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A "second brain" of nervous system cells, including glia (stained green in this cross section of a mouse esophagus), coordinates the movement and digestion of food
as it
moves through your body. in your enteric nervous system are underappreciated glial cells, which play key roles in digestion and disease that scientists are only just starting to understand...
And it does all this while moving the partially processed food one way through different factories of digestion,
Breaking down food requires coordination across dozens of cell types and many tissues - from muscle cells and immune cells to blood and lymphatic vessels.
Heading this effort is the gut's very own network of nerve cells, known as the enteric nervous system, which weaves through the intestinal walls from the esophagus down to the rectum.
This network can function nearly independently from the brain:
And just like the brain, it's made up of two kinds of nervous system cells:
Glia, once thought to be mere glue that fills the space between neurons, were largely ignored in the brain for much of the 20th century.
'Clearly,' neurons were the cells that made things happen...:
But in the last few decades, glia have shed their identity as passive servants.
Neuroscientists have increasingly discovered that glia play physiological roles in the brain and nervous system that once seemed reserved for neurons.
A similar glial reckoning is now happening in the gut.
A number of studies have pointed to the varied active roles that enteric glia play in digestion, nutrient absorption, blood flow and immune responses.
Others reveal the diversity of glial cells that exist in the gut, and how each type may fine-tune the system in previously unknown ways.
One recent study, not yet peer-reviewed, has identified a new subset of glial cells that senses food as it moves through the digestive tract, signaling to the gut tissue to contract and move it along its way.
To pursue her research documenting the variety of enteric glia, Marissa Scavuzzo of Case Western Reserve University had to develop new methods to work
in the gut's harsh, acidic environment.
They're,
They're now being linked to specific gastrointestinal disorders and pain symptoms.
Understanding the different roles they play in the gut could be critical for developing treatments, Scavuzzo said.
Glia Do Everything
Scientists have known about enteric glia for over a century, but until recently no one had tools for studying them.
Researchers could examine neurons by picking up the action potentials they fire. But compared to neurons, glial cells are electrophysiologically "boring," said Brian Gulbransen, an associate professor of neuroscience at Michigan State University.
Aside from a few reports that pointed to their roles in maintaining healthy gut tissue, they remained under-studied and underappreciated.
That changed over the last decade or so.
New tools that allow scientists to manipulate gene activity in glia or visualize them in different ways have,
For example,
Cellular staining reveals the diversity of cells in the digestive tract. Protective epithelial tissue (stained white) forms the distinct shapes of the wall of the small intestine (left) and mouse esophagus (right). Glial cells (stained red and green) innervate muscle tissue
and
help coordinate the movement of food through the gut.
Thanks to some of these newer technologies, scientists now know that enteric glia are among the first responders to,
They help maintain the gut's barrier to keep toxins out.
Glia regulate stem cells in the gut's outer layer, and are critical for tissue regeneration.
They chat with the microbiome, neurons and immune-system cells, managing and coordinating their functions.
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,
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.
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 acidic 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:
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:
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.
It's possible that each involved cell type could regulate a different type of contraction, she suggested,
There are likely many fail-safes in digestion because it's such an important process, she added.
Brian Gulbransen of Michigan State University has published new work showing how glia can contribute to gut pain, suggesting possible new treatments
for gut disorders.
The experiment offered clear evidence that, in addition to other cells,
Then, having sensed the change in force, they can shift the activity of neural circuits to trigger muscular contractions.
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.
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