Harvard Medical School researchers have analyzed the molecular crosstalk between pain fibers in the gut and goblet cells that line the walls of the intestine. The work shows that chemical signals from pain neurons induce goblet cells to release protective mucus that coats the gut and shields it from damage. The findings show that intestinal pain is not a mere detection-and-signaling system, but plays a direct protective role in the gut. Credit: Chiu Lab/Harvard Medical School
Key Points:
- New research shows that pain neurons in the mouse gut regulate the presence of protective mucus.
- The work details the steps of a complex signaling cascade, showing that pain neurons engage in direct crosstalk with mucus-containing gut cells.
- The findings indicate that the nervous system has a major role in the gut beyond just giving off an unpleasant pain sensation.
In new research, a team from Harvard Medical School shows that pain neurons in the mouse gut regulate the presence of protective mucus under normal conditions and stimulate intestinal cells to release more mucus during states of inflammation. The work details the steps of a complex signaling cascade, showing that pain neurons engage in direct crosstalk with mucus-containing gut cells, known as goblet cells.
To clarify just how this protective crosstalk occurs, the researchers analyzed the behavior of goblet cells in the presence and absence of pain neurons.
According to the study published in Cell, they found that the surfaces of goblet cells contain a type of receptor, called RAMP1, that ensures the cells can respond to adjacent pain neurons, which are activated by dietary and microbial signals, as well as mechanical pressure, chemical irritation or drastic changes in temperature.
Additionally, the receptors connect with a chemical called CGRP, released by nearby pain neurons, when the neurons are stimulated. These RAMP1 receptors, the researchers found, are also present in both human and mouse goblet cells, thus rendering them responsive to pain signals.
Experiments further showed that the presence of certain gut microbes activated the release of CGRP to maintain gut homeostasis.
“This finding tells us that these nerves are triggered not only by acute inflammation, but also at baseline,” said study senior investigator Isaac Chiu, associate professor of immunobiology. “Just having regular gut microbes around appears to tickle the nerves and causes the goblet cells to release mucus.”
This feedback loop, Chiu said, ensures that microbes signal to neurons, neurons regulate the mucus, and the mucus keeps gut microbes healthy.
In addition to microbial presence, dietary factors also played a role in activating pain receptors, the study showed. When researchers gave mice capsaicin, the main ingredient in chili peppers known for its ability to trigger intense, acute pain, the mice’s pain neurons got swiftly activated, causing goblet cells to release abundant amounts of protective mucus. By contrast, mice lacking either pain neurons or goblet cell receptors for CGRP were more susceptible to colitis, a form of gut inflammation.
The finding could explain why people with gut dysbiosis may be more prone to colitis.
Information provided by Harvard Medical School.