Recent research suggests new treatment options for neurodegenerative diseases involving the gut microbiome
By Burcin Ikiz, Ph.D.
Bowels don’t readily come to mind when talking about a neurological disorder. But for James Parkinson, they did.
In his 1817 essay on the shaking palsy, Parkinson described a syndrome that would later be renamed for him. The English surgeon and apothecary also mentioned an unexpected symptom: constipation.
“The bowels, which had been all along torpid, now, in most cases, demand stimulating medicines of very considerable power,” he wrote, “the expulsion of the faeces from the rectum sometimes requiring mechanical aid.”
Even though Parkinson’s disease mostly affects the nerve cells in the brain, the majority of patients also suffer from gut-related symptoms. Only scientists didn’t pay much attention to them until the last decade.
That changed after Heiko Braak, a neuroanatomist at the University of Ulm in Germany, discovered ɑ-synuclein aggregate in 2003. This clump of protein is characteristic in both the brain and the gastrointestinal nervous system of Parkinson’s patients. Following these observations, Dr. Braak proposed that the disease may initiate not in the brain, but in the gut.
Following studies revealed that gut plays a role in other neurological diseases too. This has led scientists to come up with new treatment options that alter or restore a healthy gut microbiome – the trillions of microorganisms that live in the intestinal tract.
Parkinson’s disease may originate in the gut
During the last decade, Braak’s theory got support from several studies on rodents and humans. These studies suggested that ɑ-synuclein aggregates may travel through the vagus nerve, which connects the abdomen to the brain. Severing that nerve through a surgical operation called a vagotomy – which was frequently used to treat ulcers in the past – could reduce the risk for Parkinson’s.
Despite all the hints at the connection between the gut and brain disease, it has only been backed up by cold, hard scientific evidence very recently. In April 2020, a Sweden-based group demonstrated a causal genetic link between the gut and Parkinson’s disease in humans for the very first time.
The group wanted to determine which cell types in Parkinson’s patients were involved in the disease. They first identified the genes that increase the risk for the disease using the world’s largest genomic database – provided by the genomics company 23andMe – that they had assembled from patients. They then mapped these genes to the known genes in the mouse nervous system to identify the specific cell types associated with them.
“[For] all the genes that increase the risk of Parkinson’s, we found the cells that express those genes,” explains Jens Hjerling-Leffler, an assistant professor from Karolinska Institute and one of the principal investigators of the study. “If you disrupt these genes, you will disrupt the symptoms. That is the risk [for] the disorder.”
The group found three cell types that were involved with the disease. One was dopaminergic neurons, the nerve cells that synthesize dopamine – often thought of as a “feel-good” neurotransmitter that is released when we do pleasant things or expect a reward. This was expected since dopamine-producing nerve cells are the ones killed by Parkinson’s disease.
But the researchers were surprised to identify the other two categories of cells that are associated with Parkinson’s. One was oligodendrocytes – the insulating non-neuronal cells in the central nervous system. The other one was nerve cells in the gut. According to Hjerling-Leffler, these nerve cells are involved very early in the disease, possibly causing it.
Gut microbiome is linked to other neurological diseases
Could the gut be involved in other diseases where nerve cells are destroyed?
This was the question that Barbara Bendlin, an associate professor at the University of Wisconsin-Madison, set out to tackle. No one had studied the whole gut microbiome of human Alzheimer’s patients. Bendlin’s group made a comprehensive survey and identified that patients with Alzheimer’s had fewer types of microbes in their gut than healthy people. The team found that healthy people with similarly impoverished microbiome diversity in their gut also showed tell-tale signs of Alzheimer’s in their brains – for some, even before they developed any behavioral changes like memory loss.
Several researchers looked for answers to the same question in the field of Amyotrophic lateral sclerosis (ALS). This neurodegenerative disease affects nerve cells in the brain and the spinal cord that control skeletal muscles. A study on a mouse model of ALS showed that modifying mice gut microbiomes changed how the disease developed. Other studies on ALS patients found that there are changes in the microbial content of patients’ feces, as well as in their gut microbiota composition during the course of the disease. Similarly, in a study that came out in November, researchers discovered that immune cells specific to gut microbiome travel to the central nervous system during active multiple sclerosis.
While all these observations suggest that gut may play a role in these diseases, they do not provide clear evidence – like the one found with Parkinson’s disease – that the changes in gut directly cause the neurodegenerative diseases. At least not yet. “It may be that gut changes are leading to brain changes, but it could also be the case that brain changes then, in turn, affect the composition of the gut, “ explains Bendlin.
In other words, the gut may contribute to these diseases not necessarily directly, but as a facilitator – potentially through inflammation and other disease mechanisms. “It sort of adds fuel to the fire,” says Nicholas Vogt, an MD/Ph.D. student from Bendlin’s group who was one of the leading scientists behind the study.
Whatever the mechanism may be, determining the exact role of the gut microbiome in these diseases will open up new possibilities for treating them using the gut microbiome. Some options are probiotics, fecal transplants, and anti-inflammatory treatments.
Neurodegenerative diseases are devastating. From slowly losing memory in Alzheimer’s to not being able to perform basic physical tasks due to tremors in Parkinson’s, they rob patients from their bodies and their lives. These incurable disorders also cause an immense economic and social burden on patients’ families, caregivers, and the modern society in general.
Thanks to the recent advances in biomedical research, however, scientists now think that by making sure that the microbes in the gut are happy and healthy, we can one day keep these brain diseases at bay.
“We don’t have any good treatments for Alzheimer’s. Haven’t had a new FDA-approved treatment for Alzheimer’s disease in over 15 years,” says Bendlin. “So if you found something that was even modestly beneficial, it seems like it would be worth pursuing.”
This piece was produced in collaboration with the NPR Scicommers
Peer-edited by Anastasia Yandulskaya
Photo credit: John Maniaci/UW Health – the author received permission from the researchers to use the images