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Signals between nervous system and intestinal cells control protective mucus layer production in gut

New research in mice has discovered connections between the nerve cells of the gastrointestinal tract and mucus production in the gut, pointing to a role for these nerves in protecting the intestinal lining from damage and inflammation. Inflammation in the gut (e.g., colitis) can cause abdominal pain, a hallmark of many gastrointestinal diseases and disorders. Pain-sensing nerve cells—called nociceptors—envelop the gut, however their interactions with the cells of the gut itself are not fully understood. By better understanding the “cross-talk” between these cells, researchers could find new ways to help resolve the inflammation or to protect the intestines from further damage. It could also help scientists understand and treat painful gastrointestinal conditions like inflammatory bowel disease.

Researchers working with a mouse model recently found that nociceptors come into close contact with goblet cells—cup-shaped cells in the intestinal lining that secrete mucus to coat the inside of the gut—suggesting that signals from nociceptors might control mucus production. The mucus layer provides nutrients and a habitat for bacteria that aid digestion. It also creates an important physical barrier to protect the gut from those bacteria, so mucus production is critical for both preventing intestinal damage and maintaining a healthy microbiome. The researchers found that male and female mice that were genetically engineered to lack nociceptors had thinner mucus layers on their intestinal linings compared to mice with an intact intestinal nervous system, demonstrating that nociceptors do indeed control mucus production. The researchers also found that capsaicin (the “spicy” chemical in peppers) or products from gut bacteria triggered the release of a chemical signal called calcitonin gene-related peptide (CGRP) from nociceptors, and the goblet cells responded to this signal by secreting mucus. This means that when the gut is exposed to potentially damaging agents—either from the diet or bacteria—nociceptors can bolster the gut’s defenses by stimulating more mucus production. Not surprisingly, the mice with thinner mucus layers also had disrupted microbiomes and were more susceptible to experimentally induced intestinal inflammation (colitis), but the mice were protected from inflammation when the researchers administered CGRP to compensate for the lack of nociceptors.

These results identify a pathway whereby nociceptors can sense insults to the gut and respond not only with pain, but also with a signal to help protect the gut. More work is needed to confirm that a similar pathway exists in humans, but these insights could help researchers develop new ways to treat intestinal inflammation and abdominal pain while minimizing disruptions to the intestinal barrier.

Yang D, Jacobson A, Meerschaert KA,…Chiu IM. Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier protection. Cell 185: 4190-4205, 2022.

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