The gut epithelium, which is the thin tissue lining that cavity, is a unique entity. Spread out all its folds and crevices and you could cover a studio apartment — one that would teem with microbes, microbial signaling molecules, food byproducts and hormones. One hormone, serotonin, is a neurotransmitter that affects mood, sleep, sex drive and bowel movements. It is produced mainly by specialized enterochromaffin cells. EC cells make up less than 1 percent of the gut epithelium (collectively, only a small end table in that studio apartment), but they excrete more than 90 percent of the serotonin.
The presence of neurotransmitters in the gut is why it's sometimes described as “the second brain.” Scientists have long known that there is cross-talk between the gut and our first brain, the central nervous system, but exactly how that communication plays out is a mystery.
Nicholas Bellono, a scientist in Julius’s lab, wanted to find out what neurotransmitters such as serotonin are doing in the gut, so Julius and Ingraham introduced him to James Bayrer, a gastroenterologist working in Ingraham’s lab. Together, they and their collaborators in Australia co-wrote a study published Thursday in the journal Cell that demonstrates how EC cells translate chemical signals into neurological ones.
To do this, the team used mouse organoids — basically, organs in a dish. The researchers isolated intestinal stem cells and used them to grow “3D mini-guts.” They challenged the mini-guts with different stimuli and measured the resulting electrical responses. The method produced “a very elegant model,” noted Diego Bohorquez, assistant professor of medicine and neurology at Duke University, who was not involved in the research.
Gut epithelial cells are known to respond to mechanical stimulation. That’s how our stomach signals that it's full. But the researchers found that even a light touch with certain compounds triggered an intense reaction. The EC cells were especially sensitive to adrenaline and the chemicals that give wasabi and horseradish their strong flavor. Plants in the mustard family evolved these compounds to protect themselves from insects. Our gut perceives them as a danger, causing inflammation.
To figure out the consequences of aggravating EC cells, the researchers used mice in which the cells were tagged with fluorescent molecules. They found that EC cells contain receptors that recognize adrenaline, spicy food compounds and foul smells such as sweaty socks or stinky cheese. They then showed that these cells form associations with nerve fibers and produce compounds that are a hallmark of synapses — the connections between nerves. When challenged with adrenaline-like compounds, the EC cells became electrically charged. And that produced a rush of serotonin that activated the nearby nerve fiber.
Bohorquez called this discovery “an important step forward” because it demonstrates what scientists have long suspected: Chemical stimulants electrically excite cells lining the gut, which then directly communicate with nerve cells.
"There is really a gut skin cell that sits there and fires action potential like a nerve cell," said Arthur Beyder, who studies EC cells at the Mayo Clinic. "It's like a Morse code ... they're communicating." The fact that these cells are activated by adrenaline means the brain is in touch with the gut, as well. But we don't know why. "It could be communicating with the microbiome," Beyder suggested.
These EC cells appear to specifically recognize compounds that could serve as a threat or reflect injury. “So you’ve got the central nervous system and the gut brain. Sometimes they talk, and sometimes they argue, and you get these gut pains,” Bayrer explained. "When EC cells detect an irritant, they speed up our bowels to get rid of the offender.”
Ingraham noted that intestinal disorders are becoming more common, especially as people age. "We don’t like to talk about these issues, but constipation and diarrhea are seriously debilitating,” she said. EC cells are probably hypersensitive in people with irritable bowel syndrome. Patients often complain of discomfort or irritation, but there is not a measurable amount of inflammation. Greater understanding of normal epithelial cell activities could improve the diagnosis of IBS, Bayrer said.
Bohorquez suggested that follow-up research could lead to new drugs to block EC receptors or even the use of electrical devices to minimize EC activity. An important next step will be determining if EC cells also affect the immune system, because “immune cells cruise along underneath epithelial cells,” Bayrer added.