Gut pain may help to maintain a healthy microbiome in mice

Neurons that transmit pain signals in the gut lining of mice are linked to the production of mucus that may maintain a healthy microbiome

By Jason Arunn Murugesu

Pain that affects the gut lining of mice may have some protective properties

Kevin Mackenzie/UNIVERSITY OF ABERDEEN/SCIENCE PHOTO LIBRARY

Neurons that transmit pain signals in the gastrointestinal lining of mice may help to maintain a healthy gut microbiome.

Isaac Chiu at Harvard University and his colleagues wanted to better understand the role that pain neurons play in the gut. “If you look for pain fibres in the gut, you usually see them close to epithelial cells [which cover the gut lining], which suggests that they can talk to each other,” says Chiu.

First, the team genetically modified mice to lack pain neurons in their gut lining.

Without these neurons, the mice had thinner layers of mucus lining their guts compared with rodents that hadn’t been genetically modified.

The modified mice also had a substantially different microbiome to their unmodified counterparts, indicating that a thicker mucus helps to maintain a healthy microbial community.

“These findings suggest that pain is quite important for keeping our mucus layer intact and also keeping our microbiome healthy,” says Chiu.

Pain that affects the gut lining may be linked to mucus production for several reasons. “Some harmful products in the GI [gastrointestinal] tract, such as salmonella or E. coli, may require immediate attention,” he says. “You may want to coat the gut with mucus to protect it or the mucus could even facilitate wound healing, though this is speculative.”

In a second part of the experiment, the researchers genetically sequenced several of the cells that were producing the mucus. They found that these goblet cells had receptors on their surface that bind to a chemical produced by neurons, specifically the neuropeptide CGRP.

“It suggests that pain fibres which make CGRP could be talking to goblet cells via this transmitter,” says Chiu.

Next, the team found that the activation of pain neurons in the mice’s gut lining led to mucus being produced by goblet cells within minutes.

In a laboratory experiment, the researchers looked at human goblet cells, finding that they also express high levels of the receptor for CGRP. “We think that human goblet cells could also respond to the same molecule from pain fibres,” says Chiu.

According to Chiu, many migraine medications block CGRP signalling. CGRP is expressed in both of the body’s nervous systems: the central nervous system, which comprises the brain and spinal cord, and the peripheral nervous system, made up of nerves that branch off from the spinal cord and extend to all other parts of the body.

“These drugs could be having a negative effect if they cause the mucus lining of the gut in people to be thinner and the microbiome in the gut to be dysregulated,” says Chiu.

The interaction between pain neurons and cells in the gut lining may be involved in the discomfort experienced by many people with ulcerative colitis, an inflammatory bowel disease, according to Chiu.

“This elegant study highlights another line of communication that has co-evolved between the intestinal microbiota and the mammalian host,” says Jon Swann at Imperial College London.

“This provides the host with a mechanism to maintain gut homeostasis and protection during intestinal inflammation and the microbes with influence over mucus secretion, a major factor in gut health.”

Journal reference: Cell, DOI: https://doi.org/10.1016/j.cell.2022.09.024