Guts and Brains

For Jo Keefe, Parkinson’s trembling hands and trouble walking were bad enough, but it was the nausea that was truly debilitating.

“For two or three years, I was having nausea for several hours every day,” said Keefe, a retired lawyer living in New Hampshire. “I’d wake up in the morning feeling sick and I couldn’t make any plans at all. Fortunately, I was retired, but I wasn’t planning on this for my retirement.”

Though Parkinson’s is considered a neurodegenerative condition affecting neurons that control movement, its sufferers and the physicians who treat them have long known that severe gastrointestinal troubles — nausea, abdominal pain, diarrhea, constipation — are part and parcel of the disease, in some cases preceding neurological symptoms by years, even decades.

But evidence has been accumulating that those early gut-centered symptoms may be more than just incidental to Parkinson’s devastating attack on the central nervous system. The gut, experts say, may be where Parkinson’s starts.

“What if you were able to get your screening colonoscopy and be told there’s a sign that you’ll progress to Parkinson’s unless we intervene now. And wouldn’t it be wonderful if we had a way to intervene now?”

–Trisha Pasricha, director of clinical research at Beth Israel Deaconess Medical Center’s Institute for Gut-Brain Research

If studies bear out that evidence, a so-called “gut-first” origin of Parkinson’s disease would revolutionize our understanding of the nation’s second most common neurodegenerative disorder. It would also open a door to developing treatments that intervene far earlier than current ones, which are typically administered — as in Keefe’s case — only after symptoms have occurred.

“Everyone’s goal is to find an early biomarker for the disease and our hope is that we can find one in the gut,” said Trisha Pasricha, director of clinical research at Beth Israel Deaconess Medical Center’s Institute for Gut-Brain Research and an instructor in medicine at Harvard Medical School. [“What if you were able to get your screening colonoscopy and be told there’s a sign that you’ll progress to Parkinson’s unless we intervene now. And wouldn’t it be wonderful if we had a way to intervene now? There are many steps that need to happen, but that’s the goal.”

The gut is also home to the microbiome, a complex community of thousands of species of bacteria and other microbes that live symbiotically within the guts of their human hosts. Those microbes release chemical byproducts that help our bodies stay healthy and function properly, strengthening gut integrity, protecting against pathogens and regulating immunity. In some cases, though, the microbial balance goes out of whack and harmful species increase. Symbiosis turns to “dysbiosis,” in which the chemicals released by our microbial companions interfere with healthful processes. Though researchers have just scratched the surface of the microbiome’s complexity, they’ve identified shifts in the gut microbial community in Parkinson’s as well as other neurodegenerative conditions, including Alzheimer’s disease, multiple sclerosis, and amyotrophic lateral sclerosis.

In addition to its potential to revolutionize Parkinson’s treatment, a deeper understanding of the gut-brain connection is enriching views of those other neurodegenerative conditions, as well as widespread but lesser- known conditions of the gut, like irritable bowel syndrome, gastroparesis, functional dyspepsia, and — more evidence of the deep connection between the gut and brain — psychiatric ills like anxiety and depression, which have been linked to childhood damage to the intestinal lining.

“Parkinson’s disease is very well known and that galvanizes a lot of research,” Pasricha said. “What we often find in science is that when we understand mechanisms behind one disease, it teaches us lessons that we can apply to the other diseases too.”

An idea whose time has come?

Parkinson’s is the nation’s second most common neurodegenerative disorder, affecting nearly one million Americans. It develops over decades and is caused by a misfolded protein — alpha synuclein — accumulating in motor neurons. That leads to its characteristic tremors, followed by slowed movements, altered gait, and impaired balance. As muscles of the face and neck become involved, speech slows and slurs and patients can experience difficulty swallowing, leading, in later stages, to the need for a feeding tube. The degeneration can spread to other types of neurons and cause difficulty sleeping, altered behavior, and in some cases dementia.

In the 1990s and early 2000s, researchers examined samples of gut tissue taken from Parkinson’s patients before they developed symptoms. They found alpha synuclein present in the gut as early as a decade before it appeared in the brain. Additional studies indicated how the protein might travel to the brain, showing that peptic ulcer patients who underwent vagotomies — severing the main nerve connecting the gut and the brain — had significantly lower incidence of Parkinson’s disease. Recent studies in lab mice also showed that Parkinson’s risk can be reduced significantly by severing the vagus nerve, Pasricha said.

That evidence has led some to embrace the idea that, in at least some forms of Parkinson’s alpha synuclein appears first in the gut. There, it likely attacks the enteric nervous system, causing severe constipation, the incomplete stomach emptying of gastroparesis, and other hallmark Parkinson’s gut symptoms. It then moves up the vagus nerve to the central nervous system, where it begins its more familiar assault on motor neurons.

In September, Pasricha and colleagues added to that emerging picture, linking damage to the mucosa that lines the upper small intestine to Parkinson’s disease. Published in the Journal of the American Medical Association, the work found that among more than 9,000 patients with no signs of Parkinson’s when they were examined, those with mucosal damage had dramatically increased risk — 76 percent — of later developing Parkinson’s.

Today, Pasricha is trying to better understand mechanisms that might be at work in an early, gut-based phase of the condition. She is looking at dopamine, a neurotransmitter already central to Parkinson’s story. It is dopamine-producing neurons in the central nervous system that are targeted by alpha synuclein. Though dopamine is best known for its function in the brain’s reward system — its release triggers pleasurable feelings — it is a versatile molecule. About half of the body’s dopamine is produced in the gut and among its many functions is protecting the mucosa from damage. That has left Pasricha wondering whether the gut damage her study linked to Parkinson’s is a cause or a symptom of something deeper at work.

“One answer could be that it’s the ulceration, the erosions, that lead to Parkinson’s. But what if we have it backwards?” Pasricha said. “What if decreases in dopamine are happening in people destined to develop Parkinson’s, and it’s the dopamine levels in the first place that are putting them at risk for developing these ulcerations.”

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When symbiosis turns to dysbiosis

Not far from Kulkarni’s lab at Beth Israel is Laura Cox’s at Brigham and Women’s Hospital. Cox came to the Brigham in 2019 for postdoctoral studies on the microbiome, focusing on another neurodegenerative disorder, multiple sclerosis, in which the body’s own immune system attacks the myelin insulation that sheathes nerve cells. She worked in the lab of Robert L. Kroc Professor of Neurology Howard Weiner who kept a plaque on his desk that read “Cure as many diseases as possible.” She took that admonition to heart.

“We said, ‘If we’re going to do the microbiome and MS, we’re going to work with our neighbors across the hall,’” said Cox, today an assistant professor of neurology at HMS and the Brigham’s Ann Romney Center for Neurologic Diseases. “A really important thing that’s emerging is that there is clear evidence that the gut microbiome can influence neurologic disease.”

Today, her lab still works on multiple sclerosis, but also on Parkinson’s, Alzheimer’s, and ALS, trying to understand how microbes in the gut influence diseases that a few decades ago were thought to have causes and effects largely occurring in the brain and central nervous system.

What she and other experts have found is that “dysbiosis” — shifts in the gut microbiome favoring one species of bacteria over another — occurs in each condition. And some of the same names keep popping up: Firmicutes and Bacteroidetes; Akkermansia, Blautia, and Prevotella, among many others.

As these bacteria live, reproduce, and die, they ingest and secrete chemicals. These byproducts can boost or harm our health, and can trigger neurodegeneration in two major ways, according to Cox. They can interfere with immune function which otherwise might remove harmful proteins like the amyloid beta that accumulates in Alzheimer’s disease. They also boost inflammation, a root of the neurological damage in Parkinson’s disease.

“What we found was that Bacteroidetes drove immunosenescence and it blocked this important repair process in which microglia go into the brain and clear out plaques,” Cox said. “In Parkinson’s there’s really strong evidence that the gut microbiota contributes to disease by driving inflammation.”

There are three routes by which these gut metabolites affect the brain, according to Professor of Neurology Francisco Quintana, who studies the gut-brain axis and neurodegeneration in his Brigham lab. 1.) As in Parkinson’s, they can travel via the nervous system and the vagus nerve. 2.) They can also go directly to the brain via the bloodstream, crossing the blood-brain barrier due to their small size. 3.) Third, they can activate immune cells in the gut that release signaling molecules called cytokines. Those signaling molecules can also cross the blood brain barrier and trigger the brain’s own immune cells into action.

In recent decades, we have come to understand better which shifts in microbial communities are associated with specific conditions, what some key metabolites are, and how those might affect disease progression. But researchers say the complexity remains is enormous and advancement comes in fits and starts.

In 2020, Aaron Burberry was a postdoctoral researcher in the lab of then Harvard professor Kevin Eggan. Eggan had developed a strain of lab mice that replicated ALS, whose deadly attack on motor neurons can kill in as little as six months.

Burberry and Eggan developed a second population of mice for a lab at the Broad Institute of MIT and Harvard. But despite being genetically identical and raised in environments as similar as researchers could make them – same food, same light-dark cycles – the Broad Institute mice remained stubbornly healthy and never developed the ALS-like immune response and nervous system inflammation. That sparked a scramble to find what differed between the two populations. Signs eventually pointed to the microbiome. Some microbes present in the guts of Harvard mice were absent in the Broad Institute mice.

Burberry and Eggan also found that manipulating the microbiome with antibiotics or fecal transplants from the Broad mice improved or prevented ALS symptoms in the Harvard mice. Burberry, now a professor at Case Western Reserve University, has built on that work, recently identifying a protein produced by gut microbes, CD80, that drives up an immune factor called Interleukin 17A. IL-17A triggers inflammation in the genetically engineered mice.   

Human trials testing fecal transplant in early ALS patients have begun in Europe. In addition, his recent IL-17A finding is encouraging because there are already FDA-approved treatments targeting IL-17A in psoriasis and rheumatoid arthritis. In addition, a treatment has been found for cases linked to one of ALS’ several genetic mutations, albeit one found in only 1 percent of cases.

“We’ve known for a long time that ALS has many different causes and certainly the biggest driver is just aging. People have to make it to their third, fourth, fifth, sixth decade of life before they’re afflicted with this terrible disease,” Burberry said. “That tells us that a lot of things have to go wrong before this certain group of motor neurons die and people get paralysis, which is good because that means our bodies have a lot of mechanisms to stop that from happening.”

While many important questions await future studies, therapeutics don’t have to, Quintana said. There are many conditions where even if we don’t know everything, we know enough to help. Using the tools of synthetic biology, Quintana is working to engineer microbes — bacteria, yeast, and viruses — to deliver drugs to the microbiome. These “bots” are designed to sense inflammation and release anti-inflammatories or other therapeutic agents to tamp down inflammation before it becomes a problem. In a similar vein, Rudy Tanzi, an expert on Alzheimer’s disease and the Joseph P. and Rose F. Kennedy Professor of Child Neurology and Mental Retardation, is developing a “snybiotic” to boost microbiome health. The synbiotic combines probiotics — healthy bacteria — and “prebiotics,” compounds that encourage their growth.

“My practical interpretation about these things is we might never be able to tell whether it is actually the microbiome exacerbating it or whether it is just reacting to a deeper perturbation in the body,” Quintana said. “But we can look: is there something in the microbiome that I can use as a biomarker? “It’s plausible, but we are trying to ask the question right now, ‘Is it just the fact that you have an accumulation of these mesodermal neurons or is it something more complex that causes a breakdown of critical processes?’” Kulkarni said. “It’s not like every single person who ages gets Parkinson’s disease. There’s complexity there.”