Harvard Medical Researchers Discover Surprising Pain Protective Properties

Researchers at Harvard Medical School have analyzed molecular crosstalk between pain fibers in the intestine and the goblet cells that line the walls of the intestine. The work shows that chemical signals from pain neurons prompt goblet cells to release protective mucus that coats the gut and shields it from damage. The results show that gut pain is not just a sensing and signaling system, but plays a direct protective role in the gut. Credit: Chiu Lab/Harvard Medical School

What if pain was more than just an alarm bell?

New research in mice sheds light on how pain neurons protect the gut from damage.

Pain is one of evolution’s most effective mechanisms for detecting injury and letting us know something is wrong. It acts as a warning system, telling us to stop and pay attention to our bodies.

What if pain was more than just a warning sign? What if pain was in itself a form of protection?

A new study by researchers at Harvard Medical School suggests that this may well be the case in mice.

The startling research reveals that pain neurons in the mouse gut regulate the presence of protective mucus under normal conditions and stimulate gut cells to release more mucus during states of inflammation. The study was published on October 14 in the journal Cell.

The work describes the steps in a complex signaling cascade, demonstrating that pain neurons engage in direct crosstalk with intestinal mucus-containing cells called goblet cells.

Goblet cells come from pluripotent stem cells and get their name from their cup-shaped appearance that resembles a goblet. Their main function is to secrete mucin and create a protective layer of mucus. Goblet cells are also thought to play a role in regulating the immune system.

“Pain turns out to be able to protect us in more direct ways than its typical job of detecting potential damage and sending signals to the brain. Our work shows how pain mediating nerves in the intestine communicate with nearby epithelial cells that line the intestines,” said study lead researcher Isaac Chiu. “This means that the nervous system plays a major role in the gut beyond just giving us an unpleasant feeling and is a key player in maintaining the gut barrier and a protective mechanism during ‘inflammation.” Chiu is an associate professor of immunobiology at the Blavatnik Institute at HMS.

A direct conversation

Our intestines and respiratory tract are dotted with goblet cells. Named after their cup-shaped appearance, goblet cells contain gel-like mucus composed of proteins and sugars that acts as a protective coating that shields the surface of organs from abrasion and damage. The new research found that intestinal goblet cells release protective mucus when triggered by direct interaction with pain-sensing neurons in the gut.

In a series of experiments, the researchers observed that mice lacking pain neurons produced less protective mucus and experienced changes in their gut microbial composition – an imbalance between beneficial and harmful microbes known as dysbiosis.

To clarify how much of this protective crosstalk occurs, the scientists analyzed the behavior of goblet cells in the presence and absence of pain neurons.

They found that goblet cell surfaces contain a type of receptor, called RAMP1, that ensures the cells can respond to adjacent pain neurons, which are activated by food and microbial cues, as well as mechanical pressure, chemical irritation or drastic temperature changes. .

The experiments further showed that these receptors connect to a chemical called CGRP, released by nearby pain neurons, when the neurons are stimulated. These RAMP1 receptors, the researchers found, are also present in human and mouse goblet cells, making them sensitive to pain signals.

Experiments have further shown that the presence of certain gut microbes activates the release of CGRP to maintain gut homeostasis.

“This finding tells us that these nerves are triggered not only by acute inflammation, but also initially,” Chiu said. “Just having regular gut microbes seems to tickle the nerves and cause the goblet cells to release mucus.”

This feedback loop, Chiu said, ensures that microbes signal to neurons, neurons regulate mucus, and mucus keeps gut microbes healthy.

In addition to microbial presence, dietary factors also played a role in activating pain receptors, the study showed. When the researchers gave mice capsaicin, the main ingredient in red chili peppers known for its ability to trigger intense, sharp pain, the mice’s pain neurons were quickly activated, causing the release of copious amounts protective mucus by goblet cells.

In contrast, mice lacking pain neurons or goblet cell receptors for CGRP were more susceptible to colitis, a form of intestinal inflammation. This finding could explain why people with gut dysbiosis may be more prone to colitis.

When the researchers administered pain-signalling CGRP to animals that lacked pain neurons, the mice experienced a rapid improvement in mucus production. The treatment protected the mice against colitis even in the absence of pain neurons.

The finding demonstrates that CGRP is a key instigator of the signaling cascade that leads to the secretion of protective mucus.

“Pain is a common symptom of chronic inflammatory bowel conditions, such as colitis, but our study shows that acute pain also plays a direct protective role,” said study first author Daping Yang. postdoctoral researcher at Chiu Lab.

A possible downside to pain suppression

The team’s experiments showed that mice lacking pain receptors also had more severe lesions from colitis when it occurred.

Since painkillers are often used to treat patients with colitis, it may be important to consider the possible adverse consequences of pain blocking, the researchers said.

“In people with bowel inflammation, one of the main symptoms is pain, so you might think we would want to treat and block pain to relieve suffering,” Chiu said. “But part of this pain signal could be directly protective as a neural reflex, raising important questions about how to carefully manage pain in a way that doesn’t lead to further harm.”

Additionally, a class of common migraine medications that suppress CGRP secretion may damage gut barrier tissue by interfering with this protective pain signaling, the researchers said.

“Given that CGRP is a mediator of goblet cell function and mucus production, if we chronically block this protective mechanism in people with migraine and they take these drugs long term, what is it happening?” Chiu said. “Will the drugs interfere with people’s mucosa and microbiomes?”

Goblet cells have several other functions in the intestine. They provide a passageway for antigens – proteins found on viruses and bacteria that trigger a protective immune response by the body – and they produce antimicrobial chemicals that protect the gut from pathogens.

“A question that arises from our current work is whether pain fibers also regulate these other goblet cell functions,” Yang said.

Another avenue of research, Yang added, would be to explore disruptions in the CGRP signaling pathway and determine whether dysfunctions are at play in patients with a genetic predisposition to inflammatory bowel disease.

Reference: “Nociceptor Neurons Direct Goblet Cells Through a CGRP-RAMP1 Axis to Drive Mucus Production and Gut Barrier Protection” by Daping Yang, Amanda Jacobson, Kimberly A. Meerschaert, Joseph Joy Sifakis, Meng Wu, Xi Chen, Tiandi Yang, Youlian Zhou, Praju Vikas Anekal, Rachel A. Rucker, Deepika Sharma, Alexandra Sontheimer-Phelps, Glendon S. Wu, Liwen Deng, Michael D. Anderson, Samantha Choi, Dylan Neel, Nicole Lee, Dennis L. Kasper, Bana Jabri, Jun R Huh, Malin Johansson, Jay R. Thiagarajah, Samantha J. Riesenfeld and Isaac M. Chiu, October 14, 2022, Cell.
DOI: 10.1016/j.cell.2022.09.024

Co-authors included Amanda Jacobson, Kimberly Meerschaert, Joseph Sifakis, Meng Wu, Xi Chen, Tiandi Yang, Youlian Zhou, Praju Vikas Anekal, Rachel Rucker, Deepika Sharma, Alexandra Sontheimer-Phelps, Glendon Wu, Liwen Deng, Michael Anderson, Samantha Choi, Dylan Neel, Nicole Lee, Dennis Kasper, Bana Jabri, Jun Huh, Malin Johansson, Jay Thiagarajah and Samantha Riesenfeld.

The work was supported by the National Institutes of Health (grants R01DK127257, R35GM142683, P30DK034854, and T32DK007447); the Food Allergy Science Initiative; the Kenneth Rainin Foundation; and the Digestive Diseases Research Core Center under P30 grant DK42086 to the University of Chicago.

Jacobson is an employee of Genentech Inc.; Chiu sits on the Scientific Advisory Boards of GSK Pharmaceuticals and Limm Therapeutics. His lab receives research support from Moderna Inc. and Abbvie/Allergan Pharmaceuticals.

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