Dementia, Parkinson’s: Do gut bacteria trigger protein clumping?
Previous research has found links between gut bacteria and degenerative brain disorders, such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS).
A new study in tiny worms provides the first evidence that “pathogenic” bacteria can promote the misfolding of proteins that is a characteristic of these conditions.
Other bacteria that produce a fatty acid called butyrate prevented protein misfolding in the worms.
The research adds to evidence that a history of antibiotic treatments may play a role in the early development and course of Parkinson’s disease.
In recent years, several studies have implicated gut bacteria in degenerative diseases that involve the formation of toxic clumps of protein in the brain, including Parkinson’s, Alzheimer’s, and amyotrophic lateral sclerosis (ALS).
However, the complexity of the human gut microbiota — which is the community of microorganisms that live in the gut — and environmental factors, such as diet, present huge challenges for scientists trying to pinpoint the role of bacteria.
To sidestep some of this complexity, researchers turned to a tiny nematode worm called Caenorhabditis elegans.
The scientists, who are based at the Institute of Food and Agricultural Sciences at the University of Florida (UF/IFAS) in Gainesville, use the worms as “test tubes” to study the effect of individual bacterial species on protein misfolding.
Each worm is only 1 millimeter in length and has exactly 959 cells, but just like larger animals, it has intestines, muscles, and nerves.
“They are like living test tubes,” says senior author Daniel M. Czyż, Ph.D., assistant professor in the department of microbiology and cell science at UF/IFAS.
“Their small size allows us to do experiments in a much more controlled way and answer important questions we can apply in future experiments with higher organisms and, eventually, people,” he adds.
The worms feed on bacteria, but in the sterile environment of the lab, they have no microbiota of their own.
“However, these nematodes can get colonized by any bacteria that we feed them, which makes them an ideal model system to study the effect of microbes on the host,” Prof. Czyż told Medical News Today.
When the researchers colonized the gut of C. elegans with pathogenic bacteria that can infect the gut of humans, the microbes not only disrupted protein folding in the worms’ intestine but also in their muscle, nerve cells, and gonads.
By contrast, “good” bacteria that synthesize a molecule called butyrate, prevented protein clumping and its associated toxic effects.
Butyrate is one of several short-chain fatty acids that friendly gut bacteria produce when they ferment fiber. The molecules nourish cells that line the colon and have several known health benefits.
Previous research has found butyrate to be beneficial in animal models of neurodegenerative diseases, for example.
The authors of the new study say their findings demonstrate the potential of using butyrate-producing microbes to prevent and treat neurodegenerative disease.
The lead author of the study, which appears in PLOS Pathogens, is Alyssa Walker, a doctoral candidate in the UF/IFAS College of Agricultural and Life Sciences.
Examples of misfolded proteins in brain diseases include the plaques and tangles that characterize Alzheimer’s, and fibrils of a protein called alpha-synuclein in Parkinson’s.
Brain disorders linked to misfolded proteins, or “protein conformational disorders,” are a leading cause of death and disability among older people. However, there are no effective cures or treatments.
Several factors that increase the risk of these disorders, including age, diet, stress, and antibiotic use, also have links to changes in the gut microbiome.
In addition, an imbalanced gut microbiome or an intestinal infection can exacerbate neurodegenerative diseases.
To identify which bacteria may be responsible for protein misfolding, the researchers fed C. elegans with different candidate species one by one.
Using a technique that makes clumps of misfolded protein glow green under a microscope, they compared the tissues of these worms with those from control worms that ate their usual diet of bacteria.
“We saw that worms colonized by certain bacteria species were lit up with aggregates that were toxic to tissues, while those colonized by the control bacteria were not,” says Prof. Czyż.
“This occurred not just in the intestinal tissues, where the bacteria are, but all over the worms’ bodies, in their muscles, nerves, and even reproductive organs,” he added.
Worms colonized by the “bad” bacteria also lost some mobility, which is a common symptom for people with 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.
By contrast, bacteria that synthesize butyrate suppressed protein clumping and its associated toxic effects.
Recent studies have found that the guts of people with Parkinson’s or Alzheimer’s disease have a deficiency in these “good” bacteria.
“There are currently no clinical trials on butyrate and Parkinson’s disease, but given the recent increasing evidence on its beneficial effect, it is possible that we could soon see some clinical studies,” Prof. Czyż told MNT.
One main limitation of the study was that the microscopic worms do not directly model Parkinson’s or any other brain disorder.
While the animals’ simplicity makes it easier for scientists to tease apart the influence of individual bacterial species on protein clumping, this also makes them a poor model for the complexity of humans.
The worst offenders for causing protein clumping in the worms were two bacterial species called Klebsiellapneumoniae and Pseudomonasaeruginosa.
Interestingly, research has linked these species to an increased risk of protein conformational diseases, such as Parkinson’s.
In their paper, the researchers note the increasing prevalence of antibiotic resistance in these species in recent years.
They speculate that antibiotic treatments may, therefore, have the perverse effect of encouraging the growth of these antibiotic-resistant bad bacteria while decreasing the abundance of good bacteria.
In support of this hypothesis, a recent population-based study found that a history of antibiotic therapy is associated with an increased risk of Parkinson’s.