Yasuhiro Sagami

Effect of a corticotropin releasing hormone receptor antagonist on colonic sensory and motor function in patients with irritable bowel syndrome

Background and aims: Corticotropin releasing hormone (CRH) is a major mediator of the stress response in the brain-gut axis. Irritable bowel syndrome (IBS) is presumed to be a disorder of the brain-gut link associated with an exaggerated response to stress. We hypothesised that peripheral administration of α-helical CRH (αhCRH), a non-selective CRH receptor antagonist, would improve gastrointestinal motility, visceral perception, and negative mood in response to gut stimulation in IBS patients. Methods: Ten normal healthy subjects and 10 IBS patients, diagnosed according to the Rome II criteria, were studied. The tone of the descending colon and intraluminal pressure of the sigmoid colon were measured at baseline, during rectal electrical stimulation (ES), and at recovery after administration of saline. Visceral perception after colonic distension or rectal ES was evaluated as threshold values on an ordinate scale. The same measurements were repeated after administration of αhCRH (10 μg/kg). Results: ES induced significantly higher motility indices of the colon in IBS patients compared with controls. This response was significantly suppressed in IBS patients but not in controls after administration of αhCRH. Administration of αhCRH induced a significant increase in the barostat bag volume of controls but not in that of IBS patients. αhCRH significantly reduced the ordinate scale of abdominal pain and anxiety evoked by ES in IBS patients. Plasma adrenocorticotropic hormone and serum cortisol levels were generally not suppressed by αhCRH. Conclusion: Peripheral administration of αhCRH improves gastrointestinal motility, visceral perception, and negative mood in response to gut stimulation, without affecting the hypothalamo-pituitary-adrenal axis in IBS patients.

Impact of serotonin transporter gene polymorphism on brain activation by colorectal distention.

BACKGROUND AND AIMS Determining the gene that plays a key role in brain-gut interactions is a crucial step for clarifying the pathophysiology of irritable bowel syndrome (IBS). We previously reported that the 5-hydroxytryptamine transporter gene-linked polymorphic region (5-HTTLPR) is related to anxiety in subjects with IBS. The amygdala is more activated during fearful face recognition in individuals with the s allele of 5-HTTLPR. Here, we tested our hypothesis that 5-HTTLPR differentially activates brain regions with colorectal distention in humans. METHODS We enrolled 28 subjects without any organic disease. The study was approved by the Ethics Committee and all subjects gave written informed consent. DNA was extracted from the peripheral blood. The genotype of 5-HTTLPR was determined using polymerase chain reaction. Age, sex, diagnosis-matched individuals with the s/s genotype (n=14) and individuals with the l allele (genotypes l/s, l/l, l/extra-l, n=14) were compared. A barostat bag was inserted to the colorectum and was intermittently inflated with no (0 mm Hg), mild (20 mm Hg), or intense (40 mm Hg) stimulation on a random order. Radioactive H2[(15-)O] saline was injected at bag inflation and then positron emission tomography was performed. Changes in rCBF were analyzed using statistical parametric mapping. RESULTS Individuals with the s/s genotype showed a significantly larger increase in rCBF by colorectal distention from 0 mm Hg to 40 mm Hg than individuals with the l allele. The significantly more activated brain regions in individuals with the s/s genotype were the left anterior cingulate cortex and right parahippocampal gyrus (p<0.0001). The increase in rCBF by colorectal distention of 20 mm Hg compared with 0 mm Hg was significantly larger in the left orbitofrontal cortex of individuals with the s/s genotype than that of individuals with the l allele (p<0.0001). CONCLUSION These data suggest that individuals with a weak function of serotonin transporter respond to gut signals more in emotion-regulating brain regions. Functional gene polymorphism may partially predict the individual effect of a selective serotonin reuptake inhibitor on visceral pain.

Exaggerated motility of the descending colon with repetitive distention of the sigmoid colon in patients with irritable bowel syndrome

Background. Visceral hypersensitivity is one of the mechanisms of irritable bowel syndrome (IBS), but it does not explain the entire symptomatology, i.e., altered bowel habit with abdominal pain relieved by defecation. We tested our hypothesis that an abnormal link between luminal stimulation and mural response may have some role in the pathophysiology of IBS. Methods. Patients with IBS (n = 10, median 21 years old, 5 male patients, 5 female patients) and healthy control subjects (n = 10, median 21 years old, 5 men, 5 women) were studied. A manometric catheter with three transducers was inserted to the descending colon and a balloon was placed in the distal sigmoid colon. Another catheter with three transducers was inserted to the duodenum. After baseline for 30 min, the sigmoid colon was stimulated by balloon distention for 30 min followed by recovery for 30min. Balloon distention was repeated 100 times, and each stimulation consisted of a 5-s inflation and a 10-s deflation, with a volume of 50 ml maximum. The sensory threshold of balloon inflation was then examined, and plasma adrenocorticotropic hormone (ACTH) was measured with radioimmunoassay. Results. Repetitive colonie distention induced a significant increase in motility indices (mmHg s/s%) of the descending colon in the IBS patients (from 118 ± 25 to 333 ± 108, P < 0.05) but not of those in controls (from 90 ± 16 to 89 ± 19). A significant group difference (P < 0.05), period effect (P < 0.02), and group X period interactions (P < 0.01) were detected with two-way ANOVA. Duodenal motility indices in controls were significantly reduced by colonic distention (from 169 ± 25 to 104 ± 14, P < 0.01), but those in the IBS patients were not (from 156 ± 17 to 124 ± 20). The sensory threshold of balloon inflation in the IBS patients (74 ± 10 ml) was significantly lower than that in controls (125 ± 6 ml, P < 0.001). There was no significant difference in plasma ACTH levels between the IBS patients and controls. Conclusions. Repetitive distention of the distal sigmoid colon below the sensory threshold induced orad exaggerated motility of the colon in IBS patients. The distention inhibited motility of the small intestine in healthy subjects, but this inhibition was blunted in IBS patients. These results suggest that IBS patients may have not only visceral hypersensitivity, but also an abnormal intestinal reflex.

Effect of alpha-helical CRH on quantitative electroencephalogram in patients with irritable bowel syndrome

Abstract  Patients with irritable bowel syndrome (IBS) may have a higher tone of corticotropin‐releasing hormone (CRH) in the brain. We tested our hypothesis that peripheral administration of CRH antagonist, α‐helical CRH9−41 (αhCRH), improves decreased alpha power spectra and increased beta power spectra of electroencephalogram (EEG) in IBS patients. A barostat bag was inserted to the descending colon of 10 normal controls and 10 IBS patients. The EEG power spectra and topography were measured during baseline period and colonic distention period with the administration of saline followed by the administration of 10 μg kg−1 of αhCRH. IBS patients showed a significantly lower alpha power percentage and a higher beta power percentage than normal controls during baseline. Colonic distention induced a decrease in the alpha power percentage and an increase in the beta power percentage in both groups without difference between groups. After the administration of αhCRH, changes in the EEG power spectra in response to colonic distention were blunted and the differences in the EEG power spectra between IBS patients and controls vanished. Peripheral administration of αhCRH almost normalized EEG activities in IBS patients. Our data strongly suggest that CRH plays an important role in IBS.

Translation and validation of a Japanese version of the irritable bowel syndrome-quality of life measure (IBS-QOL-J).

AimsTo compare quality of life (QOL) for patients with irritable bowel syndrome (IBS) between the U.S. and Japan, it is indispensable to develop common instruments. The IBS-QOL, which is widely used in Western countries, was translated into Japanese as there has been a lack of Japanese disease-specific QOL measures for IBS.MethodsThe original 34 items of the IBS-QOL were translated from English into Japanese through two independent forward translations, resolution, back translation, and resolution of differences. Forty nine patients who had GI symptoms but did not have any organic diseases (including 30 IBS patients diagnosed by Rome II criteria) were recruited from Tohoku University Hospital in Sendai, Japan and completed a Japanese version of the IBS-QOL (IBS-QOL-J) concomitant with a Japanese version of the IBS severity index (IBSSI-J) twice within 7–14 days.ResultsThe IBS-QOL-J demonstrated high internal consistency (Cronbachs alpha; 0.96) and high reproducibility (intraclass correlation coefficient; 0.92, p < 0.001). Convergent analyses confirmed that the overall score of IBS-QOL-J was significantly correlated with overall severity of IBS symptoms on the IBSSI-J (r = -0.36, p = 0.01) and with the individual items on the IBSSI-J that assess interference with life in general (r = -0.47, p = 0.001) and dissatisfaction with bowel habits (r = -0.32, p < 0.05). Eight patients who reported continuous abdominal pain in the past 6 months had significantly lower scores in the IBS-QOL-J than those who did not (53.7 +- 12.7 vs. 73.6 +- 19.5, p < 0.01). Age, sex, education or marital status did not affect scores on the measure.ConclusionThe IBS-QOL-J is a reliable instrument to assess the disease-specific QOL for IBS. Considering cross-cultural comparison, this measure is likely to be a valuable tool to investigate the QOL in Japanese patients with IBS.

Validation of the Japanese version of the Rome II modular questionnaire and irritable bowel syndrome severity index

BackgroundInstruments for measuring the presence and severity of specific irritable bowel syndrome (IBS) symptoms, comparable to those used in Western countries, have been lacking in Japan. The aim of this study was to develop, validate, and confirm the reliability of the Japanese version of the Rome II modular questionnaire for IBS (RIIMQ-J) and the IBS severity index (IBSSI-J).MethodsForty-nine patients in the university hospital with chronic or recurrent abdominal pain and discomfort and/or altered bowel habits were enrolled. With Rome II criteria, 27 patients were diagnosed as having IBS, and the other 22 patients were evaluated as having other functional bowel disorders (FBDs). The English versions of RIIMQ and IBSSI were translated into Japanese. After back-translation and approval of the questionnaire, subjects completed both questionnaires twice within 14 days.ResultsCronbachs alpha of the RIIMQ-J was high (0.72). The sensitivity of RIIMQ-J for the diagnosis of IBS was also high (89%). The specificity of RIIMQ-J for denial of IBS among patients with other FBD was satisfactory (73%). The IBSSI-J showed high internal consistency (0.69) and reproducibility (intraclass correlation coefficient, 0.86, P < 0.001).ConclusionsThe RIIMQ-J and IBSSI-J are valid, reliable, and appropriate instruments for detecting and assessing the severity of IBS status in Japanese patients.

Can modulating corticotropin releasing hormone receptors alter visceral sensitivity

Activation of corticotropin releasing hormone (CRH) receptor 2 (CRH-R2) reduces visceral sensitivity induced by colorectal distension in conscious rats. This finding is relevant to the increased interest in the potential use of therapeutic agents that act on CRH receptors in the treatment of irritable bowel syndrome.

Gastrojejunostomy and Duodenojejunostomy for Megaduodenum in Systemic Sclerosis Sine Scleroderma: Report of a Case

Systemic sclerosis is an autoimmune disease that causes sclerotic changes primarily in the skin and in other organs. Systemic sclerosis sine scleroderma (ssSSc) is a variant of the disease in which visceral involvement occurs in the absence of skin thickening [1]. Most patients with systemic sclerosis have digestive tract complications, 90% of which involve esophageal diseases such as gastroesophageal reflux disease (GERD) and Barrett esophagus [2–6]. The rate of small intestinal complications in systemic sclerosis, although lower than that of esophageal complications, is estimated to be about 50%. In systemic sclerosis, more common small intestinal complications include intestinal pseudoobstruction with dilatation of the small intestine and small intestinal diverticula [1–5]. Megaduodenum is relatively rare as a small

Primary care in the treatment of functional gastrointestinal symptoms in Japan: prescription preferences and impression of results.

Background : Functional gastrointestinal (GI) disorders are common in primary care. However, proper pharmacological approaches have not yet been established. The reason for a lack of proper approaches may be attributable to the lack in clarity of their pathogenesis and pathophysiology. Meta‐analysis of pharmacological approaches to functional GI disorders failed to identify the solid cluster of patients’ symptoms.

1101 Impact of Serotonin-3 Receptor Gene Polymorphism On Brain Activation By Rectal Distention in Human

Background& Aims: Visceral perception of functional dyspepsia (FD) is based on the braingut interaction via various neurotransmission pathways. Peripheral or central serotonergic abnormalities are associated with the pathophysiology of functional gastrointestinal disorders or psychiatric depression and anxiety. To examine the roles of the cerebral serotonin (5HT) neurotransmission systems in visceral perception of FD patients, we examined both 5HT transporter (5-HTT) binding potential in the brain and the correlation between differences between patients and controls in 5-HTT binding potential and abdominal symptoms. Methods: Patients with FD diagnosed according to the Rome III criteria (N=9, female: 6, age range 25-61 yrs) were recruited for this study. There were 9 healthy controls (female: 3, age range 36-76 yrs). To measure 5-HTT binding potential with region-of-interest data in areas of the thalamus, putamen, caudate, amygdala, midbrain, and cerebellum (as a reference region), positron emission tomography (PET) with [11C]N,N-dimethyl-2-(2-amino4-cyanophenylthio) benzylamine ([11C]DASB), which binds specifically to 5-HTT, was performed. We used the Multi-linear Reference Tissue Mode method within the standard software package of PMOD Technologies for analysis of [11C]DASB with reference to the co-registered MRI images. Clinical symptoms were evaluated on the Gastrointestinal Symptoms Rating Scale (GSRS) including subscales for abdominal pain and indigestion. Depression and anxiety were evaluated on the Self-Rating Depression Scale and the State-Trait Anxiety Inventory. Results: All scores for abdominal pain, indigestion, depression, and anxiety were higher for FD patients than for controls (p<0.01). In FD patients, the binding potential of [11C]DASB in the midbrain (p=0.001) and amygdala (p=0.065) was higher than in the corresponding areas in controls, while there were no differences between the groups in the thalamus, putamen, or caudate. Binding potential of [11C]DASB in the midbrain was correlated with total GSRS (p=0.018, r=0.572), indigestion (p=0.021, r=0.565), and abdominal pain (p=0.091, r=0.420) scores, while in the amygdala it was correlated with total GSRS (p=0.080, r=0.426), indigestion (p=0.057, r=0.469), depression (p=0.091, r=0.413), and anxiety (p=0.096, r=0.406) scores. Conclusion: These findings suggest that in FD patients there are disorders of central 5-HT neurotransmission, especially in the midbrain and amygdala, which are correlated with their visceral symptoms and psychological characteristics.