It is widely known that psychological stress influences many aspects of our health. This is particularly true in the case of inflammatory bowel disease (IBD), a widespread disease of the gut. We found that psychological stress leads to inflammation of the gut by changing the gut-residing nervous system, which may inform therapeutic approaches in the future.
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published on Jan 29, 2024
Inflammatory bowel disease (IBD) is a group of chronic intestinal disorders that mainly manifests in two forms: Crohn’s disease and ulcerative colitis. These diseases involve persistent inflammation of the gastrointestinal tract and can cause severe symptoms including abdominal pain, diarrhea, and intestinal obstruction. If left unmanaged, IBD often leads to serious complications such as colorectal cancer or sepsis. The exact cause of IBD remains elusive, though it is thought to emerge from a complex interplay of genetic predisposition, lifestyle, and environmental factors. Studies linking stressful life events with IBD flare-ups suggest that psychological stress is a pivotal contributor to IBD development. However, until recently, the underlying mechanisms responsible for this connection have remained enigmatic.
To investigate the effects of psychological stress on IBD, we used a mouse model with chemically induced bowel inflammation. We simulated stress in the mice by physically restraining them or exposing them to more aggressive mice. Interestingly, the stressed mice developed more severe colitis, mirroring the situation in humans.
When our bodies (or those of mice) get stressed, two pathways are activated: the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis which causes the release of a hormone called corticosterone. As expected, we saw that when the mice were stressed, both pathways became more active. However, when we tested blocking each pathway in turn, blocking of adrenal-gland derived corticosterone signaling, but not sympathetic signaling, provided protection against the effects of psychological stress on gut inflammation. This suggests that during stress, the release of corticosterone is the important link that connects our stressed nervous systems to the increased gut inflammation and diseases like colitis.
Next, we sought to understand mechanistically how elevated corticosterone levels contribute to inflammation of the gut. Using different experimental strategies including studying gene activity in single cells, we identified that a type of white blood cell, known as a monocyte, is a key driver of stress-induced gut inflammation. Upon psychological stress, these monocytes accumulate in the gut and produce a protein called tumor necrosis factor (TNF) which worsens colitis. However, we found that elevated corticosterone levels do not act directly on monocytes. Even when we specifically removed the corticosterone receptor in monocytes, it did not protect against colitis worsening.
These results indicated the existence of a signaling hub mediating the effects of stress-induced corticosterone on monocytes and ultimately on bowel inflammation. Thus, we focused on the gut-residing enteric nervous system, which controls many essential gut functions and is known to respond to corticosterone.
By studying gene expression in individual cell nuclei, we found that psychological stress leads to profound changes in gene activity in gut cells called enteric glial cells. We found that this stress also triggers the emergence of a new type of enteric glial cell, which we named enteric glial cells associated with psychological stress (eGAPS). These eGAPS produce a protein called CSF-1 which is known to attract monocytes, and we found this to be a driving force of the harmful effect of psychological stress on colitis via TNF production. Additionally, stress leads to distinct gene activity in enteric neurons which is influenced by a protein called TGFβ2. These changes make the neurons less mature, which causes constipation and issues with gut movement which further worsen inflammation.
Do these experimental findings mirror the situation in humans? Yes, they do. We studied data from various databases: the UK Biobank study, the myIBDcoach real-world prospective cohort study, and a colonoscopy study we conducted at Penn Medicine. We found that elevated levels of perceived stress strongly correlated with higher incidence and increased colitis severity. Furthermore, stress levels strongly correlated with the expression of distinct genes indicating monocyte recruitment, TNF production, general inflammation and elevated TGFB2 in colon biopsies from IBD patients. This provides mechanistic evidence for our findings in humans.
In summary, we unveiled a multi-step signaling link between psychological stress and the development and worsening of inflammatory bowel disease. By clarifying the intricate mechanisms by which stress impacts the gut, these findings open new avenues for understanding and treating IBD. Furthermore, they underscore the importance of addressing psychological well-being as an integral component of IBD care, offering hope for more effective and holistic treatment strategies in the future.
Schneider, K. M., Blank, N., Alvarez, Y., Thum, K., Lundgren, P., Litichevskiy, L., Sleeman, M., Bahnsen, K., Kim, J., Kardo, S., Patel, S., Dohnalová, L., Uhr, G. T., Descamps, H. C., Kircher, S., McSween, A. M., Ardabili, A. R., Nemec, K. M., Jimenez, M. T., … Thaiss, C. A. (2023). The enteric nervous system relays psychological stress to intestinal inflammation. Cell, 186(13), 2823-2838.e20. https://doi.org/10.1016/j.cell.2023.05.001