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Cited by 187Inflammatory Bowel DiseaseTryptophan and brain disordersGut microbiota and health

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Psychological stress in inflammatory bowel disease: Psychoneuroimmunological insights into bidirectional gut–brain communications

Open access
Ge, Li, Liu, Shuman, Li, Sha, Yang, Jing, Hu, Guangran, Xu, Changqing, Song, Wengang·2022·Frontiers in Immunology
DOI 10.3389/fimmu.2022.1016578PMC PMC9583867
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Abstract

Inflammatory bowel disease (IBD), mainly including ulcerative colitis (UC) and Crohn’s disease (CD), is an autoimmune gastrointestinal disease characterized by chronic inflammation and frequent recurrence. Accumulating evidence has confirmed that chronic psychological stress is considered to trigger IBD deterioration and relapse. Moreover, studies have demonstrated that patients with IBD have a higher risk of developing symptoms of anxiety and depression than healthy individuals. However, the underlying mechanism of the link between psychological stress and IBD remains poorly understood. This review used a psychoneuroimmunology perspective to assess possible neuro-visceral integration, immune modulation, and crucial intestinal microbiome changes in IBD. Furthermore, the bidirectionality of the brain–gut axis was emphasized in the context, indicating that IBD pathophysiology increases the inflammatory response in the central nervous system and further contributes to anxiety- and depression-like behavioral comorbidities. This information will help accurately characterize the link between psychological stress and IBD disease activity. Additionally, the clinical application of functional brain imaging, microbiota-targeted treatment, psychotherapy and antidepressants should be considered during the treatment and diagnosis of IBD with behavioral comorbidities. This review elucidates the significance of more high-quality research combined with large clinical sample sizes and multiple diagnostic methods and psychotherapy, which may help to achieve personalized therapeutic strategies for IBD patients based on stress relief.

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Crossref · 10.3389/fimmu.2022.1016578

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Figure 1 The mechanism by which chronic psychological stress aggravates IBD. (A) Stress activates the HPA axis: Stress induces the hypothalamus to release CRH, which triggers the release of ACTH from the hypophysis. ACTH subsequently initiates GC over-synthesis and release in the adrenal cortex. CRH reaches the colon through the blood and binds to CRHRs on the surface of MCs to promote degranulation and the production of proinflammatory cytokines IL-1β and TNF-α, which, in turn, increase the permeability of the colonic epithelial barrier. Furthermore, the overproduction of GC reduces tight junction protein expression between colonocytes, impairing the intestinal barrier function. (B) Stress activates the SNS but inhibits the vagus nerve: The sympathetic nervous system is stimulated by stress, which causes the adrenal medulla to secrete excessive AD and NE, promoting the activation of NF-κB signaling and mediating higher secretion of inflammatory cytokines in peripheral tissues. The inhibition of the anti-inflammatory effect of the vagus nerve promotes macrophage-induced TNF-α production, which aggravates the progress of colitis. (C) Stress is involved in innate and adaptive immune dysfunction by regulating specific immune cells and cytokine production: Stress induces macrophages to infiltrate the colon and polarize into an M1 phenotype. Additionally, stress promotes intestinal DCs to secrete IL-6 and IL-23, which induces Tregs to differentiate into a Foxp3+IL17+TNF-α+T cell phenotype. M1 macrophages and Foxp3+IL17+TNF-α+T cells secrete corresponding inflammatory cytokines to aggravate the colonic inflammatory response. (D) Stress induces microbiome community dysbiosis: Stress causes dysbiosis by increasing intestinal pathogens and decreasing SCFA-producing bacteria in the intestine. Intestinal pathogens can cause and exacerbate colitis by impairing the intestinal barrier and activating intestinal immunity. Decreased SCFAs lead to reduced tight junction protein expression and goblet cell numbers, which in turn lead to impaired intestinal barrier function and aggravated colonic inflammation. HPA axis, hypothalamic-pituitary-adrenal axis; CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone; GC, glucocorticoids; CRHRs, CRH receptors; ANS, autonomic nervous system; SNS, sympathetic nervous system; AD, adrenaline; NE, noradrenaline; VS, vagus nerve; MCs, mast cells; SCFAs: short-chain fatty acids; MLN, mesenteric lymph node; ENS, enteric nervous system.
Figure 1 The mechanism by which chronic psychological stress aggravates IBD. (A) Stress activates the HPA axis: Stress induces the hypothalamus to release CRH, which triggers the release of ACTH from the hypophysis. ACTH subsequently initiates GC over-synthesis and release in the adrenal cortex. CRH reaches the colon through the blood and binds to CRHRs on the surface of MCs to promote degranulation and the production of proinflammatory cytokines IL-1β and TNF-α, which, in turn, increase the permeability of the colonic epithelial barrier. Furthermore, the overproduction of GC reduces tight junction protein expression between colonocytes, impairing the intestinal barrier function. (B) Stress activates the SNS but inhibits the vagus nerve: The sympathetic nervous system is stimulated by stress, which causes the adrenal medulla to secrete excessive AD and NE, promoting the activation of NF-κB signaling and mediating higher secretion of inflammatory cytokines in peripheral tissues. The inhibition of the anti-inflammatory effect of the vagus nerve promotes macrophage-induced TNF-α production, which aggravates the progress of colitis. (C) Stress is involved in innate and adaptive immune dysfunction by regulating specific immune cells and cytokine production: Stress induces macrophages to infiltrate the colon and polarize into an M1 phenotype. Additionally, stress promotes intestinal DCs to secrete IL-6 and IL-23, which induces Tregs to differentiate into a Foxp3+IL17+TNF-α+T cell phenotype. M1 macrophages and Foxp3+IL17+TNF-α+T cells secrete corresponding inflammatory cytokines to aggravate the colonic inflammatory response. (D) Stress induces microbiome community dysbiosis: Stress causes dysbiosis by increasing intestinal pathogens and decreasing SCFA-producing bacteria in the intestine. Intestinal pathogens can cause and exacerbate colitis by impairing the intestinal barrier and activating intestinal immunity. Decreased SCFAs lead to reduced tight junction protein expression and goblet cell numbers, which in turn lead to impaired intestinal barrier function and aggravated colonic inflammation. HPA axis, hypothalamic-pituitary-adrenal axis; CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone; GC, glucocorticoids; CRHRs, CRH receptors; ANS, autonomic nervous system; SNS, sympathetic nervous system; AD, adrenaline; NE, noradrenaline; VS, vagus nerve; MCs, mast cells; SCFAs: short-chain fatty acids; MLN, mesenteric lymph node; ENS, enteric nervous system.CC BY · PubMed Central
Figure 2 IBD leads to anxiety- and depression-like behavioral comorbidities by inducing neuroinflammation. Chronic psychological stress, such as anxiety and depression, aggravates colitis by activating the HPA axis and disrupting the ANS. This is accompanied by an increase in the production of LPS, pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), and gut leak. Additionally, peripheral inflammation causes a decrease in tight junction protein expression between endothelial cells in the BBB. Then, the disruption of BBB integrity predisposes the translocation of circulating inflammatory mediators into brain tissues, which leads to the inflammatory response in the CNS by increasing IL-1β, IL-6, and TNF-α levels, activating the TLR4/NF-κB inflammatory pathway, as well as increasing iNOS and nitrite levels in brain tissues. Further, circulating inflammatory mediators reaching the brain affect neuroglial networks and activate microglial cells, which further exacerbate the inflammatory response in the CNS. Additionally, activated microglial cells can promote neurodegeneration of the hippocampal nerve, which also contributes to mood disorders. Furthermore, overactivation of the kynurenine pathway generates excess QUIN in the brain, which impairs neurons and neuroglial cells, resulting in inflammation–mediated depression. IBD, inflammatory bowel disease; HPA axis, hypothalamic-pituitary-adrenal axis; ANS, autonomic nervous system; LPS, lipopolysaccharide; BBB, blood–brain barrier; CNS, central nervous system; TRP, tryptophan; KYN, kynurenine; QUIN, neurotoxic quinolinic acid.
Figure 2 IBD leads to anxiety- and depression-like behavioral comorbidities by inducing neuroinflammation. Chronic psychological stress, such as anxiety and depression, aggravates colitis by activating the HPA axis and disrupting the ANS. This is accompanied by an increase in the production of LPS, pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), and gut leak. Additionally, peripheral inflammation causes a decrease in tight junction protein expression between endothelial cells in the BBB. Then, the disruption of BBB integrity predisposes the translocation of circulating inflammatory mediators into brain tissues, which leads to the inflammatory response in the CNS by increasing IL-1β, IL-6, and TNF-α levels, activating the TLR4/NF-κB inflammatory pathway, as well as increasing iNOS and nitrite levels in brain tissues. Further, circulating inflammatory mediators reaching the brain affect neuroglial networks and activate microglial cells, which further exacerbate the inflammatory response in the CNS. Additionally, activated microglial cells can promote neurodegeneration of the hippocampal nerve, which also contributes to mood disorders. Furthermore, overactivation of the kynurenine pathway generates excess QUIN in the brain, which impairs neurons and neuroglial cells, resulting in inflammation–mediated depression. IBD, inflammatory bowel disease; HPA axis, hypothalamic-pituitary-adrenal axis; ANS, autonomic nervous system; LPS, lipopolysaccharide; BBB, blood–brain barrier; CNS, central nervous system; TRP, tryptophan; KYN, kynurenine; QUIN, neurotoxic quinolinic acid.CC BY · PubMed Central

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Metadata

Authors
Ge, L., Liu, S., Li, S., Yang, J., Hu, G., Xu, C., & Song, W.
Affiliations
  • Shandong Provincial QianFoShan Hospital (CN)
  • Shandong First Medical University (CN)
Corresponding author
Song, Wengang
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2022-10-06
Volume
13
Pages
1016578-1016578
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2022.1016578
PMC
PMC9583867
OpenAlex
W4303184202
Cited by
187
References
225
Citations by year
2026: 58 · 2025: 74 · 2024: 42 · 2023: 12 · 2022: 1
FWCI
4.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China
  • Natural Science Foundation of Shandong Province
Topics
  • Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Keywords
inflammatory bowel disease, psychological stress, psychoneuroimmunology, gut-brain axis, ulcerative colitis, Crohn's disease, anxiety, depression, immunomodulation, gut microbiota, neuroinflammation, psychotherapy, antidepressants, recurrence
MeSH terms
Antidepressive Agents, Brain, Chronic Disease, Humans, Psychoneuroimmunology, Stress, Psychological, Inflammatory Bowel Diseases

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