October’s Paper of the Month looks the role of the enteric nervous system in mediating the aggravating effect of chronic stress on intestinal inflammation.

The enteric nervous system relays psychological stress to intestinal inflammation
Schneider KM, Blank N, Alvarez Y, et al.
Cell. 2023 Jun 22;186(13):2823-2838.e20. doi: 10.1016/j.cell.2023.05.001. Epub 2023 May 25.

What is known about the subject?

Psychological stress exerts a profound impact on inflammatory processes throughout the body, suggesting that improving a patient’s mental state might be a powerful yet underutilized strategy for the management of numerous diseases. The effect of psychological stress on disease severity is particularly striking in inflammatory bowel disease (IBD), with numerous epidemiological studies supporting the hypothesis that stressful life events can exacerbate IBD flares. However, the mechanistic basis for aggravated, stress-associated IBD flares is not fully understood.

What the study adds?

On the clinical part:

In this study, the authors uncover several mechanisms by which psychological stress influences bowel inflammation via the enteric nervous system (ENS). Unlike the central nervous system (CNS), where responses to psychological stress have been deeply characterized, ENS responses to stress and their consequences are less well understood.

Interestingly, stress experienced before the onset of colitis had the strongest effect of disease exacerbation, suggesting that psychological stress may precondition the bowel for enhanced inflammation during the subsequent encounter of a colitogenic trigger.

On research part:

The study shows how meticulous is the basic research field compared to some clinical research. This might inspire us as clinicians-scientists.

In brief, the investigators studied different cell-lines then made many experiments on each cell line to identify the suspected cell line involved in mediating inflammation. These experiments varied from genetic manipulation, blocking hormone secretion by pharmacological agents and using knocked-out mouse models. The investigators asked questions and designed experiments to answer these questions. Finally, the investigators explored the connection of psychological stress, dysmotility, and bowel inflammation in human patients by analyzing data from 502,505 individuals from the UK Biobank. Patients with ICD codes that indicate high levels of chronic psychological stress had a significantly higher risk of developing IBD during a 10-year follow-up than participants without a stressful lifestyle. In addition, psychological stress was also linked to a more severe course of IBD after diagnosis, as indicated by higher serum C-reactive protein (CRP) and increased overall mortality.

Implications for colorectal practice

First, stressed IBD patients are more likely to require surgery and to develop ileus because psychological stress is associated with dysmotility in humans and predisposes the intestinal mucosa to a subsequent colitogenic trigger.

Second, perceived stress levels strongly correlated with colonoscopic evaluation of disease severity. These findings provide evidence for the link between psychological stress and exacerbated intestinal inflammation in individuals with IBD.

Third, the study emphasizes the importance of considering a patient’s mental health in the clinical management of inflammatory diseases [1,2,3]. Given that the investigators found opposing roles of two common IBD treatment regimens (corticosteroids and monoclonal antibodies against TNF) on the severity of stress-mediated colitis in mice, it is possible that treatment effects vary depending on the psychological state of affected individuals.

Take home message

The evaluation of mental state, in conjunction with strategies to reduce stress, anxiety, and depression, could be a powerful and underutilized tool to enhance treatment success.


  1. Sebastian S, Segal JP, Hedin C, Pellino G, Kotze PG, Adamina M, Campmans-Kuijpers M, Davies J, de Vries AC, Casbas AG, El-Hussuna A, Juillerat P, Meade S, Millán M, Spinelli A. ECCO Topical Review: Roadmap to Optimal Peri-Operative Care in IBD. J Crohns Colitis. 2023 Mar 18;17(2):153-169. doi: 10.1093/ecco-jcc/jjac129.
  2. Zangenberg MS, Horesh N, Kopylov U, El-Hussuna A. Preoperative optimization of patients with inflammatory bowel disease undergoing gastrointestinal surgery: a systematic review. Int J Colorectal Dis. 2017 Dec;32(12):1663-1676. doi: 10.1007/s00384-017-2915-4.
  3. Zangenberg MS, El-Hussuna A. Psychiatric morbidity after surgery for inflammatory bowel disease: A systematic review. World J Gastroenterol. 2017 Dec 28;23(48):8651-8659. doi: 10.3748/wjg.v23.i48.8651.
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