In conversation with Dr Zlatan Mujagic, MUMC+ gastroenterologist and liver physician

How psychological stress leads to intestinal inflammation

An international research consortium, including NUTRIM researcher Zlatan Mujagic and other researchers from Maastricht, has investigated the effects of stress on the gut. At last, this research has unraveled how stress leads to worsening inflammatory bowel diseases. This knowledge opens doors for new treatments for IBD. The study was published in the leading journal Cell and recently summarized by Zlatan in the Dutch Journal of Medicine. 

A healthy mind and a healthy body

A link between a healthy mind and a healthy body has been assumed for millennia. This link also appears to be there for various immune-mediated disorders. We already suspected that psychological stress would have an impact on the immune system in patients having inflammatory bowel disease (IBD, Crohn’s disease and ulcerative colitis). 

With previous research from Maastricht UMC+ and Zuyderland MC, a link was demonstrated between acute psychological stress and subsequent flare-ups of intestinal inflammation and relation with IBD. However, it was still unknown whether there is a causal relationship here. Moreover, if so, what biological mechanism underlies it? This was the challenge for the research. 

Experimental animal and human cohort studies have uncovered the mechanism

The study showed in mice that stress could indeed be a leading factor in intestinal inflammation. Moreover, the biological mechanism was unraveled systematically, after which these findings were validated in several research cohorts with patients with Crohn's disease and ulcerative colitis. 

The study considered in more detail by Zlatan

In this study, it was shown step by step in mice that psychological stress stimulates glucocorticoid production via the hypothalamic-pituitary-adrenal cortex, that this stress hormone induces enteric glial cells to produce the protein CSF1, and that this protein in return stimulates monocytes to accumulate in the intestinal mucosa and produce the pro-inflammatory cytokine TNF. Through this mechanism, stress can cause colitis to become more severe in mice that develop intestinal inflammation.

In three different human research cohorts, including one from Maastricht UMC+ and Zuyderland MC, we could validated these findings in humans. This demonstrated the biological link between psychological stress and intestinal inflammation in humans as well. However, the described findings also raise new questions. For instance, this study shows that stress can worsen intestinal inflammation via glucocorticoids, while in daily practice; drugs like prednisone are actually used to treat intestinal inflammation in IBD. However, we also know that overuse of prednisone in patients with IBD can lead to an unfavorable course of inflammation. It is possible that the described mechanism plays a role here. Further research will need to provide further clarification.

What are glial cells?
Besides nerve cells, there are other cells found in the nervous system. These cells are called glial cells (glia is Greek for "glue"). Glial cells are cells with a supporting function in the nervous system. Among other things, they clear away dead nerve cells, care for, support and protect nerve cells (neurons) and provide strength to the brain, peripheral nerves and the enteric nervous system in the intestines. Glial cells can be and are associated with a variety of (neurological) disorders, but now also appear to play an important role in the relationship between stress and intestinal inflammation.

What were the main findings for you as a researcher?

 Psychological stress is a potential modulating factor of the immune system. People with psychological symptoms are more likely to develop IBD, both ulcerative colitis and Crohn's disease.

 We could demonstrate for inflammatory bowel disease (IBD), an association between acute psychological stress and subsequent flare-up of intestinal inflammation.

 Animal studies have demonstrated causality and unraveled the biological mechanism by which stress modulates intestinal inflammation. There is a relationship between stress and colitis in mice.

 Human cohort studies validated this and found that higher stress scores in people with IBD also led to a higher chance of IBD flare-ups in the months following the stress.

 Stress leads to the production of cortisol via the hypothalamic-pituitary-adrenal cortex, which activates glial cells in the enteric nervous system.

 Glial cells play a crucial role in the gut and trigger monocytes in the intestines to produce the pro-inflammatory cytokine TNF.

What is the impact of this research for Inflammatory Bowel Diseases (IBD) in your opinion?

This knowledge about the relationship between psychological stress and intestinal inflammation opens new doors for treatments of diseases like IBD. The biological mechanism not only opens doors for the development of non-pharmacological stress-reducing therapies for IBD. The neuroimmunological process is also interesting as a potential new target for future pharmacological therapies. The biological link between psychological stress and intestinal inflammation that we discovered has greatly increased our understanding about the relationship between psyche, nervous system and immune system. This can lead to new approaches to diseases like IBD.

Text: Danielle Vogt

Inflammatory Bowel Diseases (IBD) 
Inflammatory bowel diseases, also known as intestinal inflammation, are on the rise. Well-known examples are Crohn's disease and Ulcerative Colitis. These are the two most common forms of Inflammatory Bowel Disease (IBD). Some 100,000 Dutch people have chronic inflammatory bowel disease (IBD). Even when the inflammation in IBD is well treated, up to 40 per cent of patients experience chronic abdominal pain. This pain is difficult to treat but has a major impact on quality of life. In addition, it now appears, IBD patients with psychological complaints are more likely to experience hospitalization, emergency room visits or intensification of immune-inhibiting medication.


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