr Frederik Steyn started his career as a Biomedical Researcher in the School of Biomedical Sciences. He currently oversees a pre-clinical and clinical research program aimed at increasing understanding of the physiological response to disease, specifically Motor Neurone disease, a devastating disease of the upper and lower motor neurones.