How the Ecosystems in Our Guts Could Be Linked to Brain Disorders

How the Ecosystems in Our Guts Could Be Linked to Brain Disorders
Illustration: Elena Scotti (Photos: Wikimedia Commons)

Within our guts is a tiny ecosystem populated by trillions of microorganisms. These germs affect digestion, the immune system, and even brain functioning. Scientists have also started investigating the potential role of gut bacteria in psychiatric and neurological conditions, including neurodegenerative diseases like Alzheimer’s and Parkinson’s. If gut microbes prove influential, this could reveal how these diseases work, leading to earlier detection and new treatment targets.

Neurodegenerative diseases progressively damage and kill nerve cells, causing problems with mental or movement function, and sometimes both. Over the past 30 years, these diseases have grown more common with the world’s increasingly older population, yet there are no cures and few effective treatments. Alzheimer’s and Parkinson’s diseases lead the way, affecting millions of people worldwide.

These diseases arise from combinations of genetic, environmental, age-related, and lifestyle factors, but in most cases, doctors can’t pinpoint a cause. Given that the brain connects with the gut, scientists are increasingly looking at the possible role of gut microbes.

Much of this research has focused on Parkinson’s, which is associated with gastrointestinal issues. But preliminary connections between the gut microbiome and other neurodegenerative diseases, like Alzheimer’s and amyotrophic lateral sclerosis (ALS), are also emerging.

Bacteria account for the majority of the microorganisms in our guts, and they’re in direct and indirect communication with the nervous system, which controls mental functions, movement, sensory perception, and automatic processes like breathing.

Through a two-way connection called the gut-brain axis, our microbes could be liaising with the brain via nerves and chemical pathways. For example, gut bacteria can synthesise neurotransmitters, the brain’s molecular messengers, and other chemicals used in the brain. When absorbed by the gut walls and into the bloodstream, these molecules can travel to the brain. The bacteria also interact with immune cells. This could indirectly affect the brain through immune cell signalling pathways, or, in late neurodegenerative disease stages, directly affect the brain. During the late disease stages, it’s possible that immune cells infiltrate the brain from the bloodstream, through more porous blood vessels.

The role of gut bacteria in neurodegenerative diseases is still an emerging field of research. “There’s some rightful scepticism,” said Timothy Sampson, assistant professor of physiology at Emory University.

“It is still a relatively young field, so there are a lot of unknowns,” said Jan Pieter-Konsman, a neuroimmunologist at the University of Bordeaux. Until recently, studies of the gut microbiome and neurodegenerative diseases were limited to comparing microbial communities in people with and without the diseases. Most studies didn’t look deeper at the operations within those ecosystems.

“You’ve got to break down that community to understand those interactions,” said Maureen O’Malley, a philosophy of microbiology researcher at the University of Sydney. But in the past five years, groups are increasingly drilling into those interactions, studying which specific microbes and molecules could be involved in disease.

Parkinson’s disease, in particular, has captured the attention of researchers interested in the gut-brain axis. Gastrointestinal issues, like constipation, often occur in people years before they develop the movement-related symptoms characteristic of the disease.

“One of the cardinal features originally of James Parkinson’s diagnosis of ‘the shaking palsy,’ which has become Parkinson’s disease, was this observation of intractable constipation in patients,” said Lynne Barker, associate professor of cognitive neuroscience at Sheffield Hallam University. The fact that the gut is involved in Parkinson’s hasn’t been a secret.

Scientists look at bacterial genes in stool samples to approximate the bacterial composition of the gut. These studies have shown that microbiomes of people with Parkinson’s differ from those without Parkinson’s. These differences arise independently of other influences over the microbiome, like diet. “But that leads to this big chicken-and-the-egg problem,” said Sampson. “Did the disease cause the microbiome to change, or did the change in the microbiome influence the disease?”

In a small, preliminary study, Purna Kashyap, professor of medicine and physiology and co-director of the microbiome program at Mayo Clinic, and his team used mouse models of Parkinson’s disease and showed that mice needed gut bacteria to develop movement-related symptoms. In germ-free mice, ones without any detectable bacteria, fungi or viruses in or on their bodies, movement problems never materialised.

Studies in rats and mice have also shown that the gut bacteria Escherichia coli make proteins akin to alpha-synuclein protein clumps that form in the brain in Parkinson’s disease. In mice engineered to overexpress alpha-synuclein, Sampson has shown that this bacterial protein in the gut exacerbates both alpha-synuclein aggregation in the brain and movement symptoms.

O’Malley cautioned that while these animal experiments go deeper than earlier studies, they should be interpreted with caution, since animal studies often fail to replicate in humans. But, she said, “I think you can still get some of the suggestive findings that then allow you to build a better model of what’s going on.”

More recently, a few research groups have started looking for gut microbiome disturbances in other neurodegenerative diseases, like Alzheimer’s. Protein clumps called beta-amyloid plaques disrupt brain cell functions in people with Alzheimer’s. Mouse models of Alzheimer’s disease also suggest a role for gut microbes.

“If you keep those mice germ-free, they don’t develop as many amyloid plaques,” said Barbara Bendlin, a professor of medicine at the University of Wisconsin, Madison. “It does really suggest that in some way there’s a link between microbes and the development of Alzheimer’s disease pathology.”

As a starting point in human research, Bendlin and her team have studied gut microbiomes of people with Alzheimer’s disease by analysing stool samples. In a small study of 25 people with Alzheimer’s and 25 people without, they found that Alzheimer’s patients had a less diverse bacterial population and different amounts of certain bacteria. They also analysed the cerebrospinal fluid, which surrounds the brain and spinal cord, of participants to look for relationships between Alzheimer’s-related biomarkers and the gut microbiome.

“We found that there were relationships between the gut microbiome and those cerebrospinal fluid biomarkers, even among individuals who were asymptomatic,” said Bendlin. “That suggested to us that maybe there’s a link between the gut and brain pathology that’s present even before people develop dementia.”

Scientists have also begun exploring links between gut bacteria and ALS, a disease in which neurons powering the muscles gradually die. In a study of mice with a genetic mutation known to cause ALS in some human cases, Eran Blacher, postdoctoral fellow studying the gut-brain axis at the neurology department of Stanford University School of Medicine, and his team showed that gut microbiome changes preceded ALS symptoms. Blacher said that indicated that such changes might have to do with the disease.

The researchers also found that certain gut bacteria produced molecules that altered the disease in mice. Giving the mice a probiotic supplement with that bacteria boosted levels of the molecule nicotinamide and improved their symptoms. Nicotinamide produces key chemicals for cellular pathways scientists think are involved in ALS. “So we can change the disease progression and manifestation by treating the mice with specific bacteria, which was very surprising,” said Blacher.

Blacher’s preliminary findings in a small group of human patients supported those results: People with ALS had lower levels of bacterial genes needed for nicotinamide metabolism in their stool samples compared to people without ALS. They also had lower levels of nicotinamide in their blood and cerebrospinal fluid. “We are not saying that we were able to cure ALS, or to change anything in disease progression in humans,” said Blacher. Rather, larger follow-up studies could reveal more about mechanisms underlying ALS and reveal potential therapy targets.

But overall, the microbiome’s role in neurodegenerative diseases remains mysterious. Barker’s group is analysing data from a small feasibility study to see whether administering a common probiotic to people with Parkinson’s disease could change their microbiome composition or influence quality of life. Unlike earlier work, Barker said her group is looking beyond big-picture changes in microbial communities to zero in on specific bacterial species.

Still, studies are far from revealing microbiome-based treatments for neurodegenerative diseases. Even if some kind of probiotics or dietary changes were shown to be effective at alleviating some symptoms, it wouldn’t be a cure for these complicated diseases. If gut microbes are involved in neurodegeneration, scientists also need to figure out how this fits with other potential disease causes.

“We have not learned the mechanisms that link that to the brain, and until we firmly know those, we’re not going to be able to develop effective treatments,” said Bendlin.

@JackieRocheleau.