• Barrier function
• Enteroendocrine cells
• Gastrointestinal disease
• Gut hormone
• Intestinal homeostasis
• Nutrient absorption

• Enteroendocrine Cells/metabolism
• Humans
• Homeostasis
• Animals
• Intestinal Mucosa/metabolism
• Intestinal Mucosa/cytology
• Stem Cells/metabolism
• Stem Cells/cytology
• Cell Proliferation
• Intestinal Absorption
• Intestines/cytology
• Intestines/physiology
• Paracrine Communication

• K01 DK125341 NIDDK NIH HHS

• gastroenterology
• gastrointestinal hormones

• Male
• Female
• Humans
• Adult
• Middle Aged
• Gastrointestinal Hormones
• Irritable Bowel Syndrome
• Ghrelin
• Gastrins
• Postprandial Period
• Cholecystokinin
• Vasoactive Intestinal Peptide
• Insulins

• cell densities
• duodenum
• fecal microbiota transplantation
• gut hormones
• irritable bowel syndrome
• microbiota
• neuroendocrine
• stem cells

• Diarrhea
• Duodenum
• Enteroendocrine Cells
• Fecal Microbiota Transplantation
• Feces
• Female
• Humans
• Irritable Bowel Syndrome/therapy
• Male
• Norway

• Irritable bowel syndrome
• Watson capsule
• enteroendocrine cells
• jejunum
• morphometry

The pathophysiology of irritable bowel syndrome (IBS) is not completely understood. However, several factors are known to play a role in pathophysiology of IBS such as genetics, diet, gut microbiota, gut endocrine cells, stress and low-grade inflammation. Understanding the pathophysiology of IBS may open the way for new treatment approaches. Low density of intestinal stem cells and low differentiation toward enteroendocrine cells has been reported recently in patients with IBS. These abnormalities are believed to be the cause of the low density of enteroendocrine cells seen in patients with IBS. Enteroendocrine cells regulate gastrointestinal motility, secretion, absorption and visceral sensitivity. Gastrointestinal dysmotility, abnormal absorption/secretion and visceral hypersensitivity are all seen in patients with IBS and haven been attributed to the low density the intestinal enteroendocrine cells in these patients. The present review conducted a literature search in Medline (PubMed) covering the last ten years until November 2019, where articles in English were included. Articles about the intestinal stem cells and their possible role in the pathophysiology of IBS are discussed in the present review. The present review discusses the assumption that intestinal stem cells play a central role in the pathophysiology of IBS and that the other factors known to contribute to the pathophysiology of IBS such as genetics, diet gut microbiota, stress, and low-grade inflammation exert their effects through affecting the intestinal stem cells. It reports further the data that support this assumption on genetics, diet, gut microbiota, stress with depletion of glutamine, and inflammation.

• Diet
• Gut enteroendocrine cells
• Gut microbiota
• Low grade inflammation
• Stress

• Cell Differentiation
• Enteroendocrine Cells/physiology
• Gastrointestinal Motility/physiology
• Humans
• Intestines/cytology
• Irritable Bowel Syndrome/physiopathology
• Stem Cells/physiology

• IBS
• diet
• fecal microbiota transplantation
• gut endocrine cells
• gut microbiota

To evaluate the most common studied genetic polymorphisms that may have an etiological role in irritable bowel syndrome (IBS).

The data base PubMed was searched for studies analyzing the association between gene polymorphisms and IBS. All original full papers, written in English, were retained for further analysis. The retrieved papers were further systematized according to those polymorphisms that have been detected in IBS.

Considering these criteria, our literature search found 12 polymorphisms, residing in 10 genes, which were reported to be consistently associated with IBS. The initial search identified 189 articles, out of which 48 potentially appropriate articles were reviewed. Of these 48 articles, 41 articles were included in the review. These articles were published between 2002 and 2016. Out of these 41 studies, 17 reported analysis of the serotonin transporter (SERT) gene (SLC6A4), eight on guanine nucleotide-binding protein subunit beta-3 (GNbeta3), six on the serotonin type 3 receptor genes (HTR3A), four on (HTR3E), three on (HTR2A), three the tumor necrosis factor superfamily member TL1A gene (TNFSF15), and ten on genetic polymorphisms with limited evidence.

Current evidence for the relation between genetic polymorphisms and IBS is limited owing to the fact that high-quality prospective studies and detailed phenotyping of patients suffering from IBS and matched controls were lacking in the past.

• Irritable bowel syndrome
• Gene
• Genetic polymorphisms

Irritable bowel syndrome (IBS) is a common chronic gastrointestinal (GI) disorder that is characterized by a combination of abdominal pain or discomfort, bloating and alterations in bowel movements. This review presents recent developments concerning the roles of diet and GI endocrine cells in the pathophysiology of IBS and of individual dietary guidance in the management of IBS. Patients with IBS typically report that food aggravates their IBS symptoms. The interactions between specific types of foodstuffs rich in fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) and GI endocrine cells induce changes in cell densities. Providing individual dietary guidance about a low FODMAP intake, high soluble-fiber intake, and changing the proportions of protein, fat and carbohydrates helps to reduce the symptoms experienced by patients with IBS and to improve their quality of life. These improvements are due to restoring the densities of the GI endocrine cells back to normal. The reported observations emphasize the role of GI endocrine cells in the pathophysiology of IBS and support the provision of dietary guidance as a first-line treatment for managing IBS.

This study examined whether the densities of stem- and enteroendocrine cell progenitors are abnormal in the ileum of patients with irritable bowel syndrome (IBS), and whether any abnormalities in ileal enteroendocrine cells are correlated with abnormalities in stem cells and enteroendocrine cell progenitors.

One hundred and one IBS patients covering all IBS subtypes were recruited, and 39 non-IBS subjects were included as a control group. The patients and controls underwent standard colonoscopies, during which biopsy specimens were obtained from the ileum. The biopsy specimens were stained with hematoxylin-eosin and immunostained for Musashi-1 (Msi-1), neurogenin 3 (NEUROG3), chromogranin A (CgA), serotonin, peptide YY (PYY), oxyntomodulin (enteroglucagon), pancreatic polypeptide, and somatostatin. The immunoreactive cells were quantified by computerized image analysis.

The densities of Msi-1, NEUROG3, CgA, and serotonin cells were reduced in all IBS patients and in patients with diarrhea-predominant IBS (IBS-D), mixed-diarrhea-and-constipation IBS (IBS-M), and constipation-predominant (IBS-C) relative to the control subjects. While the PYY cell density was increased in IBS-C relative to controls, it did not differ between control subjects and IBS-D and IBS-M patients. The densities of Msi-1 and NEUROG3 cells were strongly correlated with that of CgA cells.

The abnormalities in the ileal enteroendocrine cells appear to be caused by two mechanisms: (1) decreases in the clonogenic activity of the stem cells and in the endocrine-cell progenitors differentiating into enteroendocrine cells, and (2) switching on the expression of PYY and switching off the expression of certain other hormones in other types of the enteroendocrine cells.

• Enteroendocrine cells
• IBS
• Ileum
• Immunohistochemistry
• Mushasi-1
• Neurogenin 3
• PYY
• Serotonin

The densities of enteroendocrine cells are abnormal in patients with irritable bowel syndrome (IBS); however, they tend to change toward normal levels in stomach, ileum, and colon following dietary guidance. The aim was to identify the types of duodenal enteroendocrine cells affected after receiving dietary guidance in the same group of patients with IBS. Fourteen patients with IBS and 14 control subjects were included. The patients received three sessions of dietary guidance. Both groups underwent gastroscopies at baseline, and again for the patients after 3–9 months (median, four months) from receiving dietary guidance. Tissue biopsies were collected from the descending part of the duodenum and were immunostained for all the types of enteroendocrine cells and were then quantified by using computerized image analysis. Using the Kruskal–Wallis non-parametric test with Dunn’s test as a post-test, the results showed a significant difference in the secretin cell densities between control subjects and patients with IBS prior to and following dietary guidance (P = 0.0001 and 0.011, respectively). The corresponding P values for cholecystokinin (CCK) cell densities were 0.03 and 0.42, respectively; gastric inhibitory peptide (GIP) cell densities were 0.06 and 0.43, respectively; serotonin cell densities were <0.0001 and 0.002, respectively; and for somatostatin cell densities were <0.0001 and 0.052, respectively. The Paired t-test showed a significant difference only in the serotonin (P = 0.03) and somatostatin (P < 0.0001) cell densities between IBS patients prior to and following dietary guidance. The changes in the cell densities of secretin, CCK, and GIP were not significant between IBS patients prior to and following dietary guidance. In conclusion, the densities of several duodenal enteroendocrine cells in IBS patients changed toward the values measured in control subjects following dietary guidance. The changes in serotonin and somatostatin cell densities may have contributed to the improvements in IBS symptoms, particularly pain and diarrhea.

• Computerized image analysis
• diet
• duodenum
• enteroendocrine cells
• immunohistochemistry
• irritable bowel syndrome

• Diet
• Musashi-1
• genes
• low-grade inflammation
• microbiota
• neurogenin 3
• stem cells

• diet
• enteroendocrine cells
• ileum
• image analysis
• immunohistochemistry
• irritable bowel syndrome

• chromogranin A
• genes
• low-grade inflammation
• microbiota
• peptide YY
• somatostatin
• stem cell

To determine the large intestinal endocrine cell types affected following dietary guidance in patients with irritable bowel syndrome (IBS).

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.

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/mm² 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/mm², 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/mm² for control subjects and for IBS patients before and after receiving dietary guidance, respectively (P=0.01).

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.

• Celiac Disease/diagnosis
• Diet, Gluten-Free
• Food Hypersensitivity/diagnosis
• Glutens/adverse effects
• Humans
• Inflammation/diagnosis
• Irritable Bowel Syndrome/diagnosis
• Randomized Controlled Trials as Topic
• Triticum/chemistry

AIM: To determine whether the decreased density of duodenal endocrine cells in irritable bowel syndrome (IBS) is associated with abnormalities in stem cell differentiation.

METHODS: The study sample comprised 203 patients with IBS (180 females and 23 males with a mean age of 36 years) and a control group of 86 healthy subjects without gastrointestinal complaints (77 females and 9 males with a mean age of 38 years). The patients included 80 with mostly diarrhoea (IBS-D), 47 with both diarrhoea and constipation (IBS-M), and 76 with mostly constipation (IBS-C). Both the patients and controls underwent gastroscopy and four biopsy samples were taken from the descending part of the duodenum, proximal to the papilla of Vater. The biopsy samples were sectioned and immunostained for Musashi 1 (Msi-1), neurogenin 3 (NEUROG3), secretin, cholecystokinin (CCK), gastric inhibitory peptide (GIP), somatostatin and serotonin. Immunostaining was performed with an ultraView Universal DAB Detection Kit (v1.02.0018, Venata Medical Systems, Basal, Switzerland) using the BenchMark Ultra immunohistochemistry/in situ hybridization staining module (Venata Medical Systems). Endocrine cell densities were quantified by computerized image analysis using the Olympus cellSens imaging program.

RESULTS: The densities of Msi-1 and NEUROG3 cells were significantly lower in IBS patients, regardless of the subtype, than in the controls (77 ± 17 vs 8 ± 2; P = 0.0001, and 351 ± 33 vs 103 ± 22; P = 0.00002, respectively). Furthermore, the densities of secretin, and CCK cells were significantly lower in patients with diarrhoea as the predominant IBS symptom (IBS-D) than in the controls (161 ± 11 vs 88 ± 8; P = 0.00007, and 325 ± 41 vs 118 ± 10; P = 0.00006, respectively), but not in patients with constipation as the predominant IBS symptom (IBS-C) or those with both diarrhoea and constipation (IBS-M). The GIP cell density was significantly reduced in both IBS-D (152 ± 12 vs 82 ± 7; P = 0.00003), and IBS-C (152 ± 12 vs 107 ± 8; P = 0.01), but not in IBS-M. The densities of somatostatin cells in the controls and the IBS-total, IBS-D, IBS-M and IBS-C patients were 81 ± 8, 28 ± 3, 20 ± 4, 37 ± 5 and 28 ± 4 cells/mm² epithelium, respectively. The density of somatostatin cells was lower in IBS-total, IBS-D, IBS-M and IBS-C patients than in the controls (P = 0.00009, 0.00006, 0.009 and 0.00008, respectively). The density of serotonin cells did not differ between IBS patients and controls.

CONCLUSION: The reduction in duodenal endocrine cells in IBS patients found in this study is probably attributable to the reduction in cells expressing Msi-1 and NEUROG3.

• Cholecystokinin
• Irritable bowel syndrome
• Musashi-1
• Neurogenin 3
• Secretin
• Somatostatin

• Adolescent
• Adult
• Aged
• Basic Helix-Loop-Helix Transcription Factors/analysis
• Biomarkers/analysis
• Biopsy
• Case-Control Studies
• Cell Differentiation
• Duodenum/chemistry
• Duodenum/pathology
• Enteroendocrine Cells/chemistry
• Enteroendocrine Cells/pathology
• Female
• Gastroscopy
• Humans
• Immunohistochemistry
• Irritable Bowel Syndrome/metabolism
• Irritable Bowel Syndrome/pathology
• Male
• Middle Aged
• Nerve Tissue Proteins/analysis
• Phenotype
• RNA-Binding Proteins/analysis
• Stem Cells/chemistry
• Stem Cells/pathology
• Young Adult

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder, the pathophysiology of which is not completely known, although it has been shown that genetic/social learning factors, diet, intestinal microbiota, intestinal low-grade inflammation, and abnormal gastrointestinal endocrine cells play a major role. Studies of familial aggregation and on twins have confirmed the heritability of IBS. However, the proposed IBS risk genes are thus far nonvalidated hits rather than true predisposing factors. There is no convincing evidence that IBS patients suffer from food allergy/intolerance, with the effect exerted by diet seemingly caused by intake of poorly absorbed carbohydrates and fiber. Obesity is a possible comorbidity of IBS. Differences in the microbiota between IBS patients and healthy controls have been reported, but the association between IBS symptoms and specific bacterial species is uncertain. Low-grade inflammation appears to play a role in the pathophysiology of a major subset of IBS, namely postinfectious IBS. The density of intestinal endocrine cells is reduced in patients with IBS, possibly as a result of genetic factors, diet, intestinal microbiota, and low-grade inflammation interfering with the regulatory signals controlling the intestinal stem-cell clonogenic and differentiation activities. Furthermore, there is speculation that this decreased number of endocrine cells is responsible for the visceral hypersensitivity, disturbed gastrointestinal motility, and abnormal gut secretion seen in IBS patients.

• Diet
• Endocrine cells
• Genetic factors
• Low-grade inflammation
• Microbiota
• Stem cells

• Animals
• Comorbidity
• Diet/adverse effects
• Gene-Environment Interaction
• Genetic Markers
• Genetic Predisposition to Disease
• Host-Pathogen Interactions
• Humans
• Intestines/microbiology
• Intestines/pathology
• Intestines/physiopathology
• Irritable Bowel Syndrome/etiology
• Irritable Bowel Syndrome/genetics
• Irritable Bowel Syndrome/metabolism
• Irritable Bowel Syndrome/microbiology
• Irritable Bowel Syndrome/physiopathology
• Microbiota
• Phenotype
• Risk Factors
• Signal Transduction
• Stem Cells/metabolism
• Stem Cells/microbiology
• Stem Cells/pathology

• Biomarkers
• Diagnosis
• Immunohistochemistry
• Irritable bowel syndrome
• PYY
• Somatostatin

• Adolescent
• Adult
• Biomarkers/metabolism
• Case-Control Studies
• Female
• Humans
• Irritable Bowel Syndrome/diagnosis
• Irritable Bowel Syndrome/metabolism
• Male
• Middle Aged
• Peptide YY/metabolism
• ROC Curve
• Rectum/metabolism
• Rectum/pathology
• Somatostatin/metabolism
• Young Adult

Irritable bowel syndrome (IBS) is a common chronic gastrointestinal disorder that is characterized by intermittent abdominal pain/discomfort, altered bowel habits and abdominal bloating/distension. This review aimed at presenting the recent developments concerning the role of diet in the pathophysiology and management of IBS. There is no convincing evidence that IBS patients suffer from food allergy/intolerance, and there is no evidence that gluten causes the debated new diagnosis of non-coeliac gluten sensitivity (NCGS). The component in wheat that triggers symptoms in NCGS appears to be the carbohydrates. Patients with NCGS appear to be IBS patients who are self-diagnosed and self-treated with a gluten-free diet. IBS symptoms are triggered by the consumption of the poorly absorbed fermentable oligo-, di-, monosaccharides and polyols (FODMAPs) and insoluble fibre. On reaching the distal small intestine and colon, FODMAPS and insoluble fibre increase the osmotic pressure in the large-intestine lumen and provide a substrate for bacterial fermentation, with consequent gas production, abdominal distension and abdominal pain or discomfort. Poor FODMAPS and insoluble fibres diet reduces the symptom and improve the quality of life in IBS patients. Moreover, it changes favourably the intestinal microbiota and restores the abnormalities in the gastrointestinal endocrine cells. Five gastrointestinal endocrine cell types that produce hormones regulating appetite and food intake are abnormal in IBS patients. Based on these hormonal abnormalities, one would expect that IBS patients to have increased food intake and body weight gain. However, the link between obesity and IBS is not fully studied. Individual dietary guidance for intake of poor FODMAPs and insoluble fibres diet in combination with probiotics intake and regular exercise is to be recommended for IBS patients.

To the best of our knowledge, stomach antral endocrine cells have not previously been investigated in patients with irritable bowel syndrome (IBS). Thus, in the present study, 76 patients with IBS were examined (designated as IBS-total). Diarrhoea was the predominant symptom in 26 of these patients (IBS-D), while in 21 patients, the predominant symptoms were both diarrhoea and constipation (IBS-M) and in 29 patients the predominant symptom was constipation (IBS-C). Forty-three healthy subjects were enrolled as the controls. Stomach antral biopsy samples obtained from all of the subjects were immunostained using the avidin-biotin-complex method for serotonin, gastrin, somatostatin and serotonin transporter (SERT). The immunopositive cell densities and immunoreactivity intensities were determined by computer-aided image analysis. The density of the serotonin-immunoreactive cells was significantly decreased in the IBS-M patients and increased in the IBS-C patients relative to the controls. The immunoreactivity intensity did not differ significantly between the controls and IBS-total. The density of the gastrin-immunoreactive cells was significantly greater in the IBS-D, IBS-M and IBS-C patients than in the controls. The immunoreactivity intensity of gastrin was significantly greater in the IBS-D patients than in the controls. The density of the somatostatin-immunoreactive cells cells was significantly lower in the IBS-total, IBS-D, IBS-M and IBS-C patients than in the controls. The immunoreactivity intensities of both somatostatin and SERT did not differ significantly between the controls and IBS-total. The increase in gastrin cell density and the decrease in somatostatin cell density in all IBS subtypes may cause high levels of gastric secretion, which may in turn contribute to the high incidence of dyspepsia and gastro-oesophageal reflux observed in patients with IBS.

• allergy
• cholecystokinin
• diet
• endocrine cells
• enteric nervous system
• gluten
• minerals
• polypeptide yy
• probiotics
• serotonin

• Eating
• Energy Intake/genetics
• Enteroendocrine Cells/metabolism
• Enteroendocrine Cells/pathology
• Gastrointestinal Motility
• Gastrointestinal Tract/pathology
• Humans
• Irritable Bowel Syndrome/diet therapy
• Irritable Bowel Syndrome/metabolism
• Irritable Bowel Syndrome/pathology
• Phenobarbital/therapeutic use
• Quality of Life

• IBS
• histamine
• mast cells
• proteases
• visceral hyperalgesia

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders, characterized by abdominal pain, bloating, and changes in bowel habits. These symptoms cannot be explained by structural abnormalities and there is no specific laboratory test or biomarker for IBS. Therefore, IBS is classified as a functional disorder with diagnosis dependent on the history taking about manifested symptoms and careful physical examination. Although a great deal of research has been carried out in this area, the pathophysiology of IBS is complex and not completely understood. Multiple factors are thought to contribute to the symptoms in IBS patients; altered gastrointestinal motility, visceral hypersensitivity, and the brain-gut interaction are important classical concepts in IBS pathophysiology. New areas of research in this arena include inflammation, postinfectious low-grade inflammation, genetic and immunologic factors, an altered microbiota, dietary factors, and enteroendocrine cells. These emerging studies have not shown consistent results, provoking controversy in the IBS field. However, certain lines of evidence suggest that these mechanisms are important at least a subset of IBS patients, confirming that IBS symptoms cannot be explained by a single etiological mechanism. Therefore, it is important to keep in mind that IBS requires a more holistic approach to determining effective treatment and understanding the underlying mechanisms.

• Pathophysiology
• Irritable bowel syndrome
• Inflammation
• Immunologic
• Genetics
• Microbiota
• Diet
• Enteroendocrine cell

• Animals
• Diet/adverse effects
• Enteroendocrine Cells/metabolism
• Genetic Predisposition to Disease
• Humans
• Inflammation Mediators/metabolism
• Intestinal Mucosa/metabolism
• Intestines/immunology
• Intestines/innervation
• Intestines/microbiology
• Intestines/physiopathology
• Irritable Bowel Syndrome/genetics
• Irritable Bowel Syndrome/immunology
• Irritable Bowel Syndrome/metabolism
• Irritable Bowel Syndrome/microbiology
• Irritable Bowel Syndrome/physiopathology
• Phenotype
• Prognosis
• Risk Factors
• Signal Transduction

• Computer image analysis
• Ileum
• Irritable bowel syndrome
• Peptide YY
• Serotonin

• Adolescent
• Adult
• Aged
• Biomarkers/analysis
• Biopsy
• Case-Control Studies
• Colonoscopy
• Constipation/etiology
• Diarrhea/etiology
• Endocrine Cells/chemistry
• Endocrine Cells/pathology
• Female
• Glucagon-Like Peptides/analysis
• Humans
• Hyperalgesia/etiology
• Ileum/chemistry
• Ileum/pathology
• Image Interpretation, Computer-Assisted
• Immunohistochemistry
• Irritable Bowel Syndrome/complications
• Irritable Bowel Syndrome/metabolism
• Irritable Bowel Syndrome/pathology
• Male
• Middle Aged
• Pain Measurement
• Pancreatic Polypeptide/analysis
• Peptide YY/analysis
• Serotonin/analysis
• Somatostatin/analysis
• Somatostatin-Secreting Cells/chemistry
• Somatostatin-Secreting Cells/pathology
• Surveys and Questionnaires
• Visceral Pain/etiology
• Young Adult

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.

• Cholecystokinin
• Dysmotility
• Endocrine cells
• Enteric nervous system
• Ghrelin
• Peptide YY
• Secretion
• Secretin
• Serotonin
• Visceral hypersensitivity

• Abdominal Pain/etiology
• Abdominal Pain/metabolism
• Animals
• Colon/innervation
• Colon/metabolism
• Colon/pathology
• Enteroendocrine Cells/metabolism
• Enteroendocrine Cells/pathology
• Gastrointestinal Motility
• Humans
• Irritable Bowel Syndrome/diagnosis
• Irritable Bowel Syndrome/etiology
• Irritable Bowel Syndrome/metabolism
• Irritable Bowel Syndrome/physiopathology
• Neuroendocrine Cells/metabolism
• Neuroendocrine Cells/pathology
• Risk Factors
• Signal Transduction

• Computerised image analysis
• Enteroglucagon
• PYY
• Rectum
• Serotonin
• Somatostatin

• Adolescent
• Adult
• Cell Count
• Endocrine Cells/metabolism
• Female
• Humans
• Irritable Bowel Syndrome/metabolism
• Irritable Bowel Syndrome/pathology
• Male
• Middle Aged
• Oxyntomodulin/metabolism
• Peptide YY/metabolism
• ROC Curve
• Rectum/pathology
• Serotonin/metabolism
• Somatostatin/metabolism
• Young Adult

• diabetes gastroenteropathy
• chronic idiopathic slow transit constipation
• familial amyloidosis with polyneuropathy
• irritable bowel syndrome
• inflammatory bowel disease
• lymphocytic colitis
• peptide yy
• serotonin

• Animals
• Drug Discovery
• Gastrointestinal Agents/therapeutic use
• Gastrointestinal Diseases/drug therapy
• Gastrointestinal Diseases/metabolism
• Gastrointestinal Diseases/pathology
• Gastrointestinal Diseases/surgery
• Gastrointestinal Tract/drug effects
• Gastrointestinal Tract/metabolism
• Gastrointestinal Tract/pathology
• Gastrointestinal Tract/surgery
• Humans
• Peptide YY/analysis
• Peptide YY/metabolism
• Peptide YY/therapeutic use

AIM: To investigate the effect of sulfated cholecystokinin-8 (CCK-8S) on calcium mobilization in cultured murine gastric antral interstitial cells of Cajal (ICC) and its possible mechanisms.

METHODS: ICC were isolated from the gastric antrum of mice and cultured. Immunofluorescence staining with a monoclonal antibody for c-Kit was used to identify ICC. The responsiveness of ICC to CCK-8S was measured using Fluo-3/AM based digital microfluorimetric measurement of intracellular Ca²⁺ concentration ([Ca²⁺]i). A confocal laser scanning microscope was used to monitor [Ca²⁺]i changes. The selective CCK₁ receptor antagonist lorglumide, the intracellular Ca²⁺-ATPase inhibitor thapsigargin, the type III inositol 1,4,5-triphosphate (InsP₃) receptor blocker xestospongin C and the L-type voltage-operated Ca²⁺ channel inhibitor nifedipine were used to examine the mechanisms of [Ca²⁺]i elevation caused by CCK-8S. Immunoprecipitation and Western blotting were used to determine the regulatory effect of PKC on phosphorylation of type III InsP₃ receptor (InsP₃R3) in ICC. Protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) and inhibitor chelerythrine were used to assess the role of PKC in the CCK-8S-evoked [Ca²⁺]i increment of ICC.

RESULTS: ICC were successfully isolated from the gastric antrum of mice and cultured. Cultured ICC were identified by immunofluorescence staining. When given 80 nmol/L or more than 80 nmol/L CCK-8S, the [Ca²⁺]i in ICC increased and 100 nmol/L CCK-8S significantly increased the mean [Ca²⁺]i by 59.30% ± 4.85% (P < 0.01). Pretreatment of ICC with 5 μmol/L lorglumide inhibited 100 nmol/L CCK-8S-induced [Ca²⁺]i increment from 59.30% ± 4.85% to 14.97% ± 9.05% (P < 0.01), suggesting a CCK₁R-mediated event. Emptying of intracellular calcium stores by thapsigargin (5 μmol/L) prevented CCK-8S (100 nmol/L) from inducing a [Ca²⁺]i increase. Moreover, pretreatment with xestospongin C (1 μmol/L) could also abolish the CCK-8S-induced effect, indicating that Ca²⁺ release from InsP₃R-operated stores appeared to be a major mechanism responsible for CCK-8S-induced calcium mobilization in ICC. On the other hand, by removing extracellular calcium or blocking the L-type voltage-operated calcium channel with nifedipine, a smaller but significant rise in the [Ca²⁺]i could be still elicited by CCK-8S. These data suggest that the [Ca²⁺]i release is not stimulated or activated by the influx of extracellular Ca²⁺ in ICC, but the influx of extracellular Ca²⁺ can facilitate the [Ca²⁺]i increase evoked by CCK-8S. CCK-8S increased the phosphorylation of InsP₃R3, which could be prevented by chelerythrine. Pretreatment with lorglumide (5 μmol/L) could significantly reduce the CCK-8S intensified phosphorylation of InsP₃R3. In the positive control group, treatment of cells with PMA also resulted in an enhanced phosphorylation of InsP₃R3. Pretreatment with various concentrations of PMA (10 nmol/L-10 μmol/L) apparently inhibited the effect of CCK-8S and the effect of 100 nmol/L PMA was most obvious. Likewise, the effect of CCK-8S was augmented by the pretreatment with chelerythrine (10 nmol/L-10 μmol/L) and 100 nmol/L chelerythrine exhibited the maximum effect.

CONCLUSION: CCK-8S increases [Ca²⁺]i in ICC via the CCK₁ receptor. This effect depends on the release of InsP₃R-operated Ca²⁺ stores, which is negatively regulated by PKC-mediated phosphorylation of InsP₃R3.

• Cholecystokinin octapeptide
• Interstitial cells of Cajal
• Calcium mobilization
• Protein kinase C

• Animals
• Calcium/metabolism
• Calcium Signaling
• Cells, Cultured
• Chemokines, CC
• Cholecystokinin/pharmacology
• Female
• Fluorometry
• Inositol 1,4,5-Trisphosphate Receptors/metabolism
• Interstitial Cells of Cajal/metabolism
• Male
• Mice
• Mice, Inbred BALB C
• Microscopy, Confocal
• Microscopy, Fluorescence
• Peptide Fragments/pharmacology
• Phosphorylation
• Protein Kinase C/metabolism
• Pyloric Antrum/metabolism
• Receptors, Cholecystokinin/metabolism
• Tetradecanoylphorbol Acetate/pharmacology

• Case-Control Studies
• Cytokines/immunology
• Humans
• Intestinal Mucosa/immunology
• Intestines/physiology
• Irritable Bowel Syndrome/immunology
• Lymphocytes/immunology
• Mast Cells/immunology
• Permeability

Irritable bowel syndrome (IBS) is a common gastrointestinal (GI) disorder that considerably reduces the quality of life. It further represents an economic burden on society due to the high consumption of healthcare resources and the non-productivity of IBS patients. The diagnosis of IBS is based on symptom assessment and the Rome III criteria. A combination of the Rome III criteria, a physical examination, blood tests, gastroscopy and colonoscopy with biopsies is believed to be necessary for diagnosis. Duodenal chromogranin A cell density is a promising biomarker for the diagnosis of IBS. The pathogenesis of IBS seems to be multifactorial, with the following factors playing a central role in the pathogenesis of IBS: heritability and genetics, dietary/intestinal microbiota, low-grade inflammation, and disturbances in the neuroendocrine system (NES) of the gut. One hypothesis proposes that the cause of IBS is an altered NES, which would cause abnormal GI motility, secretions and sensation. All of these abnormalities are characteristic of IBS. Alterations in the NES could be the result of one or more of the following: genetic factors, dietary intake, intestinal flora, or low-grade inflammation. Post-infectious IBS (PI-IBS) and inflammatory bowel disease-associated IBS (IBD-IBS) represent a considerable subset of IBS cases. Patients with PI- and IBD-IBS exhibit low-grade mucosal inflammation, as well as abnormalities in the NES of the gut.

• Cholecystokinin
• Chromogranin A
• Diagnosis
• Diet
• Endocrine cells
• Intestinal flora
• Hereditary
• Low-grade inflammation
• Peptide YY
• Serotonin

• colon
• computer image analysis
• ibs
• immunohistochemistry
• pyy
• serotonin

• Adolescent
• Adult
• Aged
• Colon/metabolism
• Colon/pathology
• Constipation/etiology
• Constipation/metabolism
• Constipation/pathology
• Diarrhea/etiology
• Diarrhea/metabolism
• Diarrhea/pathology
• Female
• Humans
• Irritable Bowel Syndrome/complications
• Irritable Bowel Syndrome/metabolism
• Irritable Bowel Syndrome/pathology
• Male
• Middle Aged
• Peptide YY/metabolism
• Serotonin/metabolism
• Young Adult

• Acyltransferases/metabolism
• Animals
• Gastric Mucosa/enzymology
• Gastric Mucosa/pathology
• Gastrointestinal Diseases/metabolism
• Gastrointestinal Diseases/physiopathology
• Gastrointestinal Diseases/therapy
• Ghrelin/metabolism
• Humans