We can finally know why psychological stress worsens intestinal inflammation

Researchers have identified a pathway between the brain and the immune system in mice that could explain why psychological stress can worsen gut inflammation. The finding could improve treatments for chronic gastrointestinal conditions such as inflammatory bowel disease (IBD).

For years, studies have shown an association between mental distress and inflammation. The connection is especially evident in IBD or other autoimmune conditions characterized by intestinal inflammation, abdominal pain, and intestinal damage. Even with treatment, people with IBD commonly experience flare-ups of symptoms when stressed.

To understand the mechanism behind this association, Christoph Thaiss of the University of Pennsylvania and colleagues analyzed mice with IBD-like symptoms. For a week, the researchers placed eight animals inside small tubes for 3 hours a day to induce stress. They then treated the mice with a chemical irritant for seven days to elicit IBD-like symptoms.

Three mice were given a hormone-blocking drug called glucocorticoids, which the brain tells the body to produce when it perceives distress. The researchers then performed a colonoscopy on the mice and rated intestinal inflammation and intestinal damage between 0 and 15, with higher scores indicating worse outcomes. Mice that received the drug had, on average, a score of around 5, while those without scored slightly less than 15, indicating that glucocorticoids are important for stress-induced intestinal inflammation.

The researchers then performed a genetic analysis of tissue samples collected from the animals’ colons. They found that mice with persistently elevated glucocorticoids had changes in specialized neural cells called enteric glia. Glial cells help maintain neurons and communicate with many different types of cells, and they respond to stress hormones by pumping out inflammatory molecules. Enteric glia from mice with elevated glucocorticoids showed increased activity in proinflammatory genes.

Genetic analysis also revealed that stress alters neurons in the gut, making them appear less mature. “The reason this is detrimental is because we need mature neurons in the GI tract to drive bowel movement and motility,” says Thaiss. Together, these findings highlight two branches of a pathway between the brain, gut neurons, and the inflammatory immune response.

The team validated these findings in 63 people with IBD by collecting and genetically analyzing colon tissue samples from all. The participants also completed a questionnaire to assess stress. People who experienced more stress had more intestinal damage and greater increases in inflammatory markers, similar to those seen in mice.

Saurabh Mehandru of Mount Sinai Health System in New York says these results may have finally demonstrated the exact connection between the brain and the gut that many have believed existed in gastrointestinal disorders. “He tells doctors to look at the patient as a whole, not just treat the symptoms of flare-ups, but also other problems that may be stress-related,” he says.

“The big question is whether the same pathway might dictate how responsive people are to different treatments,” says Thaiss. If so, it could improve the way IBD is treated or lead to new drug targets for the condition.