Nearly everyone will experience pain in the chest, pelvic, or abdominal organs—known as visceral pain—at some point in life, with abdominal pain being the most common type.
Unfortunately, because visceral pain is much less understood than pain involving other parts of the body, treatments are lacking. One of the biggest pieces missing from the puzzle is how visceral organs transfer information to the nervous system to cause pain.
New research from the University of California, San Francisco now makes significant inroads to answering this question.
A team of researchers report that a subtype of specialized cells in the gut called enterochromaffin (EC) cells detect information about both naturally occurring and harmful molecules in the gut. Then, they send that information to the nervous system using the neurotransmitter serotonin, a key molecule involved in how nerve cells communicate with one another.
“This is a very definitive study that uses modern molecular methods to [understand the cells and molecules responsible for] gut-nerve cell interactions and has very important implications for visceral pain,” says Karin Westlund High, University of New Mexico, Albuquerque, US, a visceral pain researcher who was not involved in the new study.
“This circuitry may be the root of the pain and other symptoms of many conditions, including irritable bowel syndrome, inflammatory bowel disease, fibromyalgia, and gastroesophageal reflux disease,” she added.
The study, led by Holly Ingraham and David Julius, was published June 29 in the journal Cell.
From the gut to the nervous system
The gut epithelium, a layer of cells that form the lining of the gut, is one of the human body’s largest exposed surfaces. Because of that, the gut encounters a wide variety of substances, including those from the diet and those that cause inflammation, as well as microbes.
A type of cell called an enteroendocrine cell in the lining of the gut respond to these substances by making hormones that control digestion, metabolism, immunity, and pain. These cells form anatomical connections with nearby neurons, so researchers have suspected that they are responsible for communication from the gut to the nervous system. However, direct evidence for this idea had been lacking until now.
The new study focused on a specific kind of enteroendocrine cell, the EC cell, because EC cells become active in inflammatory bowel diseases. In addition, although EC cells make up only one percent of intestinal epithelial cells, they make more than 90 percent of the body’s serotonin.
“When you’re interested in understanding how the gut epithelium talks to the nervous system, EC cells are a good model to use,” Julius explained.
Mini guts, mighty insights
In the new study, the researchers created intestinal organoids—tiny organs in a laboratory dish—from mice. The researchers added a fluorescent protein to the EC cells from these animals so that the cells could be easily identified under a microscope. These so-called “mini guts” stay true to the three-dimensional arrangement of the gut. In this way they mimic the natural gut environment much more realistically compared to other methods, Julius said.
The team used the mini guts to identify the substances that the EC cells recognize. Out of 30 different substances known to be present in the gut, only seven consistently activated EC cells. The fact that all seven had already been linked to inflammation in the gut suggests that EC cells may play an important role in visceral pain.
The researchers went on to identify the corresponding proteins present in EC cells that recognize these substances. Then, they used the mini guts to show that the EC cells could release serotonin onto nearby cells.
EC cells also appeared to form connections with nearby neurons that contained serotonin receptors. These receptors are proteins to which serotonin attaches.
“This study shows that EC cells are activated by information from [harmful substances in the gut] and then release serotonin onto neurons, thereby [transmitting] this information from the gut to the nervous system,” said High. Abnormal regulation of serotonin in the gut is suspected to play a role in many bowel diseases, and so modulating how serotonin is released from the EC cells could provide a therapeutic benefit, she added.
In a final experiment, the researchers found that activating the EC cells made nearby neurons more sensitive to mechanical stimulation of the colon with a thin filament (a common way to activate cells in pain studies). This increased pain sensitivity is a key feature of visceral pain syndromes. This further shows that EC cells likely play a role in these ailments.
“Treatment for visceral pain syndromes is really in the early days; there aren’t a lot of good drugs for these patients. We hope that identifying the molecules involved in these gut-neuronal signaling pathways will lead to new treatment targets,” Julius said. —Allison Marin
To read about the research in more detail, see the related IASP Pain Research Forum news story here.
Allison Marin is a neuroscientist-turned-science writer who resides in Pittsburgh, US.