Research by Milena Bogunovic, MD, PhD, associate professor of pathology, sheds light on how inflammation in the gastrointestinal (GI) tract, such as that associated with inflammatory bowel disease (IBD), can lead to long lasting consequences for patients who end up developing functional motility disorders like irritable bowel syndrome (IBS).
Published in the Journal of Experimental Medicine , the study revealed that intestinal inflammation changes how nerves are arranged in the intestine, which in turn affects how intestinal muscles contract. According to the research, this happens because intestinal (enteric) neurons get activated by inflammation and signal to immune cells known as monocytes. Monocytes then spill over into the enteric nervous system (ENS) where they develop into more specialized cells known as macrophages that typically help with repair but cause extensive remodeling and dysfunction when there are too many of them.
"We show that it's this abnormal reorganization that leads to the dysregulation and uncoordinated contractions of the intestinal muscles." said Dr. Bogunovic. "This abnormal structure resulted in the ENS not being able to properly control the surrounding muscles and contributed to symptoms like those experienced in some patients with IBD in remission."
Further research found that intensifying inflammation exposes neurons to low oxygen levels (hypoxia). In response, neurons turn on a stress response pathway that helps them survive, by suppressing the attraction of monocytes and preserving their normal organization. If this protective response is triggered early in the disease state, it could offer a promising way to curtail the development of persistent GI symptoms associated with IBD.
The ENS is a vast, semi-autonomous network of more than 100 million neurons embedded in the gut wall, stretching from the esophagus to the rectum. Often called the "second brain," it operates independently of the central nervous system to control certain autonomic functions such as digestion, nutrient absorption, peristalsis and immune response.
While great strides have been made in treating active IBD, many patients continue to experience symptoms even after inflammation has resolved itself. Why symptoms persist after remission and how to treat them remain poorly understood, however.
The prevailing belief has been that there is a fixed number of neurons when we are born and we lose them over time as we age, explained Bogunovic. Scientists, however, are beginning to find that enteric neurons behave differently than neurons in the brain.
Using a newly developed mouse model established to mimic the transient nature of colitis experienced in patients with IBD, Bogunovic and co-author Sravya Kurapati, a visiting PhD student from Penn State University College of Medicine, were able to isolate the changes to the ENS that persist after inflammation stops.
"When we looked at the ENS, after it had been exposed to the inflammatory process, what we found was really startling," said Kurapati. "The microscopy images showed a dramatic loss of neurons in some areas, but we also found areas where neurons were densely packed in tight clusters, with their fibers going off in different directions instead of being aligned in nice, neat rows that are typical of normal ENS."
Using molecular tools that can distinguish between existing neurons and new neurons, Kurapati was able to see that a new generation of neurons were responsible for the disorganization.
Additionally, Bogunovic and Kurapati found a mechanism that helps preserve the ENS during inflammation. They showed that activating a signaling pathway that enables neurons to withstand hypoxia protects them from inflammation.
"By activating the hypoxia stress response pathway," said Bogunovic, "the neurons were able to adapt to the hypoxic environment created by the inflammation, resist inflammation and retain their typical structure after the inflammation resolved. It's possible to activate this pathway through drugs, diet supplementation or microbiome manipulation in a way that could protect neurons from inflammation."
