- Previous research has linked gut bacteria to degenerative brain diseases including Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS).
- A new research in tiny worms is the first to show that “pathogenic” bacteria can encourage the protein misfolding that is a hallmark of these diseases.
- Protein misfolding in the worms was prevented by bacteria that contain butyrate, a fatty acid.
- The study adds to the growing body of evidence that a history of antibiotic treatments can play a role in the onset and progression of Parkinson’s disease.
Several studies in recent years have linked gut bacteria to degenerative diseases involving the development of toxic protein clumps in the brain, such as Parkinson’s, Alzheimer’s, and amyotrophic lateral sclerosis (ALS).
However, scientists seeking to pinpoint the function of bacteria face significant challenges due to the complexities of the human gut microbiota — the population of microorganisms that reside in the gut — and environmental factors such as diet.
Caenorhabditis elegans, a tiny nematode worm, was used by researchers to get around some of this difficulty.
The researchers at the University of Florida’s Institute of Food and Agricultural Sciences (UF/IFAS) in Gainesville use the worms as “test tubes” to investigate the impact of individual bacterial species on protein misfolding.
Each worm is only 1 millimetre long and has exactly 959 cells, but it has intestines, muscles, and nerves, much like larger animals.
Senior author Daniel M. Czy, Ph.D., assistant professor in the department of microbiology and cell science at UF/IFAS, describes them as “living test tubes.”
He continues, “Their small size helps us to do experiments in a much more organised way and address important questions that we can apply in future experiments with higher organisms and, ultimately, humans.”
The worms eat bacteria, but they don’t have their own microbiota in the lab’s sterile setting.
“However, any bacteria that we feed them will colonise these nematodes, making them a perfect model system for studying the impact of microbes on the host,” Prof. Czy told Medical News Today.
When the researchers colonised C. elegans’ guts with pathogenic bacteria that can infect humans’ guts, the bacteria disrupted protein folding not only in the worms’ intestines, but also in their muscle, nerve cells, and gonads.
Protein clumping and its toxic effects is prevented by “good” bacteria that synthesise a molecule called butyrate.
When pleasant gut bacteria digest fibre, they develop butyrate, which is one of the short-chain fatty acids. The molecules nourish the cells that line the colon’s walls and are considered to have a number of health benefits.
Butyrate has been shown to be useful in animal models of neurodegenerative diseases in the past.
The authors of the new study claim that their results show that butyrate-producing microbes can be used to prevent and treat neurodegenerative disease.
Alyssa Walker, a doctoral candidate in the UF/IFAS College of Agricultural and Life Sciences, is the lead author of the research, which was published in PLOS Pathogens.
Alzheimer’s disease plaques and tangles, as well as fibrils of a protein called alpha-synuclein in Parkinson’s disease, are examples of misfolded proteins.
Protein conformational disorders, or brain disorders caused by misfolded proteins, are a leading cause of death and disability in the elderly. However, there are no proven therapies or cures.
Changes in the gut microbiome are linked to a number of factors that raise the risk of these disorders, including age, diet, stress, and antibiotic use.
In addition, a dysbiosis in the gut microbiome or an infection in the intestine may worsen neurodegenerative diseases.
Bacteria and misfolded proteins
most common causes of protein misfolding.
The researchers fed C. elegans different candidate bacteria one by one to figure out which bacteria might be responsible for protein misfolding.
They compared the tissues of these worms to those of control worms that consumed their normal diet of bacteria, using a technique that makes clumps of misfolded protein glow green under a microscope.
Prof. Czy explains, “We saw that worms colonised by certain bacteria species were lit up with aggregates that were harmful to tissues, while those colonised by control bacteria were not.”
“This happened not only in the bacteria-infested intestinal tissues, but all over the worms’ bodies, including their muscles, nerves, and reproductive organs,” he explained.
Worms infected with the “bad” bacteria lost their mobility, which is a typical symptom of neurodegenerative diseases.
“A healthy worm moves around by rolling and thrashing. When you pick up a healthy worm, it will roll off the pick, a simple device that we use to handle these tiny animals. But worms with the bad bacteria couldn’t do that because of the appearance of toxic protein aggregates.”
– Alyssa Walker, lead author.
Protein clumping and its toxic effects were suppressed in bacteria that synthesise butyrate.
Recent research has discovered that people with Parkinson’s or Alzheimer’s disease have a deficiency in these “good” bacteria in their guts.
“There are currently no clinical trials on butyrate and Parkinson’s disease,” Prof. Czy told NCCMED. “However, given the recent increasing evidence on its beneficial effect, clinical studies may be conducted soon.”
One of the study’s major flaws was that the microscopic worms did not accurately model Parkinson’s disease or any other brain condition.
Although the animals’ simplicity allows scientists to separate the effects of individual bacterial organisms on protein clumping, it also makes them a poor model for human complexity.
Antibiotics in the frame
Two bacterial organisms, Klebsiella pneumoniae and Pseudomonas aeruginosa, were the worst offenders for causing protein clumping in the worms.
Surprisingly, studies have related these organisms to an increased risk of protein conformational diseases like Parkinson’s disease.
The researchers note in their paper that antibiotic resistance has become more common in these species in recent years.
Antibiotic treatments, they believe, can have the unintended consequence of promoting the development of antibiotic-resistant bad bacteria while reducing the abundance of good bacteria.