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Background & aims Only a fraction of IBS patients show increased perceptual sensitivity to rectal distension, suggesting possible differences in processing and/or modulation of visceral afferent signals within this group. The aim was to identify brain mechanisms which may underlie these perceptual differences. Methods 44 women with IBS and 20 female healthy control subjects (HCs) were included. Symptom severity in IBS was determined by Severity Scoring System (IBS-SSS). Anxiety and depression symptoms were assessed using the Hospital anxiety & depression score (HAD). Blood oxygen level dependent (BOLD) signals were measured by functional Magnetic Resonance Imaging (fMRI) during expectation and delivery of high (45mmHg) and low (15mmHg) intensity rectal distensions. Perception thresholds to rectal distension were determined in the scanner. Brain imaging data from 18 normosensitive, 15 hypersensitive IBS patients and 18 HCs were compared. Results were reported significant if peak p-value ≤ 0.05 with family wise error correction in regions of interest. Results The two IBS subgroups were similar in age, symptom duration, psychological symptoms and IBS symptom severity. While brain responses to distension were similar in normosensitive patients and HCs, hypersensitive IBS demonstrated greater activation of insula and reduced deactivation in pregenual anterior cingulate cortex during noxious rectal distensions, compared to both HCs and normosensitive IBS. During expectation of rectal distension, normosensitive IBS had more activation in right hippocampus than HCs. Conclusions Despite similarities in symptoms, hyper- and normosensitive IBS patients differed substantially in cerebral response to standardized rectal distensions and their expectation, consistent with differences in ascending visceral afferent input.

Background & Aims Irritable bowel syndrome (IBS) is associated with intestinal dysbiosis and symptoms of IBS develop following gastroenteritis. We aimed to study passage of live bacteria through the colonic epithelium, and determine the role of mast cells and vasoactive intestinal polypeptide (VIP) in barrier regulation in IBS and healthy individuals. Methods Colon biopsies from 32 women with IBS and 15 age-matched healthy women (controls) were mounted in Ussing chambers; we measured numbers of fluorescently labeled Escherichia coli HS and Salmonella typhimurium that passed through from the mucosal side to the serosal side of the tissue. Some biopsies were exposed to agents that block the VIP receptors (VPAC1 and VPAC2) or mast cells. Levels of VIP and tryptase were measured in plasma and biopsy lysates. Number of mast cells and mast cells that express VIP or VIP receptors were quantified by immunofluorescence. Biopsies from an additional 5 patients with IBS and 4 controls were mounted in chambers and Salmonella were added; we studied passage routes through the epithelium by transmission electron microscopy and expression of tight junctions by confocal microscopy Results In colon biopsies from patients with IBS, larger numbers of E coli HS and Salmonella passed through the epithelium than in biopsies from controls (P<.0005). In transmission electron microscopy analyses, bacteria were found to cross the epithelium via only the transcellular route. Bacterial passage was reduced in biopsies from patients with IBS and controls after addition of antibodies against VPACs or ketotifen, which inhibits mast cells. Plasma samples from patients with IBS had higher levels of VIP than plasma samples from controls. Biopsies from patients with IBS had higher levels of tryptase, larger numbers of mast cells, and a higher percentage of mast cells that express VPAC1 than biopsies from controls. In biopsies from patients with IBS, addition of Salmonella significantly reduced levels of occludin; subsequent addition of ketotifen significantly reversed this effect. Conclusions We found that colonic epithelium tissues from patients with IBS have increased translocation of commensal and pathogenic live bacteria, compared with controls. Mechanisms of increased translocation include mast cells and VIP.

Objective IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucrase–isomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase–isomaltase (SI) gene variants for their potential relevance in IBS. Design We sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p. Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population. Results CSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case–control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (p<0.05). Conclusions SI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.