The experiment offered clear evidence that, in addition to other cells, “glial cells can also sense physical forces” through this mechanosensory channel, said Vassilis Pachnis, the head of the nervous system development and homeostasis laboratory at the Francis Crick Institute. Then, having sensed the change in force, they can shift the activity of neural circuits to trigger muscular contractions. “It’s a wonderful piece of work,” he said.

Hub cells are only one of many glial subtypes that play functional roles in the gut. Scavuzzo’s new six subtypes, added to those characterized in previous research, together reveal 14 known subgroups of glia across the duodenum, ileum and colon. More are likely to be discovered in coming years, each with new potential to better explain how digestion works and enable researchers to develop treatments for a variety of gastrointestinal disorders.

A Pain in the Gut

Gastrointestinal diseases often come with a dose of pain, in addition to disruptive digestive issues. Eating the wrong food, or too much of the right one, can cause a stomachache. Those gut feelings are driven by enteric nerve cells, including glia. Because glia are now known to control the activity of immune cells, they are suspected to play a role in many gastrointestinal disorders and diseases, making them good potential targets for treatments.

Several years ago, Pachnis and his group found that glia are among the first cell types to respond to injury or inflammation in the mouse gut, and that tampering with enteric glial cells can also create an inflammatory response. In the gut glia seem to perform roles similar to those of true immune cells, Pachnis said, and so their dysfunction can lead to chronic autoimmune disorders and inflammatory bowel diseases, such as ulcerative colitis and Crohn’s disease. “Glial cells definitely play a role in the initiation, the pathogenesis and the progression of the various diseases of the gut,” he said.

Glia are likely involved because of their central role in communicating between the microbiome, immune cells and other gut cells. Healthy glia strengthen the intestines’ epithelial barrier, a layer of cells that keeps out toxins and pathogens and absorbs nutrients. But in patients with Crohn’s disease, glial cells don’t function properly, resulting in a weaker barrier and inappropriate immune response.

“Different subtypes of glia can be functioning differently or dysfunctioning in a wide range of diseases and disorders where motility is impacted,” Scavuzzo said. They have also been linked to neural inflammation, hypersensitivity in the organs and even neuron death.

For instance, Gulbransen and his team recently discovered that glia contribute to gut pain by secreting molecules that sensitize neurons. This is likely an adaptive response intended to draw the gut’s attention to damaging substances to dispose of them, Gulbransen said, which as a side effect causes pain.

The findings, published today in Science Signaling, suggest that targeting glia could help alleviate some of the pain created by inflammatory disorders of the gut.

Glia themselves can also become stressed by genetic problems, exposure to metabolites from the microbiome, bad diet or other factors. Fattahi has observed that, no matter the cause, stressed enteric glia influence the entire tissue, and sometimes even damage neighboring neurons or recruit immune cells, causing additional inflammation and pain.

These new studies in enteric glia will go a long way toward explaining many gastrointestinal disorders that researchers have struggled to understand and treat, Sharkey said. “I’m really excited to see how these cells have evolved to become central figures in enteric neurobiology over the years.”

It’s becoming ever clearer that the neuron doesn’t act alone in the enteric system, he added. “It’s got these beautiful partners in glia that really allow it to do its thing in the most efficient and effective way.”

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