Painkillers can't be eaten indiscriminately! Cell: Painful neurons in the gut promote the release of more protective mucus during enteritis

Pain has long been thought to be one of the most reliable tools in evolution, detecting the presence of injury and signaling that something is wrong with our body, telling us that we need to pay attention to
our bodies.
But what if pain is more than just a wake-up call? What if pain itself is a form of protection?

In a new study, researchers from Harvard Medical School, the University of Chicago, and the University of Gothenburg in Sweden have found that pain neurons ---nociceptor neurons in the gut of mice regulate the presence of protective mucus under normal conditions and stimulate intestinal cells to release more mucus
in an inflammatory state.
The results of the study were published online in the journal Cell on October 14, 2022 in the paper "Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier protection"
.

The new study details the steps of a complex signaling cascade, showing that pain neurons talk
directly to goblet cells.

Isaac Chiu, corresponding author of the paper and associate professor of immunobiology at Harvard Medical School's Blavatnik Institute, said: "It turns out that pain may protect us in a more direct way, rather than detecting potential harm and sending signals
to the brain in a traditional way.
Our study shows how gut-mediating pain-mediating neurons talk to
nearby intestinal epithelial cells.
This means that the main role of the nervous system in the gut is not just to bring us unpleasant sensations, it is a key role in the maintenance of the intestinal barrier and a protective mechanism
during inflammation.
”

Our intestines and respiratory tract are covered with goblet cells
.
Goblet cells, named for their goblet appearance, contain a gelatinous mucus composed of proteins and sugars that act as a protective coating that protects the surface of the organ from abrasion and damage
.
The new study found that when triggered by direct interaction with pain neurons in the gut, intestinal goblet cells release protective mucus
.

In one set of experiments, the researchers observed that mice lacking painful neurons produced less protective mucus, their gut microbial composition changed--- and the good and harmful microbes in the gut were out of balance, also known as dysbiosis
.
To elucidate how this protective conversation occurs, they analyzed the behavior
of goblet cells in the presence and absence of pain neurons.

They found that the surface of the goblet cells contained a receptor called RAMP1, which ensured that the cells were able to respond to neighboring pain neurons, which were activated
by dietary and microbial signals, as well as mechanical stress, chemical stimulation, or drastic changes in temperature.
The experiment further showed that this receptor binds
to a chemical called CGRP released by neighboring pain neurons when stimulated.
They found that RAMP1 receptors were also present in human and mouse goblet cells, allowing them to respond to
pain signals.

The study further pointed out that the presence of certain gut microbes activates the release of CGRP to maintain the balance
of the gut.

Chiu said: "This finding tells us that these neurons are triggered not only by acute inflammation, but also at baseline
.
As long as ordinary gut microbes are around, it seems to be able to activate these neurons and cause goblet cells to release mucus
.
This feedback loop ensures that gut microbes signal to these neurons, which regulate mucus, which keeps the gut microbes healthy
.
”

The new study shows that in addition to the presence of microbes, dietary factors also play a role
in activating pain receptors.
When the authors gave mice capsaicin---, the main ingredient in red pepper peppers, which triggers intense acute pain ---, the mice's pain neurons were rapidly activated, causing goblet cells to release large amounts of protective mucus
.

Image from Cell, 2022, doi:10.
1016/j.
cell.
2022.
09.
024
.

In contrast, mice lacking pain neurons or goblet cell CGRP receptors were more likely to develop colitis
.
This finding may explain why people with dysbiosis may be more likely to develop colitis
.
When the researchers injected mice lacking pain neurons with CGRP, which conducts pain signals, their mucus secretion improved
rapidly.
Even in the absence of painful neurons, this treatment protects mice from colitis
.
This finding suggests that CGRP is a key promoter
of the signaling cascade leading to protective mucus secretion.

Daping Yang, co-first author of the paper and a postdoctoral researcher in Chiu's lab, said: "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
.
”

Possible drawbacks of suppressing pain

The experiment showed that mice lacking pain receptors also suffered more severe damage
when colitis occurred.
Given that painkillers are often used to treat colitis patients, it may be important
to consider the possible adverse consequences of blocking pain, they said.

"In people with intestinal inflammation, one of the main symptoms is pain, and some parts of this pain signal may act directly as a nerve reflex, which raises important questions about how to carefully manage pain
in a way that does not lead to other harm," Chiu said.
”

In addition, the researchers say a class of common migraine drugs that inhibit CGRP secretion may damage intestinal barrier tissue
by interfering with this protective pain signal.

Chiu said, "Given that CGRP is a chemical mediator of goblet cell function and mucus secretion, what happens if we block this protective mechanism in migraine patients for a long time, if they take these drugs for a long time?" Do these drugs interfere with the surface layer of the mucous membrane and people's gut microbiome? ”

Goblet cells have a variety of other functions
in the gut.
They provide a pathway for antigens and produce antimicrobial chemicals that protect the gut from pathogens
.

Yang said: "One question that arises from our current research work is whether pain nerves can also regulate these other functions
of goblet cells.
Another line of investigation is to explore disruptions in the CGRP signaling pathway and determine whether this disruption plays a role
in patients with a genetic predisposition to inflammatory bowel disease.
”

In an earlier study (Cell, 2019, doi:10.
1016/j.
cell.
2019.
11.
014), Chiu and his team found that pain neurons embedded in the small intestine and microfold cells (M cells) lined with Peyer's patch can be activated by the presence of Salmonella.
M cells are the main entry point
for Salmonella and other dangerous bacteria to invade the small intestine.
Once activated, these neurons employ two defense strategies to stop Salmonella from infecting the gut and spreading to other parts
of the body.

Experiments have shown that in the presence of Salmonella, pain neurons in the gut fight back by releasing a neurochemical called CGRP, which slows the differentiation of M cells and thus reduces the number of
entry points that Salmonella can use.

In addition, their experiments showed that these neurons initiate another form of defense
.
By releasing CGRPs, they increase the number of protective gut bacteria called segmented filamentous bacteria (SFBs), which deter salmonella invasion
in addition to other beneficial functions.
Exactly how they do this is unclear, but Chiu and colleagues say a plausible mechanism could be that SFB bacteria use their tiny little hooks to attach themselves to the intestinal wall and form a repulsive coating
that can stop the pathogenic bacteria.

Both defense mechanisms work
reliably in mice with intact intestinal neurons.
However, this was not
the case in mice lacking these intestinal neurons.
Indeed, intestinal biopsy results from mice with inactivated intestinal neurons showed that Salmonella penetrated into their Pyle collection lymph nodes at a higher rate than mice with intact intestinal neurons
.
These mice lacking intestinal neurons also had fewer protective SFB bacteria
in their guts.
Not surprisingly, these mice had a higher chance of contracting Salmonella and spread more widely than mice with intact intestinal neurons
.