Understanding the Gut-Brain Connection

How can better understanding of the gut-brain connection drastically change our approach to healing a variety of conditions?

Ongoing research from Children’s Hospital Colorado exploring the connection between the gut and the brain gives new credence to sayings like “follow your gut” and “having a gut feeling.” This work is led by neurogastroenterologist Jaime Belkind-Gerson, MD, who has spent his entire career working to better understand this connection and the impacts of the gut microbiome within and beyond the gastrointestinal (GI) tract.

The role of microbiome diversity in gut health

Researchers have long recognized the importance of a healthy and balanced mix of bacteria in the human gut, but in recent years, they’ve begun further exploring the ways in which the gut and the brain communicate via the enteric nervous system and the immune system. The implications of this work are broad.

“We have now associated the microbiome with changes in mood, changes in appetite, changes in sleep patterns, in pain thresholds and food sensitivities,” Dr. Belkind- Gerson explains. “We’ve noted that there are changes in gastrointestinal motility and inflammation in the whole body. It’s a big deal.”

His hope is that one day, doctors will be able to examine a person’s gut microbiome and observe concerns with their microbiome diversity or abnormalities in the balance of microbial strains. With this information, he hopes to develop therapies tailored toward restoring each patient’s specific microbiome to heal a whole host of conditions, including chronic pain, inflammatory conditions, digestive disorders and even chronic depression.  

Until then, his work is focused on growing the base of knowledge related to communication between the gut and the brain. Two studies, both funded by the National Institutes of Health, further explore this connection. The first aims to characterize the gut microbiome in patients with Down syndrome who suffer from GI motility disorders, while the second focuses on mechanisms of neurogenesis within the enteric nervous system. 

Down syndrome and GI motility disorders

According to Dr. Belkind- Gerson, roughly half of people with Down syndrome develop GI motility disorders in childhood or young adulthood, and the prevalence of GI issues only increases as these patients age. Still, science has not yet been able to nail down why.

Dr. Belkind-Gerson suspects a few things may be happening, based on previous research. For example, in mice with Down syndrome, researchers found fewer neurons in the gastrointestinal tract, and some studies have shown a relationship between Down syndrome and premature development of Alzheimer’s disease.

“Neurons are kind of master regulators of how things move and feel in the gut,” Dr. Belkind- Gerson says. “There are different scientific clues that in patients with Down syndrome, the neurons may not function properly and may perhaps die prematurely, both in the brain and in the gut. We don’t know why. So, we assembled a pretty amazing multidisciplinary team to find out.”

One member of that team, Kelly Sullivan, PhD, found in a previous study that people with Down syndrome have an extra copy of a pro-inflammatory gene called interferon gamma, making them prone to hyperinflammation not just in the gut, but throughout the body. This could contribute to these patients’ gastrointestinal motility disorders.  

Dr. Belkind-Gerson and his team are now working to bring observations like these to the clinical setting to better understand exactly what’s occurring in the body.

“These are all important and interesting observations,” he says. “But it’s time to actually look and to see what’s happening to our patients. We’re hoping to put all these disciplines together to understand why patients with Down syndrome develop these problems. If it’s true to our hypothesis, then it’s due to a predisposition to gut inflammation in the GI tract. If so, how can we balance it? How can we prevent it?”

As part of this study, Dr. Belkind-Gerson and his team will study his patients’ GI motility and cognitive functioning, while infectious disease expert Dan Frank, PhD, performs microbiome analyses of each patient’s stool and Dr. Sullivan carries out RNA-sequencing and metabolomics studies to better understand the associations behind these clinical issues. Over five years, this multidisciplinary team hopes to not only learn more about GI disorders in patients with Down syndrome, but also better understand the connections between GI motility and neurodevelopmental conditions more broadly.

Uncovering the secrets of gut neurogenesis

It used to be common medical knowledge that each person was born with a certain number of neurons, and once they were gone, they couldn’t be regenerated. Over the years, researchers have discovered that this is not true. Instead, investigators found that within specific areas of the brain there is daily neurogenesis, even in adulthood. They found this by using a fluorescent-marked thymidine molecule that allowed scientists to visually see cells replicating in the brain.

Given that there are neurons in the GI tract, and that we see the gut grow as babies age, Dr. Belkind-Gerson has long suspected that neurogenesis happens in the gut as well.

But when gastroenterologists attempted to use the same approach that found neurogenesis in the brain, nothing happened. That’s because neurogenesis in the gut happens a little bit differently.

“It seems like neurogenesis does occur postnatally in the gut,” Dr. Belkind-Gerson says, “but it doesn’t happen without an injury. Something needs to happen, and then it gets triggered.”

Previous research discovered that this form of neurogenesis happens thanks to various types of glial cells, which traditionally support neurons in the gut. Dr. Belkind-Gerson’s team found that these glial cells can actually become neurons in the event of injury, through the process of transdifferentiation. Still, researchers don’t know how this happens, how robust it is or what exactly triggers the process to begin. And to make matters more complicated, researchers in Japan recently found a new method of neurogenesis in the gut, whereby a type of glial cell that lives outside the gut — Schwann cells — can be recruited to the gut and revert to a precursor cell that then becomes a neuron.

Dr. Belkind-Gerson’s second NIH-funded study aims to understand this type of neurogenesis better. The study will use marked Schwann cells and mice with various types of gut injury (e.g., colitis, inflammation and microbacterial perturbations) to attempt to watch and characterize neurogenesis in action. They will then perform GI motility studies to see whether newly made neurons can restore full function to the gut or not.

Dr. Belkind-Gerson says that he’s hopeful this research will not only make a practical difference in people’s lives, but also help physicians and scientists continue to grow their understanding of the gut-brain connection. This, he says, could unlock entirely new avenues of treatment for some of our most puzzling conditions.