Every nine minutes, someone in the United States is diagnosed with Parkinson’s disease, one of the most common neurodegenerative disorders associated with aging. Because as many as one in five Americans will reach the age of 65 or older by 2030, health care workers are bracing for a growing epidemic of these debilitating and incurable conditions. Now new Yale research suggests that several of these diseases may originate not in the nervous system, but in the gut.
As accumulating experimental evidence advances our understanding of the apparent connection between alterations in the microbiome and disorders originally thought to be exclusively of the nervous system, Yale researchers are seeking to understand the role of the gut-brain axis. Among these researchers are David Hafler, MD, chair and William S. and Lois Stiles Edgerly Professor of Neurology and professor of immunobiology, and Noah Palm, PhD, assistant professor of immunobiology, who have received support from the Aligning Sciences Across Parkinson’s (ASAP) initiative to better understand the core etiology of the disease.
“The old saying, ‘You are what you eat,’ may have more meaning than we previously thought,” says Hafler.
“All of this research is part of the next generation of the most exciting immunological discoveries,” says Palm.
What is known about the gut-brain connection to neurodegenerative conditions?
How signals from the gut influence the brain has fascinated and intrigued researchers. There have been three main hypotheses about the pathways involved.
First, emerging research in immunology over the past decade—much of which has been conducted at Yale, including by Ruslan Medzhitov, PhD, Sterling Professor of Immunobiology—has shown that the immune system has significant functions beyond simply fighting infection, including tissue regulation and cellular homeostasis. Some researchers postulated that motile immune cells in the gut are programmed to move to places they’re needed within the body to fulfill these purposes. Some of these immune cells might be homing in on the brain. Andrew Wang, MD, PhD, assistant professor of medicine and of immunobiology and Hafler are investigating how T cells migrate from the gut to the brain, both in healthy individuals and in experimental animals to better understand the role of the immune system in nervous system homeostasis.
Second, scientists believed that the microbiome could influence the brain through the neuronal circuitry that links the gut to the brain via the vagus nerve, which acts as a “superhighway” between our organs and the central nervous system, says Palm.
And finally, researchers hypothesized that the connection could be due to chemical communication through metabolites—small molecules made by the microbiome to break down food, drugs, and other natural and synthesized substances.
“It turns out that over the past five to 10 years all of these possible pathways have proven to be true in one shape or another,” says Palm.
The gut-brain connection is bi-directional
Indeed, researchers unexpectedly discovered a particular kind of plasma B cell programmed in the gut to produce a specialized antibody known as Immunoglobulin A (IgA) in the central nervous system. Evidence for the vagal nerve hypothesis stems from experiments using alpha-synuclein, a protein that scientists believe to be one of the key mediators of the death of dopaminergic neurons associated with Parkinson’s disease. When misfolded aggregates of these proteins are injected in the gut, they travel through the vagal nerve up to the brain. Evidence for the third hypothesis was found through Palm’s team’s own work, which showed that some metabolites made by gut microbes, including psychoactive metabolites, can transit from the gut across the blood-brain barrier and into the brain, where they can potentially impact mood and behavior and regulate immune cells in the brain.
Even more recently, scientists have found that this gut-brain connection isn’t one-directional. Changes that happen in the central nervous system can also be relayed to the immune system and the gut. Studies show, for example, that the activation of specific neurons in the brain in response to inflammation in the gut triggered an immune response in the gut itself. This evidence supports a bi-directional gut-brain connection.
Parkinson’s disease: Origins in the gut?
To Hafler, a leading researcher in multiple sclerosis, this gut-brain connection was not a total surprise. One of the main treatments for MS, Tysabri, works by targeting a homing receptor that is shared only between the brain and gut. Now, he and his colleagues are focusing on Parkinson’s disease, whose possible origins in the gut are backed up by emerging, convincing evidence.
Patients with neurodegenerative diseases such as MS or Parkinson’s exhibit differences in their microbiomes, but researchers don’t yet understand why this happens. An intriguing observation scientists have made about Parkinson’s disease, for instance, is that early symptoms can include dysfunction of the gut, usually resulting in constipation. “The dysfunction of the nervous system that regulates gut function actually precedes the onset of Parkinson’s disease, sometimes by decades,” says Palm.
Since 2017, the ASAP initiative has assembled highly interdisciplinary teams to learn more about the biology of Parkinson’s disease. Through funding from the initiative, Hafler’s team found that the spinal fluid in patients with an early form of Parkinson’s—known as behavioral REM sleep disorder, in which vivid, often frightening dreams occur—is highly inflamed. Now, Hafler and Palm have assembled an interdisciplinary team that includes Rui Chang, PhD, assistant professor of neuroscience and of cellular and molecular physiology and Le Zhang, assistant professor of neurology. Through their latest ASAP grant, the team plans to use novel technologies to study the role of the gut-brain axis during homeostasis, a process in which the body regulates its internal environment.
The team hopes to learn more about three key areas. First, by using single cell technologies and taking gut biopsies, they will profile immune cells to better understand the characteristics of the T cells that relay messages from the gut to the brain in various homeostatic states. Next, by manipulating the gut microbiome in mice, they hope to illuminate how immune cells in the gut are programmed to send messages to the brain. And finally, they hope to learn more about the role of gut-educated immune cells in the brain. This research will be the first of its kind to document the cellular and molecular mechanisms of the motile immune cells coordinating between the brain and gut.
Hafler hopes his team’s findings will prepare him to create a clinical trial focused on treating patients with Parkinson’s. One of the major obstacles in treating autoimmune disease is that a drug that helps one condition may trigger a different one. He believes that a more in-depth knowledge of the inflammatory nature of Parkinson’s will help him design a stronger trial.
“Rather than conducting a clinical trial blindly, I want to better understand the nature of the inflammatory insult to better target the immune system,” he says.