Pain-Sensing Neurons Can Protect the Gut From Damage

A new study from Harvard Medical School has shown that pain neurons in mice can shield the gut from damage by stimulating nearby cells to produce protective mucus. The research is published in Cell.

The gut–brain connection

Pain is an alarm bell that keeps us safe and teaches us to avoid situations that could hurt us. But could pain itself activate biological processes within our bodies to protect us?

One of our most important protective mechanisms is the gut barrier. It is made up of tight junctions joining cells together and a layer of mucus secreted by goblet cells and is the first line of defense in protecting the contents of the gut from reaching the underlying tissue. Defects in mucus production can impair the gut barrier and even lead to inflammatory bowel diseases like colitis.

We know that the gut and the brain communicate well with each other – scientists have called this the “gut–brain axis”. Pain-sensing neurons called nociceptors relay signals to the brain and spinal cord to tell us when they detect harmful stimuli – for example, when we eat capsaicin (the spicy compound in chili peppers) or experience mechanical stretch.

However, signaling mechanisms between sensory neurons and other cells in the gut aren’t as well understood. We know that nociceptors signal to neighboring immune or vascular cells by releasing calcitonin gene-related peptide (CGRP), which binds to a receptor made of proteins called Ramp1 and Calcrl. To address whether these pain-sensing neurons could activate protective processes and act not just as an alarm bell, researchers in the current study investigated if nociceptors can crosstalk with other cells in the gut to protect the gut barrier.

The protective properties of pain

The researchers showed that nociceptors and mucus-producing goblet cells are found in proximity in the colon, allowing them to interact with each other.

Goblet cells and pain-sensing neurons in close proximity in the gut.
Credit: Chiu Lab/Harvard Medical School

Mice genetically engineered to lack nociceptors produced less mucus and had an imbalance in their gut bacteria called dysbiosis. These mice were also more susceptible to colitis, an inflammatory bowel disease.

To investigate how nociceptors influence mucus production, the researchers examined the genes expressed by mucus-producing goblet cells, finding they expressed high levels of the genes that code for Ramp1 and Calcrl proteins. Therefore, when nociceptors sense pain, the CGRP produced in response can bind to the neighboring goblet cells, causing them to rapidly increase their mucus production. This maintains the gut barrier and keeps the microbes in the gut healthy.

Experiments also showed that microbes that make up the gut microbiome activated CGRP release from nociceptors under normal conditions, showing that these signals are key to maintaining a baseline level of mucus production and protection of the gut barrier.  

“[We used] different molecular genetic approaches to target pain fibers and their signaling to goblet cells to see how they regulate mucus production in mice. We found that if we chemically activate the neurons using chemogenetic approaches, there is an immediate rapid increase in mucus. Conversely, if we remove the pain fibers from the gut, there is a decreased amount of mucus,” summarized Dr. Isaac Chiu, associate professor of immunobiology at Harvard Medical School and senior author of the study.

CGRP is the key player in this protective mechanism. When the researchers supplemented mice lacking nociceptors with CGRP, they produced much more mucus than before which also protected them against colitis.

Together, this shows the nervous system protects us not only by making us experience unpleasant sensations to change our behavior, but also initiates protective mechanisms to directly protect our gut against inflammation.

Discussing the implications of the study’s findings, Chiu explained: “There are currently many people who take treatments that block CGRP or its signaling to RAMP1 for prevention of migraine. It is already known this can lead to constipation in people. I worry that this could also cause gut microbiome changes and increased risk for inflammatory bowel disease.”

He continues, “Some important next steps include defining whether the same neuron-goblet cell axis is relevant in other mucus-coated tissues like the lungs and defining how pain neurons change in the gut in different diseases such as inflammatory bowel disease, irritable bowel syndrome, celiac disease and food allergies.”

Dr. Isaac Chiu was speaking to Sarah Whelan, Science Writer for Technology Networks.

Reference: Yang D, Jacobson A, Meerschaert KA, et al. Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier protection. Cell. 2022. doi :10.1016/j.cell.2022.09.024