Hypothalamic-Pituitary-Gut Axis Dysregulation in Irritable Bowel Syndrome: Plasma Cytokines as a Potential Biomarker?
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Background & aims Irritable bowel syndrome (IBS) is a functional disorder with an etiology that has been linked to both psychological stress and infection. The primary aim of this study was to examine the hypothalamic-pituitary-adrenal axis in patients with IBS and to relate such response to plasma cytokine profiles.Methods A total of 151 subjects, 76 patients and 75 controls, were recruited. The patients with IBS were diagnosed according to Rome II criteria. Forty-nine patients and 48 matched controls had cytokine levels measured, and a subset of 21 patients and 21 controls also underwent a corticotropin-releasing hormone (CRH) stimulation test with plasma levels of adrenocorticotropic hormone (ACTH) and cortisol measured. The remaining 27 patients and 27 controls underwent a dexamethasone (1 mg) challenge.Results Cortisol and the proinflammatory cytokines interleukin (IL)-6 (together with its soluble receptor) and IL-8 were elevated in all IBS subgroups (diarrhea predominant, constipated, and alternators), although the elevation was most marked in the constipated subgroup. There was no alteration in the anti-inflammatory cytokine IL-10. Following CRH infusion, an exaggerated release of both ACTH and cortisol was observed in patients with IBS. There was a significant correlation between the ACTH response (deltaACTH) and the IL-6 levels. A similar relationship existed between the deltaACTH/deltacortisol ratio and the IL-6 levels. Dexamethasone suppression of cortisol was similar in patients and controls.Conclusions IBS is characterized by an overactivation of the hypothalamic-pituitary-adrenal axis and a proinflammatory cytokine increase.
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Patients with irritable bowel syndrome had exaggerated ACTH and cortisol responses to CRF infusion together with an altered microbiota.
“In humans, patients with irritable bowel syndrome had exaggerated ACTH and cortisol responses to CRF infusion (Dinan et al., 2006) together with an altered microbiota (Eisenstein, 2016;Grenham et al., 2011).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Dinan et al., 2006
Higher concentrations of TNFa, IL-6, IL-8 and IL-12 in blood plasma or PBMCs have been linked to IBS.
“Elevated levels of tumour necrosis factor (TNF)a , interleukin (IL)-6, IL-8 and IL-12 in plasma or peripheral blood mononuclear cells (PBMCs) have been connected to IBS. 2, 19, 20”
From Clinical trial: multispecies probiotic supplementation alleviates the symptoms of irritable bowel syndrome and stabilizes intestinal microbiota (2008) · cites this paper as [19]
Inflammation is present in IBS, as indicated by studies on mast cells and cytokines.
“Studies on mast cells and cytokines point out that inflammation is present in IBS. 2, 13-20”
From Clinical trial: multispecies probiotic supplementation alleviates the symptoms of irritable bowel syndrome and stabilizes intestinal microbiota (2008) · cites this paper as [19]
Patients with IBS have increased concentrations of inflammatory/immune cells in intestinal tissue compared with controls.
“Evidence supporting this hypothesis includes increased concentrations of inflammatory/immune cells in intestinal tissue from IBS patients, altered levels of pro- and anti-inflammatory cytokines in the GI tract and peripheral blood of patients with IBS (Table 1) (11, 13, 24, 36, 46, 50, 51, 62, 73, 75, 89, 90, 94, 98, 102, 118, 121–124, 168, 174, 185, 187), and IBS-associated polymorphisms in genes”
From Intestinal microbiota and immune function in the pathogenesis of irritable bowel syndrome (2013) · cites this paper as [51]
Patients with IBS have altered levels of pro- and anti-inflammatory cytokines in the GI tract and peripheral blood compared with controls.
“Evidence supporting this hypothesis includes increased concentrations of inflammatory/immune cells in intestinal tissue from IBS patients, altered levels of pro- and anti-inflammatory cytokines in the GI tract and peripheral blood of patients with IBS (Table 1) (11, 13, 24, 36, 46, 50, 51, 62, 73, 75, 89, 90, 94, 98, 102, 118, 121–124, 168, 174, 185, 187), and IBS-associated polymorphisms in genes”
From Intestinal microbiota and immune function in the pathogenesis of irritable bowel syndrome (2013) · cites this paper as [51]
IL-6 and IL-8 were found to be increased in the serum of patients with IBS compared with controls.
“IL-6, which is a major regulator of serum C-reactive protein levels, and IL-8 were also found to be increased in the serum of patients with IBS compared with controls, supporting a proinflammatory profile in these patients (50, 51).”
From Intestinal microbiota and immune function in the pathogenesis of irritable bowel syndrome (2013) · cites this paper as [51]
Other studies did not observe differences in IL-10 levels between IBS patients and controls.
“However, other studies did not observe differences in IL-10 levels between IBS patients and controls (50, 51, 90), leaving the relevance of IL-10 levels in patients with IBS unclear.”
From Intestinal microbiota and immune function in the pathogenesis of irritable bowel syndrome (2013) · cites this paper as [51]
The integrity of the HPA axis is important in the pathogenesis of IBS.
“which integrity is important in the pathogenesis of IBS [244,245]”
From Gut microbiota role in irritable bowel syndrome: New therapeutic strategies (2016) · cites this paper as [244]
Both acute and chronic stress are associated with the onset of GI disease as well as exacerbation of GI symptoms in individuals without ASD.
“Both acute and chronic stress are associated with the onset of GI disease as well as exacerbation of GI symptoms (Dinan et al., 2006).”
From Associations between cytokines, endocrine stress response, and gastrointestinal symptoms in autism spectrum disorder (2016) · cites this paper as Dinan et al., 2006
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“HPA axis dysregulation occurs in some IBS patients (Bohmelt, Nater, Franke, Hellhammer, & Ehlert, 2005; L. Chang et al., 2009; Dinan et al., 2006; FitzGerald et al., 2009).”
BackgroundProbiotics in irritable bowel syndrome: an immunomodulatory strategy?
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- Authors
- Dinan, T. G., Quigley, E. M. M., Ahmed, S. M. M., Scully, P., O’Brien, S., O’Mahony, L., O’Mahony, S., Shanahan, F., & Keeling, P. W. N.
- Affiliations
- University College Cork (IE)
- Trinity College Dublin (IE)
- Corresponding author
- Dinan, Timothy G.
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2006-02
- Volume
- 130
- Issue
- 2
- Pages
- 304-311
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W1976118863
- Cited by
- 636
- References
- 52
- Citations by year
- 2026: 19 · 2025: 13 · 2024: 21 · 2023: 22 · 2022: 21 · 2021: 35 · 2020: 28 · 2019: 27 · 2018: 26 · 2017: 34 · 2016: 37 · 2015: 38 · 2014: 33 · 2013: 38 · 2012: 44
- FWCI
- 39.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Health Research Board
- Science Foundation Ireland
- Wellcome Trust
- Topics
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Keywords
- irritable bowel syndrome, hypothalamic-pituitary-adrenal axis, plasma cytokines, interleukin-6, interleukin-8, IL-10, cortisol, ACTH, corticotropin-releasing hormone stimulation test, dexamethasone suppression test, inflammatory cytokines, irritable bowel syndrome with constipation, diarrhea-predominant irritable bowel syndrome, biomarkers
- MeSH terms
- Adrenocorticotropic Hormone, Adult, Alcohol Drinking, Dexamethasone, Female, Humans, Hypothalamo-Hypophyseal System, Intestines, Ireland, Male, Pain, Reference Values, Biomarkers, Interleukin-6, Cytokines, Interleukin-8, Interleukin-10, Irritable Bowel Syndrome
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