Title:Harmony in the Gut-Brain Relationship

Above: Illustration by Elisa Morsch (G’20)

When we walk into a concert, or a roomful of laughing friends, or onto a bus packed with solemn strangers, or stroll alone in the forest— we experience internal, bodily sensations that are difficult to describe with words. We feel good energy, a sense of despair, a calming quiet, an unsettled awareness. When we are paying attention we can “read the room.” We have a gut feeling about the situation—but what does that really mean? Does the gut actively feel things? What’s the role of the brain in processing and responding to that data?

For basic digestion, the gut depends on the brain to transmit signals that move a bite of sandwich down the pipe—gastric motility—and take out the needed nutrients. But now scientists are beginning to understand the reciprocal role—how the gastrointestinal tract communicates back to the brain.

“I used to think of the gut as an organ of nutrition,” says Michael Zasloff, MD, PhD, professor of surgery and pediatrics at Georgetown University School of Medicine. “But I have begun to think of it in a very different, important way: the gut is a massive sensory organ.” Zasloff, who is also the co-director of the Center for Translational Transplant Medicine at Georgetown University Medical Center and scientific director of the MedStar Georgetown Transplant Institute, studies the gut-brain axis.

In fact, the inside lining of the intestinal tube forms a protective barrier not unlike our skin. When we swallow something, the intestinal tract filters some microbes out, and takes others in, through a membrane that repeatedly “touches” what we consume. What is inside our intestines is technically outside the body, drawing comparisons to the human form as donut, with one long hole through the middle.

So how is the gut mechanically interacting with this sensory data? Research teams at Georgetown are seeking answers, unraveling the mysteries of the exquisitely intimate relationship between the brain and the gut.

The Gut in Motion

After completing her formal training as a scientist, Lorenza Bellusci, PhD, became interested in the nervous system and in particular its connection to the gut. As is often the case, the curiosity stemmed from a personal experience. She had been diagnosed with a rare immunological disease, cyclic neutropenia, and the most prominent symptoms it produces are digestive issues. Intrigued by the groundbreaking research of Georgetown neuroscientists Stefano Vicini, PhD, and Niaz Sahibzada, PhD, in the department of pharmacology and physiology, she contacted them and joined the team.

Her focus is on studying exactly how the nervous system controls the movement of food through the body.

“Basically, everything is controlled by the nervous system,” Bellusci says, “starting from the moment when you eat, to the moment you start digesting, to how the food moves in your esophagus, in your stomach. What I work on is the contraction of the muscles—how the nervous system can control different muscles and different movements at the same time.”

Out of a massive and complex brain-gut axis, Bellusci studies a very specific, small area of the hindbrain, the Nucleus of Tractus Solitarius (NTS) and the dorsal motor nucleus of the vagus nerve. The nerve fiber bundles control gastric motility including functions like the gag reflex.
She conducts her research using optogenetics, activating the neurons in live mice using light. The approach allows her to target the specific area and observe the organs in operation. “By exciting specifically one group of nerves in that area, I am able to control the changes in the contraction of the gastric muscles,” she explains.

What Happens in Vagus…

Bellusci and her team are trying to unravel the circuitry of these areas that control gastric motility. The vagus nerve plays a key role, connecting the gut, heart, lungs and other organs to the brainstem. Sometimes referred to as a neural superhighway, the long nerve arises from the brainstem, reaches the gut, and provides it with input to control its movements, but it also detects the sensations of the gut and transmits them to the brain. In other words, the vagus nerve is not a one-way street.

Not much is known about the interneurons that are connect- ed at the end of the vagus nerve. This is where Bellusci hopes to uncover some answers, by looking at the role of neurotransmitter gamma-amino butyric acid (GABA).

“What we are interested in is particularly the effect of the GABA signaling. And that’s why I am working on two different particular interneurons, the somatostatin and the neuropeptide Y neurons.”

Her research on gastric motility will have multiple applications for a host of common gut ailments, including diabetes, and others not typically considered GI disease, such as Parkinson’s.

“What we’re learning is important from different points of view. If you know how does it work, not only the ending part of the vagus nerve, but even the interneurons that are involved in the circuitry, it helps understand several diseases. There are many pathologies correlated to the gastrointestinal tract, such as reflux, and they have so many different symptoms. It can really affect people’s lives,” says Bellusci.

For health providers, diagnosing diseases affecting the gut is complicated. But, as Bellusci points out, research connecting the brain and gut disease is relatively new.

“Everything published in this field is from the last 20 years,” she notes.

Understanding the correlation between the gut and brain, and the specific functions of the connecting neurons, poses an immense challenge, but one worth pursuing.

Gut and Parkinson’s Disease

Another Georgetown scientist investigating the brain-gut connection is Michael Zasloff, MD, PhD, professor of surgery and pediatrics at Georgetown University School of Medicine, co-director of the Center for Translational Transplant Medicine at GUMC, and scientific director of the MedStar Georgetown Transplant Institute.

Like Bellusci, Zasloff did not start his research career working on the brain. He studied innate immunity for many years and described for the first time antimicrobial peptides in vertebrates.

He became interested in the role of enteric nerve cells—those of the gut. He wondered how they defend the organism from infection, and what is the effect of their malfunction on the brain.

“Why aren’t they inflamed all the time? How is it that these enteric nerves are able to live in harmony with bacteria?” he says.

Zasloff ’s interest in the gut-brain axis started about 10 years ago, when a relative of his was diagnosed with Parkinson’s disease. The symptoms of this disease appear to result from the death of dopamine-producing neurons from the brain’s substantia nigra. This may be linked to the toxic accumulation of aggregates of a protein called alpha-synuclein (αS).

The reason why these neurons die is not yet understood. However, in the last decade, pathologists all over the world found some clues along the enteric nervous system (ENS)— the neural network of the gastrointestinal tract. In patients with advanced Parkinson’s disease, tangled deposits of αS accumulate in the enteric nerve cells of the gut and travel up the vagus nerve to where it meets the brainstem. But in later, more advanced stages of the disease, scientists found the αS aggregates further along, into the more cranial portions of the brain. This led scientists to wonder: Could the neurodegenerative disease of Parkinson’s begins in the gut?

Zasloff wanted to find out if αS production increases with gut infection. With a structure similar to antimicrobial peptides which emerge to fight infection, αS might accumulate in the gut as a consequence of abnormal interactions with viruses or even bacteria. From the gut, it would then be trafficked up the vagus nerves to the brain. So Zasloff and his team started a simple study, in collaboration with the Transplant Institute at Georgetown and the NIH, to determine what the role of αS was in a healthy framework of non-Parkinsonian patients: kids.

The colleagues studied biobank samples from children who had received intestinal transplants and who had documented cases of Norovirus infection—a common occurrence among immunosuppressed transplant recipients. Would αS be found in the gastrointestinal tract when the children developed an acute Norovirus infection?

Studying serial biopsies taken over time as part of the regular follow-up of these patients, the scientists found that the kids did not have αS before the norovirus expression. During the Norovirus expression, however, they recorded the emergence of αS, which frequently persisted for months afterwards, inferring prolonged protection on the nerve.

“With my colleagues at NIH, we were able to go on and show that αS was a potent chemokine—a full-blown component of the immune system.” The findings suggest that αS, as part of the immune system, may be part of how the human body manages infection. It’s also possible that people with Parkinson’s develop the disease as a consequence of viral infections of the GI tract during childhood or early adulthood.

Harmony in the Gut

The discovery has changed profoundly the way that Zasloff thinks about the gut.

“I used to see the gut as an organ of nutrition,” says Zasloff. “Now to me the gut is a massive sensory organ. Massive. And it obviously must provide the brain with an enormous amount of information—about fluid, temperature, nutrients, numbers of immune cells, and so on. The brain hears this “music” on a regular basis. It hears the music during the morning, when it expects food. It goes into a nocturnal state at night, as the central organs cool. If the gut is not working properly, it may cause conditions when the music that the brain listens to isn’t right.”

Interpreting what enters, reading the molecules like notes in a song, perhaps the gut is like an orchestra of multiple, finely tuned instruments playing in harmony. With the inside lining of the gastrointestinal tract an extension of our skin, we compose the music by touching what we eat, all along the pathway from start to finish.

“Now the brain and the gut relationship is no different in my mind than the brain and the eye, the brain and the ears, the brain and the nose.”

The gut as one incredible sensory organ? With increasing scientific evidence that backs up his gut feeling, Zasloff says yes.

Zasloff is the Founder and Chief Scientific Officer of Enterin, Inc.