How the Pain in Your Gut Connects to Your Mind
An investigation into why a drug for irritable bowel syndrome had unexpected pain-relieving properties sheds new light on how the gut communicates with the brain.
A faint green glow reflects in the eyes of Scott Waldman, MD, the Samuel M. V. Hamilton Family Professor of Medicine and Chair of the Department of Pharmacology, Physiology, and Cancer Biology, as he pores over his microscope. His slides are fixed with tiny slivers of intestinal tissue, each containing the molecule he’s spent his career studying — guanylyl cyclase C (GCC). Marked by a fluorescent label, it acts like a tiny neon sign, pointing him in the right direction.
Dr. Waldman had spent decades tracing how GCC was key for healthy digestion. He’d connected its dysfunction to the growth of colorectal cancer, and had even begun using it to develop a cancer vaccine.
But after years of research, there was still one big question on his mind — a question that percolated as he once again examined GCC under the microscope.
In the early 2000s, researchers developed a drug called linaclotide to treat irritable bowel syndrome (IBS). Modeled on the natural gut hormones that interact with GCC to regulate digestion, the drug was designed to kick start a cascade of chemical reactions that relieved constipation.
But linaclotide also had an unexpected effect: Although nothing about its structure suggested it would have pain-relieving properties, linaclotide soothed chronic visceral pain in nearly half of the IBS patients who took it.
For years, Dr. Waldman wondered why this was. How could a drug with a simple effect on constipation — a problem of the digestive system — have an influence on chronic pain — a problem of the nervous system?
He had a feeling that the answer had something to do with the gut-brain axis, the bidirectional communication system that connects our digestive and nervous systems. But given how little scientists knew about the molecules involved in that communication at the time, he knew this wouldn’t be an easy question to answer.
“We’ve only scratched the surface of the gut-brain axis,” he says.
But when a bright MD/PhD student named Josh Barton joined his lab with an interest in the gut-brain axis, research exploring Dr. Waldman’s question began to gain momentum. Their findings show the key may be a newly-discovered cell that acts as a conduit between the brain and the gut, illuminating new ways to target visceral pain in IBS.
A Core Pain
Visceral pain — a type of pain that originates from the body’s internal organs — affects about four out of ten IBS patients, and with an estimated 10 to 15% of the population affected by IBS, chronic visceral pain is a major public health issue. The condition can present as a dull ache, cramping, or pressure, and it indicates when our internal organs are inflamed, diseased or injured.
“Generally, chronic pain is one of the major health challenges of the entire world,” says Angelo Lepore, PhD, a neuroscientist and pain expert at Jefferson. “Pain is protective, it’s evolutionary. But this system is hijacked such that it becomes pathological.”
In people with IBS, visceral pain often presents as hypersensitivity; this means their digestive organs are more tender than usual, suggesting that the signals along the gut-brain axis that normally regulate pain have gone haywire. “These types of disorders can be intractable and devastating,” says Dr. Waldman.
For IBS patients with chronic visceral hypersensitivity, there are few therapeutic options. While some doctors prescribe opioids, these can cause constipation and worsen gastrointestinal dysfunction, and they also come with serious risks of tolerance and dependence.
So linaclotide’s side effect of decreasing visceral pain was good news — but it wasn’t a miracle cure, either. It doesn’t work for everyone, and it can only be used in patients with the constipation subtype of IBS.
This gave Dr. Waldman an idea: If he could figure out the molecular mechanism behind linaclotide’s painrelieving properties, it might be possible to harness it into a new treatment for visceral hypersensitivity in IBS. And while he wasn’t sure exactly how yet, he had a hunch that the GCC receptor would be involved.
A Mysterious New Cell
The search to understand how linaclotide dulled visceral pain was slow at first.
“We were scratching our heads,” says Dr. Waldman. “There’s no obvious biological basis for this phenomenon.”
Dr. Waldman thought if he could visualize precisely where GCC was in the body, it might provide a clue. He had recently obtained genetically-engineered mice whose GCC molecules were tagged with a bright green fluorescent protein. This protein didn’t change anything about GCC function, but it revealed where GCC was most concentrated when examined under a microscope. He wanted to see if GCC was present anywhere else outside of the intestines, like the nervous system, which controls pain signals.
Dr. Waldman didn’t anticipate finding anything out of the ordinary in the tissue from the intestines, but to be thorough, he checked anyway. He expected to see a uniform green glow representing GCC distributed evenly throughout the intestinal lining, where it normally regulates water levels during digestion.
But there was something else on the microscope slides: bright green neon dots sprinkled throughout the intestines, indicating intense concentrations of GCC in small areas.
“There was a ‘starry night’ appearance of the tissue where you could see sparkles against the green background,” says Dr. Waldman, referencing Van Gogh’s famous painting The Starry Night. There were just one or two of these beaming “starry night” cells per microscopic view among thousands of faintly glowing intestinal-lining cells where GCC was known to reside.
It was Josh Barton, the new MD/PhD student in Dr. Wadman's lab, who had the idea to zoom in on these rare “starry night” cells. “Barton was the actual brains behind this phase of this project,” says Dr. Waldman.
When Barton put the sparkling cells under a high-power microscope, he noticed something unusual about their shape: They didn’t look anything like the intestinal-lining cells that normally contained GCC, which resemble rectangular brick pavers along a winding garden path. The “starry night” cells instead were shaped like little pyramids, with skinny tails jutting from one side and burrowing deep into the walls of the intestine.
Though nobody in the lab had seen these cells before, Barton had an inkling about what they might be. He had been reading a paper about a newly discovered cell type called a neuropod cell, and the similarities were eerie.
Neuropod cells are a sort of hybrid: Half intestinal-lining cell, half nerve cell or neuron, these cells share characteristics of both the digestive and the nervous system. Like intestinal-lining cells, they make GCC, and like neurons, they make the cellular machinery necessary to rapidly communicate with the rest of the nervous system. They are perfectly designed to act as a middleman between the gut and the nervous system.
“It’s a unique and newly described cell that was under everybody’s radar,” says Dr. Waldman.
While Barton had a different topic in mind for his dissertation research at first, the puzzle of the “starry night” cells captivated him, and he changed course to focus on them. Wondering if these mysterious triangular cells might be neuropod cells, he isolated and analyzed them for the specific genetic markers that set neuropod cells apart from intestinal-lining cells. They were a match.
Inside the Intestine
Neuropod cells look like a cross between intestinal lining cells and neurons. They are located along the intestinal lining, and they “reach out” to neurons that communicate with the brain.
Neuropod Cells: The Key to Visceral Pain?
Barton had shown that linaclotide’s target, the GCC receptor, was highly concentrated in neuropod cells. This gave Barton and Dr. Waldman an idea: What if the GCC in neuropod cells was the key to understanding linaclotide’s effects on visceral pain?
To find out, they needed to know what happened when GCC was removed from neuropod cells. If their theory was true, linaclotide wouldn’t be able to alleviate visceral pain without GCC present.
Because it’s not possible to do this sort of experiment in humans, Dr. Waldman used genetically-engineered mice as a model. “Mice have many of the same neural pathways that control pain as humans,” says pain expert, Dr. Lepore, “So researchers can observe certain behaviors in mice that mimic visceral pain.”
Without GCC in their neuropod cells, “the mice behavior mirrored symptoms of people with IBS,” says Dr. Waldman. “In the absence of any external stimulation, they had pain.”
And when the genetically engineered mice were given linaclotide to quell their visceral pain, it did little to help. Without GCC in neuropod cells, linaclotide no longer worked.
But what were the neuropod cells doing at the cellular level to relieve pain? To answer that question, Dr. Waldman recruited the help of neuroscientist Manuel Covarrubias, MD, PhD and MD/PhD student Tyler Alexander to examine the electrical activity of neuropod cells up close.
If neuropod cells really were the middlemen that relayed pain in the digestive system back to the brain, then they needed to directly communicate with the nervous system. To see if they did, Alexander grew neuropod cells in a petri dish alongside dorsal root ganglion cells, a type of neuron that transmits pain sensations from the body to the brain.
He found that when neuropod cells and dorsal root ganglia were placed next to each other, they naturally began to form synapses, or connection points, like tiny bridges between buildings. But just observing physical connections between the two cells wasn’t enough to prove they were communicating; Dr. Covarrubias and Alexander also needed to observe electrical activity, the language of the nervous system.
Using a tiny electrode to measure the electrical activity in a single cell, Alexander found that as the neuropod cells reached out and formed synapses, the dorsal root ganglia went from quiet and calm to buzzing with electrical activity.
“When these gut cells were making contact with the neurons,” says Dr. Covarrubias, “the neurons actually started to generate multiple impulses.” In the body, repeated electrical impulses would represent a pain signal being sent back up to the brain.
When Alexander sprinkled linaclotide over the neuropod cell, the pain signals from the dorsal root ganglion went quiet again. Whatever communication was naturally occurring between neuropod cells and the nervous system was blocked by the drug.
“Putting all of these pieces together,” says Dr. Waldman, “We believe that the neuropod cell is the missing link between linaclotide’s ability to fix visceral pain and its connection to the nervous system.”
The Missing Piece
When linaclotide (or the natural hormones it mimics) is not present to bind to GCC, neuropod cells act like a “megaphone” for visceral pain, amplifying slight feelings of sensitivity into intense signals of pain. When linaclotide is present to bind to GCC, it “quiets” or “turns off” the megaphone.
Dialing Down the Pain "Amplifier"
Barton says that when he conceptualizes the role of the gut-brain axis in visceral pain, he imagines an amplifier.
When you plug in an electric guitar, explains Barton, a dial on the amplifier controls how much louder the guitar gets as it comes out of the speakers. Visceral pain, he believes, works the same way. If the volume of the music coming from the speaker represents the intensity of pain, the GCC molecules in neuropod cells control the dial. When linaclotide — or the natural hormones it’s based on — is plentiful, the dial turns down, quieting or even muting visceral pain. When linaclotide isn’t present, or natural gut hormone levels are too low, the dial turns up and the neuropod cells fire repeatedly, amplifying loud signals of pain back to the brain.
Dr. Waldman believes these findings suggest that IBS isn’t just a disorder of digestion; it’s also a dysregulation of the hormones that bridge the gap between the gut and the brain. Because linaclotide is modeled on natural digestive hormones, this research implies that if these hormones run low, it may lead to the excessive pain experienced by those with IBS. Barton agrees. “IBS is really this black box for us right now,” he says.
Dr. Waldman says continuing to untangle the complexities of the gut-brain axis will be key to treating diseases like IBS.
“We’re still understanding the molecular components of neuropod cells,” says Dr. Waldman. “With this knowledge, we can identify new therapies to silence the pain signals traveling from the gut to the brain, and potentially bring relief to patients with these intractable pain syndromes.”
