Unraveling the Relationship Between Chronic Stress and Inflammatory Bowel Disease

Summary

Mental health profoundly impacts inflammatory responses in the body. This is particularly evident in inflammatory bowel disease (IBD), where psychological stress is associated with disease exacerbations. Here, we uncover a critical role for the enteric nervous system (ENS) in mediating the aggravating effect of chronic stress on intestinal inflammation.

We found that chronically elevated levels of glucocorticoids drive the generation of an inflammatory subset of enteric glia that promotes monocyte- and TNF-mediated inflammation through CSF1. Furthermore, glucocorticoids cause transcriptional immaturity in enteric neurons, acetylcholine deficiency, and dysmotility through TGF-β2. We verified the connection between psychological state, intestinal inflammation, and dysmotility in three cohorts of IBD patients.

Together, these findings offer a mechanistic explanation for the brain’s impact on peripheral inflammation, define the ENS as a relay between psychological stress and gut inflammation, and suggest that stress management could serve as a valuable component of IBD care. .

Comments

For the first time, cells involved in the communication between stress responses in the brain and inflammation in the gastrointestinal (GI) tract have been identified in animal models, according to findings from the Perelman School of Medicine at the University of Pennsylvania, published recently in Cell .

Glial cells, which support neurons, communicate stress signals from the central nervous system (CNS) to the semiautonomous nervous system within the gastrointestinal (GI) tract, or enteric nervous system (ENS). These signs of psychological stress can cause inflammation and exacerbate inflammatory bowel disease (IBD) symptoms.

An estimated 1.6 million Americans currently have IBD, which refers to two conditions, Crohn’s disease and ulcerative colitis , which are characterized by inflammation of the gastrointestinal tract and can cause symptoms such as persistent diarrhea, abdominal pain, and stool. with blood. Prolonged inflammation can also cause permanent damage to the gastrointestinal tract. Current treatments consist of anti-inflammatory medications, immunosuppressants, dietary changes, and steroids.

"Doctors have long noted that chronic stress can worsen IBD symptoms, but so far no biological connection has been identified to explain how the digestive system knows when someone is stressed," said lead author Christoph Thaiss, PhD, assistant professor of Microbiology.

In the study, researchers found that, like humans, mice with IBD developed severe symptoms when stressed. They traced the initial stress response signals to the adrenal cortex, which releases glucocorticoids, steroid hormones that activate physiological stress responses throughout the body. The researchers found that neurons and glia in the ENS responded to chronically elevated levels of glucocorticoids, suggesting that they are the link between the brain’s perception of stress and intestinal inflammation.

While glucocorticoids generally have an anti-inflammatory effect on the body, researchers found that when glia in the ENS were exposed to steroid hormones for a prolonged period, such as during chronic stress, they attracted white blood cells to the GI tract that increase inflammation. Researchers also found that when exposed to chronic stress, neurons in the ENS in the GI tract stop functioning as they normally do, which can lead to defecation problems and exacerbated IBD symptoms.

Thaiss and colleagues verified the connection between psychological stress and IBD symptoms in humans using the UK Biobank and a cohort of patients from the IBD Immunology Initiative at Penn Medicine . They found that in patients diagnosed with IBD, the level of reported stress correlated with greater severity of IBD symptoms.

"This finding highlights the importance of psychological assessments in patients treated for IBD, as well as in informing treatment protocols," said Maayan Levy, PhD, assistant professor of Microbiology and co-senior author of the study. "One of the most common treatments for IBD flares is steroids , and our research indicates that in IBD patients who experience chronic stress, the effectiveness of this treatment could be affected."

The researchers highlight the opportunity for more research into the biology of enteric glial cells and the role they play in many regulatory systems within the body, including communication between the nervous system and the immune system.

This study was supported by the National Institutes of Health.