Harvard Medical Researchers Discovered Surprising Pain Preventing Properties / Goblet cells Protective Mechanism / CGRP
Harvard Medical School researchers analyzed the molecular crosstalk between pain fibers in the intestine and the goblet cells that line the intestinal walls. The work shows that chemical signals from pain neurons stimulate goblet cells to release the protective mucus that coats the intestines and shields them 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
Goblet cells come from pluripotent stem cells and get their name from their cup-shaped appearance. Its main function is to secrete mucin and create a protective mucous layer. Goblet cells are also thought to play a role in regulating the immune system.
What if pain was more than 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 that something is wrong. It serves as a warning system, telling us to stop and pay attention to our bodies.
What if pain was more than a warning sign? What if pain itself was a form of protection?
A new study by researchers at Harvard Medical School suggests this may be the case in mice.
The startling research reveals that pain neurons in the gut of mice regulate the presence of protective mucus under normal conditions and stimulate gut cells to release more mucus during inflammatory states. The study was published Oct. 14 in the journal Cell .
The work describes the steps in a complex signaling cascade, demonstrating that nociceptive neurons engage in direct crosstalk with mucus-containing intestinal cells, called goblet cells.
“Pain turns out to be able to protect us in more direct ways than its traditional job of sensing potential damage and sending signals to the brain. Our work shows how pain-mediating nerves in the gut talk to nearby epithelial cells lining the gut,” said study lead author Isaac Chiu. The nervous system has a major role in the gut that goes beyond just unpleasant sensation and is a major 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.
Our intestines and respiratory tract are dotted with goblet cells. Goblet cells, named for their cup-shaped appearance, contain a gel-like mucus composed of proteins and polysaccharides that acts as a protective layer that shields the surface of organs from abrasion and damage. The new research found that intestinal goblet cells secrete protective mucus when stimulated by direct interaction with pain-sensing neurons in the gut.
Dysbiosis
In a series of experiments, the researchers observed that mice lacking pain neurons produced less protective mucus and exhibited changes in their gut microbial composition – an imbalance of beneficial and harmful microbes known as dysbiosis.
How goblet cells function to Protect the surface of organs?
To clarify how this protective crosstalk occurs, the scientists analyzed the behavior of goblet cells in the presence and absence of pain neurons.
They found that the surfaces of goblet cells contain a type of receptor called RAMP1, which ensures that the cells respond to nearby pain neurons, which are activated by nutritional and microbial signals, as well as mechanical stress, chemical irritation or drastic changes in temperature.
The experiments further showed that these receptors bind to a chemical called CGRP, which is released by nearby pain neurons, when the neurons are stimulated. The researchers found that RAMP1 receptors are also present in human and mouse goblet cells, causing them to respond to pain signals.
The experiments also showed that the presence of certain gut microbes activated the release of CGRP to maintain gut homeostasis.
"This finding tells us that these nerves arise not only from acute inflammation, but also initially," Chiu said. The mere presence of the gut microbiome appears to jostle nerves and cause goblet cells to secrete mucus.
This feedback loop ensures that microbes get sent to neurons, neurons regulate mucus, and mucus keeps gut microbes healthy, Chiu said.
The study showed that in addition to the microbial presence, dietary factors also play a role in the activation of pain receptors. When the researchers gave mice capsaicin, the main ingredient in hot peppers known to cause sharp, sharp pain, the mice's pain neurons quickly fired, causing the goblet cells to release large amounts of protective mucus.
Colitis
In contrast, mice lacking neurites or goblet cell receptors were more likely to develop colitis, a form of intestinal inflammation. This discovery could explain why people with intestinal dysbacteriosis are more likely to develop colitis.
When the researchers gave CGRP signals to animals that lacked pain neurons, the mice experienced a rapid improvement in mucus production. The treatment protects mice from colitis even in the absence of pain neurons.
The finding demonstrates that CGRP is the primary inducer 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 Dapeng Yang. postdoctoral researcher in Qiu's laboratory.
Possible downside of pain relief
The team's experiments showed that mice lacking pain receptors also had more severe lesions from colitis when it occurred.
The researchers said that since painkillers are often used to treat patients with colitis, it may be important to consider the potential adverse consequences of pain prevention.
"For people with IBD, pain is a major symptom, so you might think we want to treat and stabilize pain to alleviate suffering," Chiu said. “But part of this pain signal may be directly protective as a neural response, raising important questions about how to carefully manage pain in a way that does not lead to further harm.
Migraine medications inhibits CGRP secretion
Additionally, researchers say, a class of common migraine medications that inhibit CGRP secretion can damage gut barrier tissues by interfering with protective pain signals.
“Given that CGRP is a mediator of goblet cell function and mucus production, if we chronically block this protective mechanism in people with migraines and if they take these drugs long term, what does he pass? said Chiu. Will the drugs interfere with the mucous membrane and microbiome of humans?
Goblet cells protect the gut from pathogens
Goblet cells have several other functions in the intestine. They provide a pathway for antigens – proteins in viruses and bacteria that trigger a protective immune response by the body – and produce antimicrobial chemicals that protect the gut from pathogens.
“One of the questions 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, is to explore disruptions in the CGRP signaling pathway and whether the dysfunctions play a role in patients with a genetic predisposition to IBD.
Reference: "Pain Receptor Neurons Direct Goblet Cells Through the CGRP-RAMP1 Axis to Stimulate Mucus Production and Protect the Gut Barrier" by Daping Yang, Amanda Jacobson, Kimberly A. Merchert, Joseph Joy Sivakis, Meng Wu , Shi Chen, Tiandi Yang, Yulian Zhou, Brago Vikas Anikal, Rachel A. Rucker, Deepika Sharma, Alexandra Sontheimer Phelps, Glendon S Wu, Lewin Deng, Michael D. Anderson, Samantha Choi, Dylan Neal, Nicole Lee, Dennis L. Casper, Bana Jabri, John R. . Huh, Malin Johansson, Jay R. Thiagarajah, Samantha J. Riesenfeld and Isaac M. Chiu, 14 October 2022 Available here. cell .
DOI: 10.1016/j.cell.2022.09.024
Co-authors included Amanda Jacobson, Kimberly Merchert, Joseph Sivakis, Meng Wu, Qi Chen, Tiandi Yang, Julian Zhou, Praju Vikas Anikal, Rachel Rucker, Deepika Sharma, Alexandra Sontheimer Phelps, Glendon Wu, Lewin Deng, Michael Zhou and Michael Andersen and Dylan Neal, Nicole Lee, Dennis Kasper, Bana Gebre, John Huh, Malin Johansson, Jay Thiagarajah and Samantha Riesenfeld.
The work was supported by the National Institutes of Health (grants R01DK127257, R35GM142683, P30DK034854, and T32DK007447); Food Allergy Science Initiative; Kenneth Rainen Foundation; and Core Center for Gastroenterology Research under P30 grant DK42086 to University of Chicago .
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