Discovery Grant helps researchers explore the brain-gut connection and potential for future ALS therapies

The relationship between the gut and the brain has received increasing attention in recent years, and while there is evidence that probiotics support gut health – new research shows that probiotics may also have intriguing possibilities for applications in ALS. A team led by Dr. Alex Parker (Department of Neuroscience, CRCHUM, Université de Montréal), has shown that certain probiotic bacteria seem to suppress motor deficits and motor neuron degeneration in ALS animal models. Collaboration with Dr. Matthieu Ruiz, (Department of Nutrition, Université de Montréal and co-director of the metabolomics platform at the Montreal Heart Institute), has led to a greater understanding of the biology, specifically the lipid mechanisms involved.

But more work needs to be done to explain exactly how these particular probiotic bacteria influence disease progression in animal models – and to see whether these probiotics could one day be included in the treatment of people living with ALS. With a $125,000 Discovery Grant, from the ALS Canada Research Program in partnership with Brain Canada, Drs. Parker and Ruiz are empowered to take the next step.

The Discovery Grant competition has been made possible by matched funds contributed by the Canada Brain Research Fund, an innovative partnership between the Government of Canada (through Health Canada) and Brain Canada, and by the generosity of provincial ALS Societies, and ALS Canada donors.

Worm models and the microbiome

Their project stemmed from Parker’s work with probiotics in worm models. Whereas work with mouse models can be costly and time-consuming, the tiny roundworm, C. elegans, can be replicated quickly, allowing researchers to test thousands of molecules – and to see results in a fraction of the time. “You change their food source, and you change their microbiome,” Parker explains, “and our team found two probiotics that were really effective in our ALS worm models.” Of particular interest was one specific probiotic strain, HA-114.

Doctoral student Audrey Labarre was key to this work: “She has been the driving force behind this project from day one,” says Parker. A recipient of an ALS Canada Trainee Award, Labarre, who currently has a first-author paper on the team’s work under review, has long been convinced of the impact of gut bacteria on the brain. “I’m lucky because I stuck to my research question and my hypothesis is supported by a lot of data now,” she says.

The next step: unlocking the mechanism

What’s next? Supported by the Discovery Grant, the research teams will be able to test HA-114 more robustly with mouse models, analyzing the full spectrum of metabolic changes prompted by HA-114 – and ideally, onward to the clinical setting.

“We’re working together to really get down to the molecular cell biology, to clarify the lipid mechanisms involved, because this is what could set the stage for clinical testing,” says Parker.

Parker’s early results had been intriguing: the science demonstrated a consistent effect, but also a clear need. “We had to bring in experts in large-scale lipidomics biology,” Parker recalls, to understand how and why the disease was slowing as it did in ALS worm models. “We have to figure out the mechanism, specifically.” Lipidomics is a growing field of study that uses analytical chemistry approaches to study the lipid content of cells; understanding lipid metabolism can help us understand the molecular mechanisms in disease, including how dysfunctional energy metabolism in ALS can contribute to illness progression.

Enter Dr. Matthieu Ruiz. An expert on metabolomics with significant experience in mitochondrial disease, Ruiz was keen to bring his expertise to bear in the study of ALS. “One thing we try to do, on our side, is to isolate and identify specific signatures of the clinical manifestations of disease,” he explains. “Untargeted lipidomics is interesting, because you can even find new markers – and using the knowledge in one rare disease can potentially be applied to others.”

Parker feels that in examining mitochondrial beta oxidation – the metabolic process by which fatty acids are broken down into energy – his group has identified a novel mechanism. Equally novel is the partnership with Ruiz, bringing genetics work with model organisms together with lipid biology.

From worms to mice – to clinical testing

Supported by the Discovery Grant, the teams are now poised to scale their study from the simple worm model to the more complex mouse model. Looking ahead towards the clinical stage, which could follow, the probiotic may have a particular advantage. As Ruiz explains, “Other pharmacological approaches can be more toxic – pathotoxic, neurotoxic and cardiotoxic – but probiotics are safer.” Parker notes that many new drugs fail at the clinical stage due to adverse side effects that could be harmful even to healthy people. By contrast, probiotics are easily tolerated, which may benefit the project as it moves to future stages – and ultimately could position HA-114 as a promising therapeutic complement to ALS treatments.

Important note: The work done by Drs. Parker and Ruiz relates to a non-marketed probiotic called HA-114 and any consideration of taking probiotic supplements is recommended to first be discussed with members of an ALS clinical team.

Funding that makes a difference

The Discovery Grant program makes these connections possible with a funding model that favours interdisciplinary collaboration, bringing the best minds together to tackle complex problems. A key component of the ALS Canada Research Program, Discovery Grants give promising novel ideas the fuel they need to gain traction; in 2021, eight projects will benefit from $1M in total funding.

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Posted in: Research