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Researchers Pain Surprising Protective Effects

Researchers from Harvard Medical School have examined the molecular interactions between gut pain fibres and the goblet cells that coat the intestine's walls. The research demonstrates that goblet cells release protective mucus that covers the gut and protects it from harm in response to chemical signals from pain neurons. The results demonstrate that intestinal pain performs a direct protective role in the gut and is not only a detection-and-signaling mechanism. Chiu Lab/Harvard Medical School is to blame.

What if pain is more than just an ailment signal?

New studies in mice shed light on how pain neurons protect the gut.

One of evolution's most useful methods for identifying damage and alerting us to a problem is pain. It serves as a warning mechanism, informing us to pause and pay attention to our body.

Image 2021 Goblet Cells : Simple columnar epithelial cells known as goblet cells release mucins that create gels, such as mucin MUC5AC. The goblet cells typically secrete vesicles into a duct using the merocrine mechanism, but under stress they may switch to the apocrine method of budding off their secretions.

However, what if pain is more than just an alarm? What if suffering itself serves as a type of defence?

According to a recent study done by Harvard Medical School scientists, mice may very well exhibit this behaviour.

The unexpected findings show that pain neurons in the mouse gut control the amount of protective mucus under normal circumstances and trigger intestinal cells to release more mucus during inflammatory states. On October 14, the work appeared in the journal Cell.

The study outlines the processes of an intricate communication cascade and shows that goblet cells, which are gut cells that produce mucus, and pain neurons directly interact.

"It seems that pain might protect us more directly than only by carrying out its typical role of spotting possible hazards and alerting the brain. Senior research scientist Isaac Chiu claims that "Our work illustrates the interaction between the stomach's pain-mediating nerves and the epithelial cells that line the intestines next door. This suggests that the nervous system, in addition to only giving us a bad feeling, also plays a crucial role in maintaining the intestinal barrier and acting as a protective mechanism during inflammation. Chiu is an associate professor at the HMS Blavatnik Institute where she teaches immunobiology.

Direct communication

Our airways and intestines are covered in goblet cells. Goblet cells, so named because of their cup-like shape, contain a mucus-like gel comprised of proteins and sugars that serves as a protective covering to protect the surface of organs from friction and damage. The most recent study discovered that intestinal goblet cells secrete protective mucus in response to direct contact with pain-sensing gut neurons.

In a series of tests, the researchers discovered that mice without pain neurons produced less protective mucus and underwent changes in the composition of the bacteria in their intestines, a condition known as dysbiosis, which is an imbalance of helpful and harmful germs.

The researchers studied how goblet cells behaved in the presence and absence of pain neurons to better understand how this protective crosstalk functions.

They discovered that goblet cells have a specific receptor, known as RAMP1, on their surfaces that enables the cells to react to nearby pain neurons that are activated by food and microbial cues, as well as mechanical pressure, chemical irritation, or significant changes in temperature.

Further research revealed that when neighbouring pain neurons are triggered, these receptors make a connection with a substance called CGRP. The researchers discovered that these RAMP1 receptors are also present in mouse and human goblet cells, making them sensitive to pain signals.

Further research revealed that the presence of specific gut microorganisms triggered the production of CGRP in order to preserve gut homeostasis.

This finding demonstrates that these nerves are activated not only in response to acute inflammation but also on a chronic basis, according to Chiu. The mere presence of common gut microorganisms seems to irritate the nerves and trigger the release of mucus from the goblet cells.

According to Chiu, this feedback loop guarantees that microorganisms communicate with neurons, neurons control mucus production, and mucus maintains the health of gut microbes.

The study found that dietary factors, in addition to the presence of microbes, also contributed to the activation of pain receptors. Capsaicin, the primary component of chilli peppers recognised for its propensity to cause strong, acute pain, was administered to mice by researchers. This quickly triggered the mouse's pain neurons, forcing goblet cells to secrete copious amounts of protective mucus.

On the other hand, animals lacking either pain neurons or CGRP goblet cell receptors were more prone to colitis, a kind of gut inflammation. The discovery may help to explain why colitis may be more common in those with gut dysbiosis.

Animals lacking pain neurons were given the pain-signaling CGRP, and the mice's mucus production increased quickly. Even in the absence of pain neurons, the therapy prevented mice from developing colitis.

The results show that CGRP is a critical initiator of the signalling chain that results in the release of protective mucus.

According to Daping Yang, a postdoctoral researcher at the Chiu Lab and the study's first author, "our work demonstrates that acute pain serves a direct protective effect as well." Pain is a typical sign of long-term inflammatory gastrointestinal illnesses like colitis.

A potential drawback of pain suppression

The research team's findings revealed that mice lacking pain receptors also experienced severe colitis damage.

Given that painkillers are frequently prescribed to patients with colitis, it may be crucial to take into account any negative effects that may result from inhibiting pain, the researchers stated.

Discomfort is a common indication of gut inflammation, so it seems sense that treating and blocking pain would help patients feel better, according to Chiu. However, a portion of this pain signal may actually be directly protective as a neuronal reaction, raising significant concerns about how to carefully control pain in a way that does not result in additional damages.

The researchers added that a class of widely used migraine drugs that inhibit CGRP release may harm gut barrier tissues by interfering with this protective pain signalling.

In the intestines, goblet cells serve a variety of additional purposes. They allow the passage of antigens, which are proteins on viruses and bacteria that cause the body's immune system to mount a defence. They also create antimicrobial compounds that shield the gut from pathogens.

If pain fibres also control these other goblet cell functions is an issue that comes up in our current research, Yang said.

Yang continued, "Exploring anomalies in the CGRP signalling system and determining if malfunctions are at play in patients with hereditary propensity to inflammatory bowel disease would be another area of inquiry."

Citation: Meng Wu, Xi Chen, Tiandi Yang, Youlian Zhou, Praju Vikas Anekal, Rachel A. Rucker, Deepika Sharma, Alexandra Sontheimer-Phelps, Daping Yang, Amanda Jacobson, Kimberly A. Meerschaert, Joseph Joy Sifakis, Goblet cells are controlled by nociceptor neurons through a CGRP-RAMP1 axis to produce mucus and preserve the intestinal barrier.

Along with Samantha Riesenfeld, co-authors of the paper included Amanda Jacobson, Kimberly Meerschaert, Joseph Sifakis, Meng Wu, Xi Chen, Tiandi Yang, Youlian Zhou, Praju Vikas Anekal, Rachel Rucker, Deepika Sharma.

The Food Allergy Science Initiative, the Kenneth Rainin Foundation, the National Institutes of Health (grants R01DK127257, R35GM142683, P30DK034854, and T32DK007447), the University of Chicago's Digestive Diseases Research Core Center under grant P30 DK42086, and the Food Allergy Science Initiative all provided funding for this research.