When stress affects the gut, the stomach tightens and digestion slows. For some, these symptoms resolve quickly. For others — particularly people with constipation-predominant irritable bowel syndrome (IBS-C) and related conditions — they don’t.
A team led by Harvard Medical School investigators at Beth Israel Deaconess Medical Center has now identified the biological mechanism behind this experience. In a recent study published in the Journal of Biological Chemistry, the researchers showed how stress hormones directly interfere with gut function, slowing digestion through a newly defined pathway.
Existing treatments for IBS-C include a combination of dietary changes, psychotherapy, over-the-counter laxatives, and prescription medications — and it can still be challenging for some patients to find long-term relief. The research, conducted in mice and in vitro tissue cultures, points toward a potential new way to treat stress-associated constipation.
“This study identifies both the basic biology for why stress slows down your gut and creates a platform through which novel therapeutics can be generated and tested for treating stress-associated constipation,” said Srinivas Puttapaka, HMS research fellow in medicine at Beth Israel Deaconess and co-first author of the study with Jared Slosberg, a doctoral candidate at Johns Hopkins University School of Medicine.
A puzzle in the gut
The research, led by senior author Subhash Kulkarni, HMS assistant professor of medicine at Beth Israel Deaconess, centered on the enteric nervous system, often called the “second brain” of the gastrointestinal tract. This network of nerves in the gut controls how food moves through the digestive system. It can also coordinate digestion on its own, without input from the brain or spinal cord.
However, the enteric nervous system is connected to the rest of the body’s nervous system and also receives signals from the outside world, meaning that stressors big and small can override its normal functions.
Scientists already knew that stress hormones can disrupt signaling in the enteric nervous system and had demonstrated this in patients with IBS. What was not clear was exactly how that disruption happens or whether it could be reversed.
In the new study, Kulkarni, Puttapaka, Slosberg, and colleagues showed that stress interferes with a specific signaling pathway and demonstrated that restoring that pathway improved gut function in preclinical models. They identified a receptor expressed by enteric neurons as a promising target for new IBS treatments.
A key receptor
The researchers found that stress hormones suppress the gut’s cell-to-cell communication, slowing gastrointestinal movement and increasing the risk of persistent constipation.
The team traced this breakdown to a specific chemical signaling pathway in the gut — involving a protein called BDNF and its receptor, TrkB — that helps keep digestion responsive.
When the researchers activated this pathway using a compound that stimulates the TrkB receptor, they were able to restore normal gut movement in experimental models of stress.
The work identifies TrkB as an important therapeutic target to ease symptoms of IBS-C and other gut-brain interaction disorders, Kulkarni said.
“By pinpointing how stress disrupts this pathway and showing that its function can be restored, we’ve identified a clear and actionable target for developing new treatments for IBS,” said Puttapaka.
Adapted from a Beth Israel Deaconess news release.
Authorship, funding, disclosures
Additional authors are Philippa Seika, Su Min Hong, Alpana Singh, Gamze Sonmez, and Ainsleigh Scott.
This research was supported by the National Institutes of Health (grants R01AG066768, R21AG072107, UM1TR004408, T32GM148383); the DiaComp Foundation (pilot award Augusta University); a pilot grant from Harvard Digestive Disease Core; the Maryland Genetics, Epidemiology, and Medicine training program sponsored by the Burroughs Wellcome Fund; TUBITAK 2214-A International Research Fellowship Program; Deutsche Forschungsgemeinschaft (Walter Benjamin Fellowship 528835020); and Harvard University and its affiliated academic health care centers.
