Yale Scientists Will Use $9M Grant to Create Map of Gut-brain Axis

Communication route thought to play key role in Parkinson's

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by Patricia Inácio, PhD |

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Researchers at Yale School of Medicine will use a $9 million grant to generate a detailed map of the “gut-brain axis,” the complex communication route between brain and belly — focusing on the gut microbiome — that is increasingly thought to play a key role in Parkinson’s and other neurodegenerative diseases.

The funding is part of $18 million in total grants to Yale scientists from the Aligning Science Across Parkinson’s initiative for research into the progressive disorder, which, the nonprofit estimates, affects 7 to 10 million people worldwide. This project will involve the use of novel technologies in the hope of uncovering new treatments for Parkinson’s.

The work is being led by David Hafler, MD, a professor of neurology and immunobiology, and Noah Palm, PhD, a professor of immunobiology, both at Yale School of Medicine. The multidisciplinary team also includes Le Zhang, PhD, an assistant professor of neurology from Hafler’s team, and Rui Chang, PhD, an assistant professor of neuroscience and cellular and molecular physiology.

The goal, according to Hafler, is to better understand the role of gut immune cells in Parkinson’s disease to help design stronger clinical trials for this patient population.

“Rather than conducting a clinical trial blindly, I want to better understand the nature of the inflammatory insult to better target the immune system,” Hafler said in a university press release.

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Increasing evidence has mounted in support of a connection between the gut and the brain, and its involvement in neurodegenerative diseases.

In fact, constipation and other gastrointestinal problems are common early non-motor symptoms of Parkinson’s, which can occur years before disease onset.

“The dysfunction of the nervous system that regulates gut function actually precedes the onset of Parkinson’s disease, sometimes by decades,” Palm said.

Gut involvement in Parkinson’s

Previous research, much of it conducted at Yale, showed that immune cells exert key functions beyond fighting infections. These cells also work to maintain tissues and cells in a steady and balanced state, known as homeostasis.

To achieve this, gut immune cells may be able to move to other parts of the body, including the brain, according to some researchers. But little still is known about the exact mechanisms behind these processes, leading to an unmet need for a detailed model of the gut-brain axis.

Notably, in a separate project, Hafler and Andrew Wang, MD, PhD, another Yale scientist, are evaluating how immune T-cells migrate from the gut to the brain, both in healthy people and in animal models. Hafler and Wang, an assistant professor of medicine and of immunobiology at Yale School of Medicine, hope to better understand the role of the immune system in nervous system homeostasis.

The gut microbiome, the population of microorganisms living in the intestines, also may impact brain function via different mechanisms.

One of these is through the vagus nerve — one of the longest nerves in the body — which regulates the functions of internal organs, such as digestion. It works as a type of superhighway between internal organs and the central nervous system, according to Palm. Palm’s own team found that some substances made in the gut can transit into the brain.

Researchers at the California Institute of Technology also showed, in a previous study, that aggregates or clumps of alpha-synuclein protein — a hallmark of Parkinson’s — were able to spread from the gut to the brain in aged mice through the vagus nerve.

Another of its mechanisms works through the release of gut microbiome-derived metabolites — small molecules involved in food and medication breakdown in the body — that may promote a pro-inflammatory state in Parkinson’s.

The prior research from Palm’s lab showed that human gut bacterial-derived metabolites were able to reach the brain and regulate immune cells, as well as make an impact on mood and behavior.

“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,” Palm said.

Added Hafler: “The old saying, ‘You are what you eat,’ may have more meaning than we previously thought.”

This gut-brain communication is actually bi-directional, research has shown, with changes in the brain also seeming to affect the gut. Studies have reported that the activation of certain brain nerve cells in response to gut inflammation caused an immune response in the gut itself.

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Creating a new model of the gut-brain axis

Now, the Yale researchers have devised a three-way strategy to tackle the complex interplay that regulates the gut-brain axis.

First, the researchers will harness the power of single-cell technologies to conduct a complete profile of single immune cells collected from gut biopsies in different homeostatic states. Of particular interest is understanding the characteristics of the immune T-cells that relay messages from the gut to the brain.

In addition, the team will alter the gut microbiome of mice to unveil the mechanisms by which gut immune cells can transmit messages into the brain. The research also will examine 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,” the release stated, noting that the funding will be spread over three years.

The other Yale team will use its $9 million grant to study how gene mutations associated with Parkinson’s affect the function of brain cells during disease progression.

The findings, overall, are likely to provide new information on gut-brain communication and genetic alterations in Parkinson’s, and lead to more in-depth knowledge of the disease’s inflammatory nature. The teams hope their research may help identify new disease-specific therapies.

“All of this research is part of the next generation of the most exciting immunological discoveries,” Palm said.

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