Cell's surprising pain-protecting properties

Our intestines and airways are lined with goblet cells
.
Named for its goblet appearance, goblet cells contain gelatinous mucus made up of proteins and sugars that act as a protective coating that protects the surface of the organ from wear and damage
.
The new study found that protective mucus is released when intestinal goblet cells interact directly with pain-sensing neurons in the gut
.
In a series of experiments, the researchers observed that mice lacking painful neurons produced less protective mucus and experienced changes in the composition of the gut microbe—an imbalance of beneficial and harmful microbes known as dysbiosis
.
To figure out how this protective crosstalk occurs, the scientists analyzed the behavior
of goblet cells when pain neurons were present and absent.

They found that the surface of goblet cells contains a receptor called RAMP1, which ensures that the cells respond to neighboring pain neurons that are activated
by dietary and microbial signals, mechanical stress, chemical stimulation, or drastic temperature changes.
The experiments further showed that when pain neurons are stimulated, these receptors connect with a chemical called CGRP, which is released
by nearby pain neurons.
The researchers found that these RAMP1 receptors are also present in the goblet cells of humans and mice, thus making them responsive
to pain signals.
Experiments further showed that the presence of certain gut microbes activated the release of CGRP to maintain intestinal homeostasis
.

"This finding tells us that these nerves are triggered not only by acute inflammation, but also at baseline," Chiu said
.
"As long as there are regular gut microbes around, it seems to stimulate the nerves and cause the goblet cells to release mucus
.
" This feedback loop ensures that microbes send signals to neurons, which regulate mucus, which keeps gut microbes healthy
.
Studies have shown that in addition to the presence of microbes, dietary factors also play a role
in activating pain receptors.
When the researchers fed capsaicin to mice, the mice's pain neurons were rapidly activated, causing the goblet cells to release large amounts of protective mucus
.
Capsaicin, the main ingredient in chili peppers, is known
for causing severe acute pain.
In contrast, mice lacking CGRP pain neurons or goblet cell receptors were more likely to develop colitis, a type of intestinal inflammation.

This finding could explain why people with dysbiosis are more likely to develop colitis
.
When the researchers injected the pain signal CGRP into animals lacking pain neurons, the mice's mucus secretion increased
rapidly.
Even in the absence of painful neurons, this treatment protects mice from colitis
.
This finding suggests that CGRP is a key stimulatory factor
leading to a signaling cascade of protective mucus secretion.

"Pain is a common symptom of chronic inflammation of the gut, such as colitis, but our study shows that acute pain also plays a direct protective role," said Daping Yang, first author of the study, a postdoctoral researcher
in Chiu's lab.