Maintaining a healthy intestine is a complex process. Repairing tissue after infection or other types of injury depend on the integrated activity of multiple cell types. While research in this area has focused on the activity of different immune cells, mysteries about the mechanisms behind inflammatory bowel diseases, such as Crohn’s disease and colitis, remain.

Now, researchers at the Francis Crick Institute in London have uncovered a fundamental role of glial cells in the nervous system of the gut in maintaining a healthy intestine. These cells have been found to coordinate the immune responses of the gut following pathogen invasion and could be key targets when exploring new treatments for inflammatory bowel conditions.

This work is published in Nature in the paper, “Regulation of intestinal immunity and tissue repair by enteric glia.

“Sadly, currently treatments for inflammatory bowel disease are often limited to alleviating the symptoms, rather than tackling the cause,” said Fränze Progatzky, PhD, first author and postdoctoral scientist in the lab of Vassilis Pachnis, MD, PhD, group leader at the Francis Crick Institute. “Our insights into the importance of enteric glial cells in maintaining a healthy intestine open the door to further studies into how these cells work and interact with the immune system and in the future could help us develop potential new treatments for these conditions.”

Researchers studied the role of enteric glial cells in response to tissue damage. These cells lie within the gut wall and form part of the enteric nervous system which governs the contractions of intestinal muscles and other aspects of digestive function.

They infected mice with a common roundworm parasite, Heligmosomoides polygyrus, and found that when the parasite invades the gut wall, it leads to an upregulation of an interferon gamma (IFNγ) gene signature. Although IFNγ was thought to target immune cells, these findings show that one of its first targets are nearby glial cells. IFNγ activates these cells which then release signals that attract other immune cells to the site of damage to fight the infection.

To identify if similar mechanisms occur in humans, the researchers analyzed data previously collected by others of colon samples from people with ulcerative colitis, a long-term condition where the colon and rectum become inflamed, and which causes severe diarrhea and stomach cramps. Similar to the mouse cells, IFNγ-dependent gene modules were also induced in enteric glial cells from patients with inflammatory bowel disease, suggesting that glial cells in the human gut are also implicated in inflammatory conditions of this organ.

The team also studied the role of glial cells in maintaining healthy intestinal gut tissues, in the absence of infection. To do this, they blocked the ability of enteric glial cells to be activated by interferon gamma and found that this led to tissue inflammation even in normal mice. This shows the cells are also important outside of disease or injury, in maintaining healthy intestinal tissue.

The authors noted that single-cell transcriptomics analysis of the tunica muscularis showed that, “glia-specific abrogation of IFNγ signaling leads to tissue-wide activation of pro-inflammatory transcriptional programs. Furthermore, disruption of the IFNγ–EGC signaling axis enhanced the inflammatory and granulomatous response of the tunica muscularis to helminths.”

“Glial cells are present in many organs,” said Pachnis, “so it’s possible they also play similar roles in maintaining healthy tissue and mounting appropriate responses to pathogens or toxins in other parts of the body. It will be exciting to explore this possibility further.”

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