For much of the 20th century, most people thought that stress caused stomach ulcers.

But that belief was largely dismissed 38 years ago when a study, which led to a Nobel Prize in 2016, described the bacterium that generates inflammation in the gastrointestinal tract and causes peptic ulcers and gastritis.

“The history of the idea that stress causes ulcers took a side step with the discovery of Helicobacter pylori,” said Dr. David Levinthal, director of the University of Pittsburgh Neurogastroenterology & Motility Center. “For the longest time — most of the 20th century — the dominant idea was that stress was the cause of ulcers until the early 1980s with discovery of Helicobacter pylori that was tightly linked to the risk of ulcers. That discovery was critical but maybe over-generalized as the only cause of ulcers.”

Now in an important world first, a study co-authored by Levinthal and Peter Strick, both from the Pitt School of Medicine, has explained what parts of the brain’s cerebral cortex influence stomach function and how it can affect health. “Our study shows that the activity of neurons in the cerebral cortex, the site of conscious mental function, can impact the ability of bacteria to colonize the stomach and make the person more sensitive to it or more likely to harbor the bacteria,” Levinthal said.

The study goes far beyond ulcers by also providing evidence against the longstanding belief that the brain’s influence on the stomach was more reflexive and with limited, if any, involvement of the thinking brain. And for the first time, the study also provides a general blueprint of neural wiring that controls the gastrointestinal tract.

“This is a very important study and a continuation of several other studies that Dr. Strick has carried out in the last few years,” said Peter Sterling, professor of neuroscience in the University of Pennsylvania School of Medicine and author of the recent book, “What is Health.” He had no involvement in the study.

“It’s been traditional in biology and medicine that the internal organs are self-regulatory through the autonomic nervous system, largely independent of higher brain regions,” he said. “Peter Strick is a world leader in establishing evidence that internal organs are strongly modulated at the highest levels by the cerebral cortex.”

Strick’s previous research, for instance, showed that similar areas of the cerebral cortex also control kidney and adrenal function. That course of research now could extend to “the heart, liver and pancreas to discover more about how the brain coordinates control of internal organs,” said Sterling, who holds a Ph.D. in neuroscience.

Influencing the gut

The Pitt study goes even further by demonstrating that widespread and different regions of the cerebral cortex influence stomach function in different ways.

The study, published May 18 in the Proceedings of the National Academy of Sciences, describes how portions of the brain’s cerebral cortex — including the rostral insula and medial prefrontal cortex — connect with and can affect the microbiome.

That those areas of the brain also are associated with emotional control helps explain how mental activity — how you think, feel and prepare to move — may create an encouraging environment for Helicobacter pylori.

The sympathetic nervous system generates the “fight or flight” response — an involuntary response that sends more blood flow rushing to the muscles and the release of hormones to boost awareness and heart rate. It also reduces blood flow for digestion during stressful or life-threatening situations.

On the other hand, the parasympathetic nervous system also produces involuntary signals that maintain regular bodily functions such as digestion, normal breathing and the routine heartbeat.

As the study now reveals, these two limbs of autonomic control over the stomach are influenced by distinct cortical networks.

When it comes to trusting your gut, it already is well-established that the stomach and gut send “ascending” signals to the brain in a way that influences brain function. It helps to explain how the microbiome affects brain function. But the study has found that the “central nervous system both influences and is influenced by the gastrointestinal system.”

What people haven’t understood to date, Strick said, is that the brain also has “descending influences on the stomach” with various parts of the brain involved in that signaling, including those areas that control movement and emotions. That helps explain how stress disrupts and why exercise improves the functioning of the GI tract.

‘Not trivial influences’

“What’s new here is the extent and range of cortical areas that influence the stomach,” said Strick, the study’s senior author. Those areas control the stomach “as directly as cortical control of movement. These are not trivial influences.”

Key to the study, which involved rats, was the use of a rabies virus to trace nerve-system pathways backward from the gut to the areas of the brain involved in signaling the microbiome. The rabies virus placed in the stomach wall hops from neuron to neuron in a direction opposite that of nerve impulses.

That identified the areas of the cerebral cortex that send signals to the stomach, allowing the researchers to map the brain network influencing the microbiome and GI tract.

As such, Levinthal said, the study serves as a foundation for studies focused on controlling stomach function with electromagnetic stimulation to potentially treat and, in time, reverse gastrointestinal disorders including inflammatory bowel syndrome and dyspepsia by restructuring the microbiome.

“I think this opens up a whole new way of thinking,” he said.

That motor areas of the brain also help control the GI tract explains why exercise improves digestion and makes one feel better.

“Building stress resilience — working on skills to arm ourselves with resilience in dealing with COVID-19, finances and job loss and how we cope with exposure to stress — are something to work on,” Levinthal said.

Scott Grafton, the director of the University of California Santa Barbara Brain Imaging Center among other positions, said the Pitt study, in which he was not involved, is important on three key levels.

The first expands on the longstanding belief that the gut is controlled by the brain stem and more primitive areas of the brain that generate mostly reflexive responses.

“The critical missing link is where in the cortex does the thinking brain — our moods and our mind — have inputs into the stomach, and no one really established that before,” he said.

Another links the mind and microbiome — how bacteria interact with the gut and influence well-being. The third focus is the pathways that abnormal proteins, which could be involved in triggering Alzheimer’s and Parkinson’s diseases, might use to get from the gut to the brain.

“Until now, this was all speculation about the brain and how we think it influences the stomach — what the connection is and where is the wiring,” Grafton said. “Strick’s expertise is how the wiring works — how the nervous system interacts with all parts of the body. We need to know the wiring.”