- Studies suggest that the gut microbiota and the brain communicate in a bidirectional manner, with changes in gut microbiome composition and function associated with neurodegenerative conditions.
- A recent study found that a probiotic bacterial strain could prevent the development of paralysis and degeneration of motor neurons in a worm model of amyotrophic lateral sclerosis (ALS).
- The study found that the ALS worm model showed alterations in lipid metabolism, and the neuroprotective effects of the probiotic bacterial strain were mediated by normalizing these changes.
- These findings suggest that probiotics could potentially have a role in the treatment of neurodegenerative conditions, but further research is needed.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative condition that commonly appears later in life and is characterized by paralysis caused by the degeneration of motor neurons.
In addition to these changes in the nervous system, neurodegenerative conditions, including ALS, are also characterized by metabolic changes.
A recent study published inCommunications Biology showed that the bacterial strain Lacticaseibacillus rhamnosus HA-114 was able to prevent motor degeneration and paralysis in an ALS roundworm model.
The study found that L. rhamnosus HA-114 exerted its neuroprotective effects by restoring alterations in lipid (fat) metabolism observed in the ALS worm model.
Because the researchers conducted this study in an invertebrate model, they have to replicate these findings in mammals.
Study author Dr. Alex Parker, a neuroscientist at the University of Montréal in Canada, told Medical News Today:
“We discovered a natural, probiotic bacterium that has the ability to suppress degeneration of motor neurons in animal models of ALS. The work, for the time being, is restricted to simple animal models (published), but work is ongoing in mammalian models (mice), and a clinical trial for ALS patients is planned for 2023.”
Studies have shown that the gut microbiome can modulate the function of the nervous system and vice-versa. Besides modulating the function of the brain, studies show that germ-free animals that lack gut microorganisms show altered brain development.
The gut microbiota can influence brain development and function by modulating immune function, metabolic pathways, or by directly acting on the nervous system.
These findings have led to a surge in interest in the role of gut microbiota in the development of neurodegenerative disorders.
For instance, several recent studies have shown that changes in the gut microbiome composition and function are associated with neuropsychological conditions, including Alzheimer’s disease and Parkinson’s disease.
However, there are limited data showing a causal association between gut microbiota and neurological disorders.
Amyotrophic lateral sclerosis is a progressive neurodegenerative condition characterized by the loss of motor neurons.
The degeneration of motor neurons leads to the weakness of muscles and, eventually, the loss of control over movements and paralysis.
Animal models are essential for studying the mechanisms underlying the development of neurological conditions such as amyotrophic lateral sclerosis that affect the central nervous system.
In the present study, the researchers used a nematode, or roundworm, called Caenorhabditis elegans as a model to study the impact of probiotic bacteria on the development of ALS-like symptoms.
C. elegans is one of the most common invertebrate models used for studying animal development and behavior. C. elegans has a short life cycle, completing development from a fertilized egg to an adult in about 3 days at 20 degrees Celsius.
Moreover, the entire genome of C. elegans has been published, and specific genes can be easily altered to study their function.
Adult C. elegans are about 1 millimeter long and utilize bacteria as their food source. Thus, these worms can be maintained in the laboratory on cultures of E. coli grown in Petri dishes.
Researchers can thus examine the neuroprotective effects of individual gut bacteria by feeding C. elegans a specific bacterial strain.
For instance, previous studies have shown that certain probiotic bacterial strains can prevent or slow down neurodegenerative symptoms in C. elegans models of Alzheimer’s disease and Parkinson’s disease.
Around 5–10% of ALS cases are inherited, while the rest are caused by a combination of environmental and genetic factors. Mutations in the FUS and TDP-43 proteins are common in cases of familial ALS.
In the present study, the researchers used C. elegans worms that they genetically modified to express mutant forms of FUS or TDP-43 in motor neurons.
These genetically modified — or transgenic — C. elegans worms expressing mutated FUS or TDP-43 genes tend to develop paralysis and exhibit degeneration of motor neurons between 6–12 days of adulthood.
The researchers first examined whether feeding the transgenic C. elegans ALS models different strains of probiotic bacteria could prevent or reduce the expression of these ALS-like symptoms.
Specifically, the researchers maintained the transgenic C. elegans ALS models on 13 different bacterial strains and three combinations of two strains each. The control group animals were maintained on a strain of E.coli.
The researchers found that only the bacterial strain L. rhamnosus HA-114 was able to prevent the development of paralysis and the degeneration of motor neurons in transgenic ALS models.
The experiment also involved three other L. rhamnosus strains, but these strains were unable to prevent the development of ALS-like traits.
The researchers then examined the potential mechanisms that could explain the ability of the HA-114 bacterial strain to rescue these ALS-like symptoms.
Some of the common mechanisms implicated in neurodegenerative conditions include oxidative stress and aggregation of misfolded proteins. However, the neuroprotective effects of HA-114 were independent of these pathways.
To further examine the mechanisms underlying the neuroprotective effects of HA-114, the researchers assessed differences in the gene expression profile of the ALS worm models maintained on HA-114 and E. coli.
The transgenic worms maintained on HA-114 showed higher expression of genes involved in lipid metabolism than those maintained on the E. coli strain.
Hence, the researchers individually targeted the expression of three genes — acdh-1, kat-1, and elo-6 — involved in lipid metabolism in the ALS worm models.
Using transgenic C. elegans ALS models carrying mutations in these lipid metabolism genes in addition to those in the FUS or TDP-43 genes, the researchers found that HA-114 was no longer able to prevent paralysis in these strains.
In other words, these genes involved in lipid metabolism were essential for mediating the neuroprotective effects of HA-114.
The researchers found that even heat-killed HA-114 was able to prevent paralysis in the transgenic C. elegans ALS model.
Moreover, fatty acids, but not protein extracts, derived from HA-114 were able to rescue the ALS-related symptoms in transgenic worms.
The researchers also found that both HA-114 and HA-114-derived fatty acids also enhanced the expression of the acdh-1 gene. Notably, HA-114 was unable to prevent the paralysis of the transgenic C. elegans ALS model in the presence of an inhibitor of acdh-1 gene expression.
The genes acdh-1 and kat-1 are involved in fatty acid metabolism and mitochondrial beta-oxidation, the process by which fatty acids are broken down inside the mitochondria to produce energy.
Together these results suggest that the bacterial strain HA-114 influences lipid metabolism, specifically beta-oxidation, to exert its neuroprotective effects.
Hence, the researchers further examined whether the ALS C. elegans models showed deficits in lipid metabolism and whether the HA-114 bacterial strain could help normalize these deficits.
They also examined whether such deficits in lipid metabolism were also present in a C.elegans model of Huntington’s disease, another age-related neurodegenerative condition.
The C. elegans models of both ALS and Huntington’s disease showed a greater accumulation of lipids than wild-type control animals.
Moreover, when the transgenic ALS and Huntington’s disease worm models were maintained on HA-114, they showed similar levels of lipid accumulation to that observed in wild-type C. elegans.
In sum, these results show a disruption of lipid metabolism in C. elegans models of age-related neurodegeneration, with HA-114 being sufficient to normalize these alterations in lipid metabolism.
Additional experiments also demonstrated that the transgenic ALS models showed deficits in pathways associated with beta-oxidation.
The present study found a disruption in lipid metabolism in the transgenic ALS model that was not restricted to motor neurons but also extended to organs such as the liver.
This suggests that ALS could impact other organ systems and highlights the need for a more comprehensive understanding of the disease.
Lastly, although ALS, like Alzheimer’s disease, is also associated with the aggregation of misfolded proteins, HA-114 was unable to prevent the aggregation of proteins. Instead, HA-114 may help attenuate the deficits in metabolism due to mutant genes and prevent or delay the degeneration of neurons.