Haugesund, Norway
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Mazzawi T.,University of Bergen | Hausken T.,University of Bergen | Gundersen D.,Helse Fonna | El-Salhy M.,University of Bergen
European Journal of Clinical Nutrition | Year: 2016

Background/Objectives:To determine the large intestinal endocrine cell types affected following dietary guidance in patients with irritable bowel syndrome (IBS).Subjects/Methods:The study included 13 IBS patients and 13 control subjects. The patients received three sessions of individualized dietary guidance. Both the control subjects and the patients were scheduled for colonoscopies at baseline and again for the patients at 3-9 months after dietary guidance. Biopsy samples were taken from the colon and rectum and were immunostained for all types of large intestinal endocrine cells. The endocrine cells were quantified using computerized image analysis.Results:The daily total consumption (mean±s.e.m. values) of fruits and vegetables rich in FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) decreased significantly from 16.2±5.3 g before receiving dietary guidance to 9.2±3.2 g after receiving dietary guidance (P=0.02). In the total colon, the densities of serotonin cells were 46.8±8.9, 10.5±2.1 and 22.6±3.2 cells/mm 2 in control subjects and in IBS patients before and after receiving dietary guidance, respectively (P=0.007); the corresponding densities of peptide YY cells were 11.6±1.8, 10.8±1.7 and 16.8±2.1 cells/mm 2, respectively (P=0.06). The cell densities for both serotonin and peptide YY did not change significantly in the rectum. The densities of somatostatin cells in the rectum were 13.5±3.0, 13.2±3.0, and 22.3±3.2 cells/mm 2 for control subjects and for IBS patients before and after receiving dietary guidance, respectively (P=0.01).Conclusions:The densities of the large intestinal endocrine cells tend to normalize following dietary guidance that may have contributed to the improvement of the patients with IBS symptoms. © 2016 Macmillan Publishers Limited All rights reserved.


El-Salhy M.,Stord Helse Fonna Hospital | El-Salhy M.,University of Bergen | Wendelbo I.H.,Stord Helse Fonna Hospital | Wendelbo I.H.,University of Bergen | Gundersen D.,Helse Fonna
Molecular Medicine Reports | Year: 2013

Irritable bowel syndrome (IBS) is a common disorder that considerably reduces the quality of life and productivity of patients. Chromogranin A (CgA) is a common marker for endocrine cells. CgA cell density has been reported to be reduced in the duodenum and colon of IBS patients. This study was undertaken to investigate CgA cell density in the ileum of these patients. The study involved 98 patients with IBS, according to the Rome III Criteria (77 females and 21 males, with an average age of 35 years). In total, 35 patients had diarrhoea-predominant symptoms (IBS-D), 32 had constipation-predominant symptoms (IBS-C), and 31 had a mixture of both diarrhoea and constipation (IBS-M). In this study, 27 subjects were used as controls (16 females and 11 males, with an average age of 52 years). Colonoscopies were performed on the patients and controls and biopsies were obtained from the ileum. Sections were immunostained with the avidin-biotin complex (ABC) for CgA and quantified using computerized image analysis. The CgA density in the controls was 63.2±4.4 (mean ± SEM), for all IBS patients it was 28.6±2.1, for IBS-D it was 28.8±3.4, for IBS-M it was 26.5±3.9 and for IBS-C it was 30.3±3.7. There was a statistically significant difference between the controls and all IBS patients (IBS-D, IBS-M and IBS-C; P<0.0001 for all). The present study showed that CgA cell density in the ileum of IBS patients was reduced, regardless of subtype. Thus, it appears that there is endocrine cell depletion in both the small and large intestine of IBS patients, whereas IBS is normally considered to be a functional condition without any detectable abnormalities. The present finding lends support to the suggestion that IBS is caused by a biological abnormality, and intestinal CgA cell density may be used as a biological marker for the diagnosis of IBS. Copyright © 2013 Spandidos Publications Ltd.


El-Salhy M.,Stord Helse Fonna Hospital | El-Salhy M.,University of Bergen | Wendelbo I.,Stord Helse Fonna Hospital | Wendelbo I.,University of Bergen | Gundersen D.,Helse Fonna
Molecular Medicine Reports | Year: 2013

Irritable bowel syndrome (IBS) is a common chronic gastrointestinal disorder, which considerably reduces the quality of life of patients and represents an economic burden to society. In previous studies, the density of serotonin-expressing cells in the rectum of IBS patients did not differ from that of control subjects. The present study was undertaken to investigate the immunoreactivity intensity of serotonin and serotonin-selective reuptake transporter (SERT) in the rectum of IBS patients. A cohort of 50 patients with IBS (41 females and 9 males) were included in the study. Thirty patients had diarrhoea (IBS-D) and 20 had constipation (IBS-C) as the predominant symptom. Twenty-seven subjects were included as controls (19 females and 8 males). Rectal biopsy specimens were immunostained using the avidin-biotin complex method for serotonin and SERT. The immunoreactivity intensity was quantified by computerised image analysis using Olympus cell Sens imaging software. There was no statistical difference of serotonin immunoreactivity intensity in multiple comparisons between controls, IBS-total, IBS-D and IBS-C. Dunn's post test did not reveal any statistical differences among the four groups. There was a significant statistical difference in multiple comparisons between controls, IBS-total, IBS-D and IBS-C regarding the SERT immunoreactivity intensity. SERT immunoreactivity intensity of IBS-total, IBS-D and IBS-C differed significantly from that of controls. It was concluded that the reduced rectal SERT in the IBS patients could be one of the factors contributing to the development of both diarrhoea and constipation in these patients, and that the increasing body of evidence of a genetic abnormality involving SERT underlines the importance of the role of SERT in the pathophysiology of IBS.


El-Salhy M.,Stord Helse Fonna Hospital | El-Salhy M.,University of Bergen | Mazzawi T.,Stord Helse Fonna Hospital | Gundersen D.,Helse Fonna | Hausken T.,University of Bergen
Molecular Medicine Reports | Year: 2012

In a previous study, chromogranin A (CgA) cell density in the colon of patients with irritable bowel syndrome (IBS) was found to be reduced. It has been suggested that intestinal CgA cell density may be used as a marker for the diagnosis of IBS. The rectum harbours a larger number of large intestinal endocrine cells and is more accessible for biopsies than the colon. The present study aimed at determining the CgA cell density in the rectum of IBS patients. A total of 47 patients with IBS that fulfilled the Rome Criteria III (39 females and 8 males; average age, 38 years) were included. A total of 28 patients had diarrhea (IBS-D) and 19 had constipation (IBS-C) as the predominant symptom. A total of 27 subjects that underwent colonoscopy with rectal biopsies were used as the controls. These subjects underwent colonoscopy due to gastrointestinal bleeding (the source of which was identified as haemorrhoids or angiodysplasia; 19 females and 8 males; average age, 49 years), or health worries. The rectal biopsies were immunostained for CgA and quantified by computer image analysis. The CgA density in the controls was 206.3±22.2 (mean ± SEM), in all IBS patients 190.2±14.3, in IBS-D patients 188.8±14.7 and in IBS-C patients 195.3±34.1. There was no statistically significant difference between the controls, IBS, IBS-D or IBS-C patients (P=0.5, 0.5 and 0.7, respectively). The present study showed that although the rectum comprises the same endocrine cell types as the colon, attention must be paid when drawing conclusions regarding the whole large intestine from studies carried out on the rectum. This particularly applies when endocrine cells are investigated. As CgA cell density represents the total endocrine cell content of the rectum, changes in specific endocrine cells in IBS patients cannot be excluded.


El-Salhy M.,University of Bergen | Gundersen D.,Helse Fonna | Hatlebakk J.G.,University of Bergen | Hausken T.,University of Bergen
Digestive Diseases and Sciences | Year: 2012

Background: Lymphocytic colitis (LC) can be mistakenly diagnosed as irritable bowel syndrome (IBS). In a previous study on IBS, some patients showed extremely high colonic chromogranin A cell density. Further examination of these patients showed that they suffered from LC. Aims: To investigate whether chromogranin A cell density is increased in LC patients and to examine the possibility of using this increase as a marker for the diagnosis of LC. Methods: Fifty-seven patients diagnosed with LC and 54 controls were included in the study. Biopsies from the right and left colon were obtained from both patients and controls, which were immunostained using the Avidin-biotin-complex method for chromogranin A, and cell density was quantified. Results: In both the right and left colon of patients with LC, the density of chromogranin A was significantly higher than in controls. This increase in chromogranin A cells occurs whether the number of these cells is expressed as number/mm2 epithelium or as number/field. Chromogranin A cell density for the right and left colon expressed as number of cells/mm2 epithelium or as cell number/field showed a high sensitivity and specificity as a diagnostic marker for LC. Conclusions: Chromogranin A is a common marker for endocrine cells, and the present finding suggests that colonic hormones are involved in the pathophysiology of LC. The chromogranin cell density seems to be a good diagnostic marker with high sensitivity and specificity in both the right and left colon, thus sigmoidoscopy can be used in the diagnosis of LC using with this marker. © 2012 The Author(s).


El-Salhy M.,Stord Helse Fonna Hospital | El-Salhy M.,University of Bergen | Gundersen D.,Helse Fonna | Gilja O.H.,University of Bergen | And 2 more authors.
World Journal of Gastroenterology | Year: 2014

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that is generally considered to be functional because there appears to be no associated anatomical defect. Stress and psychological factors are thought to play an important role in IBS. The gut neuroendocrine system (NES), which regulates all functions of the gastrointestinal tract, consists of endocrine cells that are scattered among the epithelial cells of the mucosa, and the enteric nervous system. Although it is capable of operating independently from the central nervous system (CNS), the gut NES is connected to and modulated by the CNS. This review presents evidence for the presence of an anatomical defect in IBS patients, namely in the gastrointestinal endocrine cells. These cells have specialized microvilli that project into the lumen and function as sensors for the luminal content and respond to luminal stimuli by releasing hormones into the lamina propria, which starts a chain reaction that progresses throughout the entire NES. The changes in the gastrointestinal endocrine cells observed in IBS patients are highly consistent with the other abnormalities reported in IBS patients, such as visceral hypersensitivity, dysmotility, and abnormal secretion. © 2014 Baishideng Publishing Group Co., Limited. All rights reserved.


El-Salhy M.,Stord Helse Fonna Hospital | Gundersen D.,Helse Fonna | Hatlebakk J.G.,University of Bergen | Hausken T.,University of Bergen
World Journal of Gastroenterology | Year: 2012

Aim: To investigate colonic endocrine cells in lymphocytic colitis (LC) patients. Methods: Fifty-seven patients with LC were included. These patients were 41 females and 16 males, with an average age of 49 years (range 19-84 years). Twenty-seven subjects that underwent colonoscopy with biopsies were used as controls. These subjects underwent colonoscopy because of gastrointestinal bleeding or health worries, where the source of bleeding was identified as haemorrhoids or angiodysplasia. They were 19 females and 8 males with an average age of 49 years (range 18-67 years). Biopsies from the right and left colon were obtained from both patients and controls during colonoscopy. Biopsies were fixed in 4% buffered paraformaldehyde, embedded in paraffin and cut into 5 μm-thick sections. The sections immunostained by the avidin-biotin-complex method for serotonin, peptide YY (PYY), pancreatic polypeptide (PP) enteroglucagon and somatostatin cells. The cell densities were quantified by computerised image analysis using Olympus software. Results: The colon of both the patient and the control subjects were macroscopically normal. Histopathological examination of colon biopsies from controls revealed normal histology. All patients fulfilled the diagnosis criteria required for of LC: an increase in intraepithelial lymphocytes (> 20 lymphocytes/100 epithelial cells) and surface epithelial damage with increased lamina propria plasma cells and absent or minimal crypt architectural distribution. In the colon of both patients and control subjects, serotonin-, PYY-, PP-, enteroglucagon- and somatostatin-immunoreactive cells were primarily located in the upper part of the crypts of Lieberkühn. These cells were basket- or flask-shaped. There was no statistically significant difference between the right and left colon in controls with regards to the densities of serotonin- and PYYimmunoreactive cells (P = 0.9 and 0.1, respectively). Serotonin cell density in the right colon in controls was 28.9 ± 1.8 and in LC patients 41.6 ± 2.6 (P = 0.008). In the left colon, the corresponding figures were 28.5 ± 1.9 and 42.4 ± 2.9, respectively (P = 0.009). PYY cell density in the right colon of the controls was 10.1 ± 1 and of LC patients 41 ± 4 (P = 0.00006). In the left colon, PYY cell density in controls was 6.6 ± 1.2 and in LC patients 53.3 ± 4.6 (P = 0.00007). Conclusion: The change in serotonin cells could be caused by an interaction between immune cells and serotonin cells, and that of PYY density might be secondary. © 2012 Baishideng. All rights reserved.


El-Salhy M.,Stord Helse Fonna Hospital | El-Salhy M.,University of Bergen | Lomholt-Beck B.,Haugesund Helse Fonna Hospital | Gundersen D.,Helse Fonna
Molecular Medicine Reports | Year: 2011

The diagnosis of irritable bowel syndrome (IBS) is based on symptom assessment such as the Rome III criteria. It is sometimes difficult to clinically distinguish IBS from adult-onset celiac disease (CD), individuals with CD presenting with relatively vague abdominal symptoms are at risk of been dismissed as having IBS. This study aimed to investigate the prevalence of patients with CD among those that fulfil the Rome III criteria for IBS from among patients referred to the gastroenterology section of our hospital over the last 5 years. The study included a total of 968 patients with an average age of 32 years (range 18-59 years). Females constituted 95% of all patients. Duodenal biopsies were obtained during standard gastroscopy. Sections from these biopsies were stained with haematoxylin and eosin and immunostained for human leucocytes CD45 using the avidin-biotin complex (ABC) method. The sections were then histopathologically examined. Four patients had CD: one with Marsh type 3b, and 3 with Marsh type 1. All four of these patients were positive for tissue transglutminase antibodies (anti-t-TG) IgA and were females aged 24, 20, 36 and 38 years. These 4 patients fulfilled the Rome III criteria for the sub-type IBS-diarrhea. This amounts to a prevalence of 0.4% of CD in IBS patients. The present fndings support the notion that IBS patients should be routinely examined for CD. This applies to all subtypes of IBS.


El-Salhy M.,Stord Helse Fonna Hospital | El-Salhy M.,University of Bergen | Gilja O.H.,University of Bergen | Gundersen D.,Helse Fonna | And 2 more authors.
World Journal of Gastroenterology | Year: 2014

Aim: To study the ileal endocrine cell types in irritable bowel syndrome (IBS) patients. Methods: Ninety-eight patients with IBS (77 females and 21 males; mean age 35 years, range 18-66 years) were included, of which 35 patients had diarrhea (IBS-D), 31 patients had a mixture of both diarrhea and constipation (IBS-M), and 32 patients had constipation (IBS-C) as the predominant symptoms. The controls were 38 subjects (26 females and 12 males; mean age 40 years, range 18-65 years) who had submitted to colonoscopy for the following reasons: gastrointestinal bleeding, where the source of bleeding was identified as hemorrhoids (n = 24) or angiodysplasia (n = 3), and health worries resulting from a relative being diagnosed with colon carcinoma (n = 11). The patients were asked to complete the: Birmingham IBS symptom questionnaire. Ileal biopsy specimens from all subjects were immunostained using the avidinbiotin- complex method for serotonin, peptide YY (PYY), pancreatic polypeptide (PP), enteroglucagon, and somatostatin cells. The cell densities were quantified by computerized image analysis, using Olympus cellSens imaging software. Results: The gender and age distributions did not differ significantly between the patients and the controls (P = 0.27 and P = 0.18, respectively). The total score of Birmingham IBS symptom questionnaire was 21 ± 0.8, and the three underlying dimensions: pain, diarrhea, and constipation were 7.2 ± 0.4, 6.6 ± 0.4, and 7.2 ± 0.4, respectively. The density of serotonin cells in the ileum was 40.6 ± 3.6 cells/mm2 in the controls, and 11.5 ± 1.2, 10.7 ± 5.6, 10.0 ± 1.9, and 13.9 ± 1.4 cells/mm2 in the all IBS patients (IBS-total), IBS-D, IBS-M, and IBS-C patients, respectively. The density in the controls differed significantly from those in the IBS-total, IBS-D, IBS-M, and IBS-C groups (P < 0.0001, P = 0.0001, P = 0.0001, and P < 0.0001, respectively). There was a significant inverse correlation between the serotonin cell density and the pain dimension of Birmingham IBS symptom questionnaire (r = -0.6, P = 0.0002). The density of PYY cells was 26.7 ± 1.6 cells/mm2 in the controls, and 33.1 ± 1.4, 27.5 ± 1.4, 34.1 ± 2.5, and 41.7 ± 3.1 cells/mm2 in the IBStotal, IBS-D, IBS-M, and IBS-C patients, respectively. This density differed significantly between patients with IBS-total and IBS-C and the controls (P = 0.03 and < 0.0001, respectively), but not between controls and, IBS-D, and IBS-M patients (P = 0.8, and P = 0.1, respectively). The density of PYY cells correlated significantly with the degree of constipation as recorded by the Birmingham IBS symptom questionnaire (r = 0.6, P = 0.0002). There were few PP-, enteroglucagon-, and somatostatin-immunoreactive cells in the biopsy material examined, which made it impossible to reliably quantify these cells. Conclusion: The decrease of ileal serotonin cells is associated with the visceral hypersensitivity seen in all IBS subtypes. The increased density of PYY cells in IBS-C might contribute to the constipation experienced by these patients. © 2014 Baishideng Publishing Group Co., Limited. All rights reserved.


El-Salhy M.,Stord Helse Fonna Hospital | El-Salhy M.,University of Bergen | Gundersen D.,Helse Fonna | Hatlebakk J.G.,University of Bergen | And 2 more authors.
Regulatory Peptides | Year: 2014

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder. In a previous study the total number of endocrine cells in the rectum of IBS patients, as detected by chromogranin A, did not differ from that of healthy controls. While the total endocrine cell content of the rectum appears to be unchanged in IBS patients, changes in particular endocrine cells cannot be excluded. This study was undertaken, therefore, to investigate the cell density of different rectal endocrine cell types in (IBS) patients. Fifty patients with IBS (41 females and 9 males) were included in the study. Thirty patients had diarrhoea (IBS-D) and 20 had constipation (IBS-C) as the predominant symptom. Twenty-seven subjects were included as controls (19 females and 8 males). Rectal biopsy specimens were immunostained using the avidin-biotin-complex method for serotonin, peptide YY (PYY), pancreatic polypeptide (PP), and oxyntomodulin and somatostatin cells. The cell densities were quantified by computerised image analysis. The serotonin cell density did not differ significantly, although a type II statistical error cannot be excluded, due to the small size of the sample. The densities of PYY and Oxyntomodulin cells were significantly lower and that of somatostatin were significantly higher in IBS patients than controls. These abnormalities were observed in both IBS-D and IBS-C patients. The abnormalities in the endocrine cells observed in this study in the rectum differed considerably from those seen in the colon of IBS patients. This indicates that caution in using the rectum to represent the large intestine in these patients. These abnormalities could be primary (genetic) or secondary to changes in the gut hormones found in other segments of the gut and/or other pathological processes. Although the-cause-and effect relationship of the abnormalities found in rectal endocrine cells is difficult to elucidate, they might contribute to the symptoms associated with IBS. The densities of PYY and somatostatin cells are potential biomarkers with good sensitivity and specificity for the diagnosis of IBS. © 2013 Elsevier B.V.

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