“We think that they do everything,” Gulbransen said. “The more that people find out about them, it’s less surprising that they do these diverse roles.”

They can also move between roles. They’ve been shown to change their identities, shifting from one glial cell type to another, in lab dishes—a useful ability in the ever-changing gut environment. They’re “so dynamic, endowed with the functional capacity to do so many different things, sitting in this incredibly fluctuating and complex environment,” Scavuzzo said.

Even as excitement builds about glia in the enteric nervous system, scientists like Scavuzzo have fairly basic questions still to work out—such as how many types of enteric glia even exist.

A Force to Reckon With

Scavuzzo became fascinated with digestion in childhood when she witnessed her mother’s medical troubles due to a congenitally shortened esophagus. Watching her mother go through gastrointestinal complications compelled Scavuzzo to study the gut in adulthood to find treatments for patients like her mom. “I grew up knowing and understanding this stuff is important,” she said. “The more we know, we can intervene better.”

In 2019, when Scavuzzo started her postdoctoral research at Case Western under Paul Tesar, a world expert in glial biology, she knew she wanted to unravel the diversity of enteric glia. As the only scientist in Tesar’s lab examining the gut and not the brain, she often joked with her colleagues that she was studying the more complex organ.

The first year, she struggled massively in trying to map out the individual cells in the gut, which proved to be a harsh research environment. The very start of the small intestine, the duodenum, where she focused her studies, was especially tough. The bile and digestive juices of the duodenum degraded RNA, the genetic material that held clues to the cells’ identities, making it nearly impossible to extract. Over the next few years, however, she developed new methods to work on the delicate system.

Those methods allowed her to get the “first glimpse into the diversity of these glial cells” across all tissues of the duodenum, Scavuzzo said. In June, in a paper published on the Biorxiv.org preprint server that has not yet been peer-reviewed, she reported her team’s discovery of six subtypes of glial cells, including one that they named “hub cells.”

Hub cells express genes for a mechanosensory channel called PIEZO2—a membrane protein that can sense force and is typically found in tissues that respond to physical touch. Other researchers recently found PIEZO2 present in some gut neurons; the channel allows neurons to sense food in the intestines and move it along. Scavuzzo hypothesized that glial hub cells can also sense force and instruct other gut cells to contract. She found evidence that these hub cells existed not only in the duodenum, but also in the ileum and colon, which suggests they’re likely regulating motility throughout the digestive tract.

She deleted PIEZO2 from enteric glia hub cells in mice, which she thought would make the cells lose the ability to sense force. She was right: Gut motility slowed, and food contents built up in the stomach. But the effect was subtle, which reflects the fact that other cells are also playing a role in physically moving partially digested food through the intestine, Scavuzzo said.