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      Imbalanced shift of cytokine expression between T helper 1 and T helper 2 (Th1/Th2) in intestinal mucosa of patients with post-infectious irritable bowel syndrome

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          Abstract

          Background

          Irritable bowel syndrome (IBS) is a common functional bowel disorder. The post-infectious IBS (PI-IBS) occurs in IBS patients with a history of intestinal infection preceding the onset of symptoms. However, the underlying cause of PI-IBS is not fully understood, and the purpose of this study was to investigate the immune regulatory mechanism of PI-IBS.

          Methods

          Participants enrolled in this study were divided into three groups including PI-IBS patients (n = 20), IBS patients without a history of infection (non-PI-IBS, n = 18), and healthy controls (n = 20). The expression levels of the Th1-derived cytokines IFN-γ and IL-12, and the Th2-derived cytokines IL-4 and IL-10 in the mucosal specimens, and in the ascending colon, the descending colon, and the rectal segments were measured by RT-PCR and western blot.

          Results

          The IFN-γ mRNA levels in the intestinal mucosa were significantly higher in the PI-IBS group than in the non-PI-IBS or control group (both P < 0.05), but there was no difference between the non-PI-IBS and control groups. A trend toward IFN-γ protein upregulation was found in the PI-IBS group, while the IL-12 and IL-4 mRNA and protein levels were not different between any groups. The IL-10 mRNA and protein levels in the PI-IBS group were both significantly lower than in the non-PI-IBS or control groups (P < 0.05, respectively), but there was no difference between the non-PI-IBS and control groups. There were no differences in the cytokine mRNA and protein levels among the ascending colon, the descending colon, and the rectum of all groups.

          Conclusions

          An increase in IFN-γ levels and a decrease in IL-10 levels were found in the intestinal mucosa of PI-IBS patients, suggesting that the infection may affect the Th1/Th2 balance. Thus, the dysregulation of the immune response is likely an important cause of IBS.

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          Most cited references13

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          Hypothalamic-pituitary-gut axis dysregulation in irritable bowel syndrome: plasma cytokines as a potential biomarker?

          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. 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. 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. IBS is characterized by an overactivation of the hypothalamic-pituitary-adrenal axis and a proinflammatory cytokine increase.
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            Mucosal immune activation in irritable bowel syndrome: gender-dependence and association with digestive symptoms.

            Immune activation may be involved in the pathogenesis of irritable bowel syndrome (IBS). However, the relative magnitude of this immune component and its correlation with gender and gastrointestinal complaints in IBS patients remains poorly elucidated. We enrolled 48 IBS patients, with either diarrhea or constipation, 12 patients with microscopic colitis, 20 patients with ulcerative colitis, and 24 healthy controls. Colonic immunocytes were identified with quantitative immunohistochemistry on mucosal biopsies. Gastrointestinal symptoms were assessed using a validated questionnaire. IBS patients showed a significant 72% increase in mucosal immune cells compared to controls (P<0.001). Further analyses showed that increased immune cells were present in 50% of the IBS patients. The magnitude of the immune infiltrate in IBS was significantly lower than that of microscopic colitis or ulcerative colitis (42% and 124% increases vs. IBS, respectively; P<0.001). Compared with controls, IBS patients had increased numbers of CD3+, CD4+, and CD8+ T cells and mast cells (P<0.001). Compared to male IBS patients, female IBS patients had greater numbers of mast cells (P=0.066), but lower numbers of CD3+ and CD8+ T cells (P=0.002 and <0.001, respectively). Mucosal mast cell infiltration of IBS patients was significantly associated with abdominal bloating frequency (P=0.022) and with symptoms of dysmotility-like dyspepsia (P=0.001), but not ulcer-like dyspepsia. A large subset of IBS patients shows gender-dependent mucosal infiltration of immunocytes that correlates with abdominal bloating and dysmotility-like dyspepsia. These results provide the rationale for considering immune mechanisms as a pathophysiological component in a subset of IBS patients.
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              Abdominal pain in Irritable Bowel Syndrome: a review of putative psychological, neural and neuro-immune mechanisms.

              Chronic abdominal pain is a common symptom of great clinical significance in several areas of medicine. In many cases no organic cause can be established resulting in the classification as functional gastrointestinal disorder. Irritable Bowel Syndrome (IBS) is the most common of these conditions and is considered an important public health problem because it can be disabling and constitutes a major social and economic burden given the lack of effective treatments. IBS aetiology is most likely multi-factorial involving biological, psychological and social factors. Visceral hyperalgesia (or hypersensitivity) and visceral hypervigilance, which could be mediated by peripheral, spinal, and/or central pathways, constitute key concepts in current research on pathophysiological mechanisms of visceral hyperalgesia. The role of central nervous system mechanisms along the "brain-gut axis" is increasingly appreciated, owing to accumulating evidence from brain imaging studies that neural processing of visceral stimuli is altered in IBS together with long-standing knowledge regarding the contribution of stress and negative emotions to symptom frequency and severity. At the same time, there is also growing evidence suggesting that peripheral immune mechanisms and disturbed neuro-immune communication could play a role in the pathophysiology of visceral hyperalgesia. This review presents recent advances in research on the pathophysiology of visceral hyperalgesia in IBS, with a focus on the role of stress and anxiety in central and peripheral response to visceral pain stimuli. Together, these findings support that in addition to lower pain thresholds displayed by a significant proportion of patients, the evaluation of pain appears to be altered in IBS. This may be attributable to affective disturbances, negative emotions in anticipation of or during visceral stimulation, and altered pain-related expectations and learning processes. Disturbed "top-down" emotional and cognitive pain modulation in IBS is reflected by functional and possibly structural brain changes involving prefrontal as well as cingulate regions. At the same time, there is growing evidence linking peripheral and mucosal immune changes and abdominal pain in IBS, supporting disturbed peripheral pain signalling. Findings in post-infectious IBS emphasize the interaction between centrally-mediated psychosocial risk factors and local inflammation in predicting long-term IBS symptoms. Investigating afferent immune-to-brain communication in visceral hyperalgesia as a component of the sickness response constitutes a promising future research goal. Copyright © 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                BMC Gastroenterol
                BMC Gastroenterol
                BMC Gastroenterology
                BioMed Central
                1471-230X
                2012
                20 July 2012
                : 12
                : 91
                Affiliations
                [1 ]National Hepatobiliary & Enteric Surgery Research Center, Ministry of Health, Central South University, Changsha, 410008, China
                [2 ]Digestive System Department, Baogang Hospital, the 3rd affiliated Hospital of Inner Mongolia Medical College, Baotou, 014010, China
                [3 ]Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, 410008, China
                Article
                1471-230X-12-91
                10.1186/1471-230X-12-91
                3439383
                22816602
                d8978ade-572a-4cbd-baa0-f6934c8dbf71
                Copyright ©2012 Chen et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 29 February 2012
                : 29 June 2012
                Categories
                Research Article

                Gastroenterology & Hepatology
                intestinal mucosa,cytokine,th1/th2,irritable bowel syndrome
                Gastroenterology & Hepatology
                intestinal mucosa, cytokine, th1/th2, irritable bowel syndrome

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