Summary: New research suggests that a controlled amount of psychological stress can stimulate aspects of the immune system and may provide protection against subsequent intestinal injury.
Source: Case Western Reserve
Stress is often linked to health problems such as insomnia, high blood pressure, obesity and heart disease. Yet some stress — the kind that sharpens focus for a deadline or a challenge — can be helpful. A recent study from Case Western Reserve University School of Medicine examined whether certain chronic stress exposures might actually benefit immune function.
Researchers published their findings in Proceedings of the National Academy of Sciences and found that, in a mouse model of Crohn’s disease–like ileitis, chronic psychological stress promoted formation of colonic tertiary lymphoid organs (TLOs) and increased production of immune signaling molecules that support mucosal protection.
“This is one of the few studies showing that chronic stress could have a beneficial, rather than solely negative, effect,” said senior author Fabio Cominelli, professor of medicine and pathology and associate dean for program development at the School of Medicine. “The results were surprising and suggest a more nuanced role for stress in immune regulation.”
The study
Psychological stress has previously been associated with worsening symptoms in inflammatory bowel disease (IBD). Tertiary lymphoid organs (TLOs) — organized immune cell structures that arise during chronic inflammation or tissue injury — have also been linked to more severe intestinal inflammation in some settings. The role of TLOs and stress in IBD has been debated, and prior to this work the impact of chronic psychological stress on TLO formation had not been thoroughly investigated.
In the new study, SAMP1/YitFc (SAMP) mice, a model that develops Crohn’s-like ileitis, were subjected to 56 consecutive days of restraint stress. After this six-week period, stressed mice showed a significant increase in TLO formation in the colon. Notably, the imposed stress did not produce a corresponding increase in inflammation in the small intestine or colon when compared to unstressed controls.
The researchers analyzed the gut microbiome and found no genus-level compositional differences between stressed and control mice using 16S sequencing. To test whether the microbiome mediated the observed effects, fecal microbiota transplantation (FMT) was performed: germ-free SAMP mice received stool from either stressed or unstressed donors. While recipients mirrored the behavioral characteristics of their donors, FMT did not transfer increased TLO formation, indicating the microbiome was unlikely to be the primary driver of the effect.
Further investigation revealed that chronic stress elevated production of the cytokines interleukin-23 (IL-23) and interleukin-22 (IL-22), both implicated in pathways that support TLO development. IL-22 is known to contribute to epithelial repair and can have complex roles that are either protective or pro-inflammatory depending on context.
To probe causality, the team used SAMP mice lacking the IL-23 receptor (SAMP × IL-23r−/−). These knockout mice did not increase TLO formation in response to chronic stress. In these animals IL-23 levels rose but IL-22 did not, and administration of recombinant IL-22 restored TLO formation, implicating IL-23/IL-22 signaling as a key mechanism linking stress to TLO development.
Because TLOs are sometimes associated with disease progression, the researchers tested whether stressed mice would be more vulnerable to a secondary colonic injury. Unexpectedly, when exposed to dextran sodium sulfate (DSS) to induce colitis, previously stressed mice showed less severe colitis by both colonoscopy and histological assessment compared with unstressed mice. These findings suggest that stress-induced TLOs may help strengthen the mucosal barrier and afford protection against subsequent injury.
“Our data show that psychological stress induces formation of colonic TLOs by upregulating IL-23, and that these TLOs may improve mucosal defense against a second insult,” Cominelli said. “While stress is typically linked to worse inflammation, not all patients experience disease worsening with stress. This study identifies a context in which chronic, daily stress appears to have a protective immune effect.”
Cominelli emphasized careful interpretation: “Whether you want to be stressed depends on how stress is defined. ‘Stimulated’ might be a more accurate term. A modest, sustained immune stimulus appears beneficial in this model, but more research is required to determine whether similar mechanisms operate in other diseases or in humans.”
About this stress research news
Author: Press Office
Source: Case Western Reserve
Contact: Press Office – Case Western Reserve
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Original Research: Closed access.
“Chronic stress induces colonic tertiary lymphoid organ formation and protection against secondary injury through IL-23/IL-22 signaling” by Adrian Gomez-Nguyen et al. PNAS
Abstract
Chronic stress induces colonic tertiary lymphoid organ formation and protection against secondary injury through IL-23/IL-22 signaling
Psychological stress has been associated with worsening of inflammatory bowel disease (IBD), and intestinal tertiary lymphoid organs (TLOs) are often linked with chronic inflammation. However, the interaction between chronic psychological stress and TLO formation had not been previously studied. Using the SAMP1/YitFc mouse model of Crohn’s disease–like ileitis subjected to 56 days of restraint stress, investigators observed a marked increase in colonic TLO formation without a corresponding rise in small- or large-intestinal inflammation.
Microbiome analysis (16S) revealed no genus-level differences between stressed and unstressed mice, and fecal microbiota transplant from stressed donors into germ-free recipients reproduced behavioral traits but did not transfer increased TLO formation. Instead, stressed mice showed upregulated production of IL-23 and IL-22 and increased expression of antimicrobial peptides. IL-23 receptor knockout mice failed to form additional TLOs under stress; IL-22 administration rescued TLO development in that setting.
When challenged with a secondary colonic insult (dextran sodium sulfate), previously stressed mice experienced reduced colitis severity on histologic and endoscopic measures. These results indicate that chronic psychological stress can drive colonic TLO formation via intrinsic IL-23/IL-22 signaling and that such TLOs may confer protection by enhancing the mucosal barrier, independent of microbiome changes.