Changes in gut bacteria could signal the onset of a rare genetic disease

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Graphic abstract. Credit: Neurobiology of disease (2023). DOI: 10.1016/j.nbd.2023.106051

New research may have uncovered a relationship between changes in gut bacteria and a rare neurodegenerative disease that primarily affects people in a remote indigenous community in the Northern Territory.

Researchers at Macquarie University have discovered a possible link between Machado-Joseph disease (MJD) and changes in the bacteria and other microorganisms that inhabit the gut.

Similar to Huntington’s disease and motor neuron disease (MND), MJD is a debilitating neurodegenerative condition that causes progressive loss of neurons in parts of the brain and spinal cord.

Neurons are the body’s messenger cells, carrying information to and from the central nervous system, and their loss results in loss of coordination, balance, and motor skills, muscle atrophy, and impaired vision, speech, and swallowing. It is incurable and ultimately fatal.

Patients begin to feel muscle weakness, then begin to stagger when walking but as the disease progresses they end up dependent on a wheelchair and require high levels of assistance.

This puts a strain on their families and communities, especially in remote locations where MJD is most concentrated. It affects people in a number of isolated communities.

Groote Eylandt, 50km off the Northern Territory mainland in the Gulf of Carpentaria, has the highest prevalence of MJD in the world. The tiny island has a population of just 3,000, many of whom are Aboriginal and Torres Strait Islander.

More than 100 people in the community have MJD and many hundreds more have the gene that causes it.

In some families, three generations are battling the disease simultaneously.

The role of intestinal bacteria

The intestinal tracts of humans and other mammals are naturally home to thousands of species of microbes, including bacteria, fungi, archaea and viruses.

These microscopic organisms make up the gut microbiota and, when in balance, work with our bodies to help maintain metabolic, immune and brain health.

Growing evidence shows a relationship between imbalances in the microbiota and metabolic and immune conditions including inflammatory bowel disease, diabetes and obesity.

Such imbalances have also been found in people with depression, autism spectrum disorder, and neurodegenerative diseases such as Parkinson’s, Alzheimer’s, Huntington’s, and MND.

Now, for the first time, Associate Professor Angela Laird and her research team have discovered that mice with MJD also have microbiota imbalances and have published their findings in an article in the journal Neurobiology of disease.

Researchers Dr Hasinika Hewawasam Gamage, pictured left, Associate Professor Angela Laird, pictured centre, and PhD student Katherine Robinson, pictured right, have discovered a possible link between Machado-Joseph disease and changes in bacteria and in other microorganisms that inhabit the intestine. Credit: Jesse Taylor

“The gut and central nervous system have their own communication pathway, the gut-brain axis,” says Associate Professor Laird.

“When the gut microbiota is out of balance, it can have much broader effects than simply disrupting the digestive system.

“Some people with neurodegenerative diseases such as Parkinson’s disease have gastrointestinal symptoms early in the disease course.

“From what we know about the gut, it seemed possible that these changes could be caused by an imbalance in the microbiota.”

By looking at mice specially bred to carry the MJD gene, the team was able to observe an increase in the levels of some naturally occurring gut bacteria and a decrease in others well before the onset of any neurological symptoms.

Ph.D. candidate Katherine Robinson says that while the genetic cause of MJD has been known since the 1990s, little progress has been made in identifying new treatments that could slow or halt the development of MJD.

“Exploring how changes in the gut microbiota may relate to MJD is an exciting new area to explore that could lead to a therapeutic breakthrough,” she says.

“MJD is caused by the inheritance of extra nucleotides, one of the building blocks of human DNA in a gene called ATXN3 found on chromosome 14.

“The more additional nucleotides are inherited in the ATXN3 gene, the more likely it is that early symptoms will appear and the faster the disease progresses.

“We also observed this in the mice we studied, and it is particularly interesting that we saw changes in the gut microbiota well before the onset of neurological symptoms.

Looking forward to a possible treatment

Lead author Dr Hasinika Hewawasam Gamage says MJD was linked to substantial changes in the microbiome and these changes were different in male and female mice.

“However, there have been consistent declines in the abundance of the bacterial families Lachnospiraceae, Oscillospiraceae, and Rikenellaceae in both males and females well before any of the known symptoms were detected,” he says.

“Interestingly, the magnitude of the decline in these gut bacteria in the pre-symptomatic stages was indicative of how severe MJD symptoms were in the advanced stages of the disease.

Some of the byproducts of microbial metabolism produced in the gut are known to protect the nervous system by potentially encouraging the recycling of dead or damaged cells.

“One of our theories is that changes in the gut microbiota may lead to changes in the production of microbial metabolites, such as the short-chain fatty acid butyrate and the amino acid tryptophan, which could impact this recycling mechanism and prevent neurons to function properly”. in MJD.

“We hope that further investigations into how gut microbes affect MJD progression may offer options for treatment in the future.

“We are now looking at how changes in gut microbes affect disease progression, in order to identify how we might make changes in the microbiome to at least help reduce symptom severity.”

The next step for the team is to begin investigating whether the same changes seen in mice are also seen in human patients.

More information:
Hasinika KAH Gamage et al, Machado Joseph disease severity is linked to gut microbiota alterations in transgenic mice, Neurobiology of disease (2023). DOI: 10.1016/j.nbd.2023.106051

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Neurobiology of disease

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