New Study Looks At How Gut Disorders Are Possibly Influenced By Our ‘Second Brain’


In a new study, scientists are looking into glial cells and how they function when it comes to the gut. Glial cells, which are described by Wikipedia as ‘non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses.’

They help fine-tune the communication of the neurons within the brain, while also playing a key role when it comes to specific brain circuits. Much like the role of the enteric nervous system, they work to regulate the way food travels through the gut.

Scientists were unsure about whether the glial cells belonged to particular circuits in the enteric nervous system of the gut, or if they had an overall general role. In the new study, they found that glial cells do actually belong to distinct circuits that help interact with specific neurons to create a precise functional result.

These results could eventually help generate treatments for such conditions like irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), gut issues that affect hundreds of thousands of people in America alone.

There are two primary cell types in the nervous system, the neurons and glia cells. The neurons use electrical or chemical signals to transmit messages, while scientists believed the glial cells were just there to provide support and protection.

But recent evidence has revealed that glial cells actually have the ability to directly communicate with neurons, while influencing or regulating the important transmission of signals that goes on between neurons.

Meanwhile, other studies have shown the way that glial cells play a key role in brain circuits as they aid in the ‘interacting with certain types of neurons to modulate the transmission of specific information.’

Lead author of the recent study, Dr. Brian Gulbransen, who happens to be a professor at Michigan State University in East Lansing, shares with MSU Today about the role of glial cells by using the ‘analogy of notes produced by an electric guitar.’

He said, “[G]lia aren’t carrying the notes played on an electric guitar; they’re the pedals and amplifiers modulating the tone and volume of those notes.”

The enteric nervous system is the local nervous system of the digestive system, and it has around the same amount of neurons as the spinal cord. This is precisely why scientists sometimes refer to this as the “second brain.”

Incredibly, the enteric nervous system still has the ability to control gut motility in the event that the nerve connections with the brain and spinal cord are severed for one reason or another. Scientists understand that the glial cells in the enteric nervous system also vigorously communicate with neurons and affect the gut function.

Nevertheless, scientists were still unclear if the enteric glial cells were part of the integral network. Meaning, they weren’t sure if these glial cells in the enteric nervous system worked specifically with particular neurons to create a response to certain stimuli or if they just create particular outputs.

Published in the journal Proceedings of the National Academy of Sciences, what the new study discovered is that the glial cells found in the enteric nervous system do belong to particular networks.

Lead author Dr. Gulbransen explained of the results, “The main finding of this study is that there are distinct subsets of enteric glia that ‘listen’ to specific neural pathways and that these subsets of glia play specialized roles in modifying those, and the surrounding pathways.”

He also shared that this was an interesting outcome “because it highlights a new mechanism whereby neural circuits in the gut are ‘tuned’ by enteric glia. […] This finding highlights a new layer of complexity in how enteric neurocircuits work, and this is important in understanding how gut motility is controlled.”

The scientists also explain how being able to understand gut motility is truly important because of the way these motility changes play a part in certain conditions such as IBD, IBS, and gastroesophageal reflux disorder.


Enteric Nervous System and Peristalsis

Peristalsis is a process where food is pushed through the digestive system that requires ‘involuntary contradictions of the smooth muscle wall of the digestive tract.’ During this process, the gut segment that’s directly above the swallowed food contracts, while the muscles in the are below the food relax. This is what makes the food go through the digestive tract.

There are three enteric nervous system pathways that control peristalsis, which is the ascending, the descending, and the circumferential.

When the food passes through the system, the gut’s circular muscles stretch, which causes the pathways to activate. The contraction of the segment above the food activates the ascending pathway, while the relaxing of the gut segment below the food activates the descending pathway.

The ascending pathway is said to consists of ‘excitatory neurons that mostly release the neurotransmitter acetylcholine. Neurons in the descending pathway generally release nitric oxide or purines to communicate with other neurons. The circumferential pathway consists of neurons that encircle the wall of the digestive tract and relays changes in the smooth muscle wall to neurons in the ascending and descending pathways.’


Giving a Selective Response

For the new study, the research team took tissue that was dissected from the gastrointestinal (GI) tract of female and male mice to better understand the way the enteric nervous system cells managed to work together in a network.

What they first figured out was if some glial cells responded selectively to the activation of the three major pathways of the enteric nervous system. What they found was that the glial cells managed to individually stimulate the ascending, descending, and circumferential pathways, while also measuring the glia activation in response to each pathway’s stimulation.

What the scientists found was that ‘a majority of glia responded upon the activation of all three pathways.’ This showed a significant response of more than 10% of glia selectively responding to the stimulation of just the ascending pathway at 13% or the descending pathway at 12%.

What these results mean is that there are subpopulations of glial cells that belong particularly to either the ascending pathway or to the descending pathway.

The study authors also happened to observe similar outcomes with the neuron response to the stimulation of the ascending and descending pathways.

Notably, they also mention that the amount of responses of glial cells in the ascending and descending pathways in female mice was higher than that of the male mice.


How About the Response of Glial Cells to Neurotransmitters?

As shared in Medical News Today (MNT), one of the neurotransmitters that neurons use in the descending pathway in order to communicate with each other are called purines. On the other hand, ‘acetylcholine is mostly released by neurons to communicate with other neurons in the excitatory ascending pathway.’

To take a closer look at whether the neurotransmitters generate a particular response in glial cells, the scientists used inhibitors for purine and acetylcholine receptors. What these inhibitors did was selectively block the response of neurotransmitters on glia, but they didn’t impact the signaling going on between neurons.

According to the research team, they discovered that the stimulation of the ascending or descending pathways when in the presence of any of the neurotransmitter inhibitors mobilized a particular population of the glia and neurons, as compared to those in the untreated control group.

What the researchers saw was that ‘the glial purine receptor blocker increased the proportion of neurons solely activated upon stimulation of the descending pathway while reducing the proportion of neurons activated by both pathways.’

Moreover, with the stimulation of both the ascending and descending pathways, the acetylcholine receptor blocker increased the proportion of glia.

When scientists blocked the action of the neurotransmitters on the glial cells, it also influenced the activity in the pathways. Further explained in MNT, ‘the purine receptor blocker reduced the activation of the ascending pathway but not the descending pathway. By contrast, the acetylcholine receptor blocker increased neuronal response in the descending pathway but not in the ascending pathway.’

What these experiments showed that when neurons release purines and acetylcholine, the glial cells respond, which results in a change in neuron population and glia cells that are associated with each pathway, which then modulates the activity of each of the pathways.


Glial Cells Effects On Neurons

The research team also looked into the role of glial cells when it comes to regulating particular motor pathways using a technique called chemogenetics.

Chemogenetics is a technique where selective activation or inhibition is allowed in a specific subset of cells like glial cells, using an engineered protein created in a lab.

The study authors used this technique to selectively activate the glial cells, where the activation inhibited  the ascending and descending pathways, was where they saw how the glial cells influenced downstream neurons.

In addition, the stimulation of these glial cells also lessened the neuron response in both the ascending and descending pathways in female mice, but interestingly, only the descending pathway in male mice.

The previous experiment’s results that only used glial receptor blockers and the use of the same blockers with the chemogenetic technique helped ‘the researchers elucidate how neurotransmitters activated glial cells to modulate the response of neurons in the ascending and descending pathways.’

According to the study authors, ‘These experiments showed that the activation of glial cells by acetylcholine played an important role in inhibiting the descending pathway. However, glial cells activated by acetylcholine also seemed to inhibit the ascending pathway to a certain extent.’

In addition, the purine neurotransmitter-induced activation of glial cells happened to stimulate the ascending excitatory pathway.

The end results of these experiments happened to show that ‘the release of purines and acetylcholine activate glial cells to result in the recruitment of neurons to either the ascending or descending pathway, leading to specific changes in gut motility.’

Professor at the University of Calgary in Canada, Dr. Keith Sharkey, who was not part of the study shared with MNT that these results explain that “the neural networks of the enteric nervous system that control all gut function are very finely regulated in a directional and sex-specific manner by enteric glial cells.”


Other Implications Of the Study

As for Professor at Flinders University in Australia, Dr. Nick Spencer, who was also not involved with the study, told MNT that the study shows that “enteric cells actually interact with certain types of enteric neurons in a highly specific and network-specific manner. Until now, it had remained mysterious whether enteric glia communicate in any ordered pattern with the known, highly polarized ascending excitatory and descending inhibitory enteric neural pathways in the gut wall.”

He added, “These findings open the way for a new level of scientific enquiry in glial cell neurobiology in the [GI] tract.”

As for Dr. Sharkey, he shared that the study findings “allow for a completely new understanding of gut dysmotility, which are common and highly debilitating disorders of gut function, such as [IBS], to be reframed as diseases of neural network connections — that is, conditions in which network-level [perturbations] drive disease and the symptoms experienced by patients.”

“These findings will therefore allow for the development of better diagnostics and treatment, as well as novel therapies, etc. This work will allow for more personalized approaches to treatment as well — as opposed to the one-size-fits-all model that is common in much of medicine,” he added.

He also said, “Moreover, by showing that the glial control is sex-specific, these authors help us understand why so many [GI] diseases occur in a sex-specific manner. And beyond these more practical implications, the work also has a lot of biological and physiological implications for understanding neural control mechanisms.”

Dr. Gulbransen added that when it comes to the direction of future research, “We have ongoing studies that are addressing how glia and enteric motor neurocircuits are affected following inflammation. This is important, since neuroplasticity following acute inflammation is thought to produce [GI] dysmotility in common diseases, such as [IBS] and [IBD].”

He continued,“The hope is that by understanding how the glial control over motor neurocircuits is changed during inflammation, we will identify ways in which this mechanism can be harnessed to improve gut motility.”