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Background: The objectives of the present study were to (a) measure the prevalence of defecation symptoms in IBS, (b) investigate the relationship between stool consistency and defecation symptoms in IBS, and (c) investigate the association of defecation symptoms with health-related quality of life (HRQL) and self-reported stress in patients with IBS cared for in a primary health care setting. Methods: Ten primary health care centres joined the study. 282 patients with IBS as well as 372 non-IBS controls filled in gastrointestinal symptom diaries prospectively for two weeks as well as the Perceived Stress Scale-14 (PSS14) and the EuroQol barometer to measure perceived stress and HRQL, respectively. Results: Incomplete evacuation was present in 51% vs. 21% of the stools among the IBS patients and the non-IBS controls, respectively. The need to strain during defecation was existing in 41% vs. 33% of the stools for the IBS patients and the non-IBS controls, respectively. Urgency was experienced in 37% of the stools in the IBS patients compared with 18% of the stools in the non-IBS controls. Patients with IBS experienced in a significant higher degree of overlapping symptoms per stool (p < 0.001 to p = 0.007). The occurrence of all defecation symptoms in the same patient was related to decreased HRQL, and increased stress (p = 0.001 to p < 0.001). Conclusions: An overlap between IBS and symptoms from the anorectal region related to defecation was found in a primary health care population. Defecation symptoms are very common in primary care IBS-patients, it co-occurs with increased self-perceived stress, and decreased HRQL., Funding Agencies|FORSS (Medical Research Council of Southeast Sweden) [FORSS-188561, FORSS-229601, FORSS-307031]

Goals: To evaluate the usefulness of a 2-week patient-completed bowel habit and symptom diary as a screening tool for disordered rectoanal coordination (DRC).Background: DRC is an important subgroup of chronic constipation that benefits from biofeedback treatment. Diagnosis of DRC requires a dyssynergic pattern (DP) of attempted defecation in high-resolution anorectal manometry (HRAM) and at least 1 other positive standardized examination, such as the balloon expulsion test or defecography. However, HRAM is generally limited to tertiary gastroenterology centres and finding tools for selecting patients for referral for further investigations would be of clinical value.Study: Retrospective data from HRAM and a 2-week patient-completed bowel habit and symptom diary from 99 chronically constipated patients were analyzed.Results: Fifty-seven percent of the patients had a DP pattern during HRAM. In the DP group, 76% of bowel movements with loose or normal stool resulted in a sense of incomplete evacuation compared with 55% of the non-DP group (P=0.004). Straining and sensation of incomplete evacuation with the loose stool were significantly more common in the DP group (P=0.032). Hard stool was a discriminator for non-DP (P=0.044). Multiple logistic regression including incomplete evacuation and normal stool predicted DP with a sensitivity of 82% and a specificity of 50%.Conclusions: The sensation of incomplete evacuation with loose or normal stool could be a potential discriminator in favor of DP in chronically constipated patients. The bowel habit and symptom diary may be a useful tool for stratifying constipated patients for further investigation of suspected DRC., Funding Agencies|FORSS-Research Council of Southeast Sweden; Region Ostergotland, Sweden

Introduction: Robot-assisted laparoscopic radical prostatectomy (RALP) is a common procedure for the treatment of localised prostate cancer. Anorectal symptoms such as fecal incontinence (FI), rectal urgency or disturbed defecation have been reported after the operation. Anorectal function is dependent on the integrity of anal and pelvic nerves and muscles, rectal sensory function as well as rectal reservoir function. The aim of this study was to investigate the potential influence of RALP on anorectal physiological function and bowel symptoms. Materials and Methods: In this pilot study, 29 patients with localised prostate cancer scheduled for RALP were included. Anorectal physiology was used to measure rectal sensitivity and reservoir function as well as anal sphincter pressures. Bowel symptoms were measured by a bowel function questionnaire and a 2-week bowel function diary. Measurements were done before the operation and repeated at 6 months after the operation. Results: The study observed a significant postoperative increase in rectal sensory threshold for rectal balloon distention, from 20 to 40 mmHg, P < 0.001. This change is indicative of a decrease in rectal sensation after RALP. There were no other statistical significant differences in any of the physiological tests performed. Importantly, there was no change in any of the bowel symptoms after surgery. Conclusion: This study showed that RALP may lead to impaired rectal sensory function. This finding did not, however, seem to have any influence on the patients postoperative clinical bowel function.

Background Psychological stress and increased permeability are implicated as contributing factors in the initiation and worsening of gastrointestinal diseases. A link between stress and intestinal permeability has been shown in animal models as well as in human small intestine, but stress effects on the human colorectal mucosal barrier has not been reported. Objective To investigate the potential effects of acute psychological stress on colorectal mucosal barrier function and to explore stress-induced molecular events in the rectal mucosa under healthy conditions. Methods Endoscopic biopsies were taken from the rectosigmoid region of healthy volunteers, who had been subjected to dichotomous listening stress and after a control session, respectively. Paracellular and transcellular permeability were assessed in modified Ussing chambers. RNA expression (microarray technology confirmed by quantitative real-time polymerase chain reaction) and biological pathway analysis were used to investigate the local mucosal response to acute stress. Results Dichotomous listening stress induced a subjective and objective stress response, and significantly increased paracellular but not transcellular permeability. We also identified a stress-induced reduction in RNA expression of genes related to immune cell activation and maturation (CR2, CD20, TCLA1, BANK1, CD22, FDCSP), signaling molecules of homing of immune cells to the gut (chemokines: CCL21, CXCL13, and CCL19, and receptors: CCR7, CXCR5), and innate immunity (DUOX2). Eight of the 10 top down-regulated genes are directly involved in B cell activation, signaling and migration. The systemic stress response correlated positively with paracellular permeability and negatively with DUOX2 expression. Conclusion Dichotomous listening stress increases paracellular permeability and modulates immune cell activity in the rectal mucosa. Further studies are warranted to identify the primary mechanisms of stress-mediated reduction of mucosal d, Funding Agencies|Fondo de Investigacion Sanitaria and CIBERehd, Instituto de Salud Carlos III, Subdireccion General de Investigacion Sanitaria, Ministerio de Economia y Competitividad [PI17/0190, PI19/01643]; Futurum, Region Jonkoping County [12406, 1460]; Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas [CB06/04/0021]; Vetenskapsradet [2014-02537, 2017-02475]; Forskningsradet i Sydostra Sverige [37841]

Eosinophils have been linked to functional dyspepsia; however, less is known about their role in irritable bowel syndrome (IBS). This study tested the hypothesis of alterations in levels of fecal eosinophil-derived neurotoxin (F-EDN) and eosinophil density and degranulation within the colonic mucosa of IBS patients compared with healthy controls (HC). Colonic biopsies were collected from 37 IBS patients and 20 HC and analyzed for eosinophil numbers and local degranulation of eosinophil cationic protein (ECP) by histologic procedures. Fecal samples were collected for F-EDN and microbiota analysis. Differentiated 15HL-60 cells were used in vitro to investigate the direct effect of live bacteria on eosinophil activation measured by a colorimetric assay with o-phenylenediamine (OPD) substrate. We observed a higher number of eosinophils and increased extracellular ECP in the mucosa of IBS patients compared with HC. Moreover, F-EDN levels in IBS samples were elevated compared with HC and positively correlated to extracellular ECP. Metagenomic analysis showed significant correlations between bacterial composition and eosinophil measurements in both HC and IBS patients. In vitro experiments revealed an increased degranulation of 15HL-60 after stimulation with Salmonella typhimurium, Salmonella enterica, and Yersinia enterocolitica. To conclude, we could demonstrate alterations related to eosinophils in IBS, and, for the first time, a positive correlation between F-EDN levels and degranulated eosinophils in the colonic mucosa of IBS patients. Together our results suggest that eosinophils play a role in the pathophysiology of IBS and the mechanisms might be linked to an altered microbiota., Funding Agencies:Apotekare Hedberg Foundation Bengt Ihre Foundation SLS-788111 SLS-882561Ruth and Richard Julin Foundation 2017-00350 2019-00347County Council of Östergötland Lio-934618Mucosa Infection and Inflammation Center-MIIC Medical Faculty, Uppsala University, Uppsala Sweden

Background Irritable bowel syndrome (IBS) is a disorder with a predominance in women; IBS in men is less studied. The present study evaluated symptoms as well as health and social experiences of men with IBS. Methods This cross-sectional study included 293 patients with IBS (64 men) and 363 non-IBS controls (62 men). Gastrointestinal symptom diaries were filled in prospectively, and data on comorbidities and healthcare-seeking behavior were assessed by questionnaires. Men with IBS were compared with men without IBS and women with IBS. Key results Compared with women with IBS, men with IBS had fewer contacts with the healthcare system, fewer psychiatric comorbidities, fewer sleeping problems, and less chronic pain. Urgency to defecate and nausea were less common, and stool frequency was higher in men with IBS. There was no difference between men with and without IBS in terms of educational level, satisfaction with household economy, or living with a partner. In contrast, women with IBS more often lived alone, were more often dissatisfied with household economy, and had a lower educational level than women without IBS. Men with IBS had the same proportion of full-time employment as men without IBS but in contrast, the proportion of women with IBS in full-time employment was only 34%, compared to 50% of the women without IBS. Conclusion and inferences The present study improves the understanding of mens experiences of IBS and suggests that sex and gender may be integrated into the biopsychosocial model of IBS., Funding Agencies|County Council of Ostergotland

Background: Impaired intestinal permeability and microbial dysbiosis are important pathophysiological mechanisms underlying irritable bowel syndrome (IBS). ReFerm (R)( ), also called Profermin (R), is a postbiotic product of oat gruel fermented with Lactobacillus plantarum 299v. In this study, we investigated whether ReFerm (R) has a beneficial effect on the intestinal epithelial barrier function in patients with IBS.Materials and methods: Thirty patients with moderate to severe IBS-diarrhoea (IBS-D) or IBS-mixed (IBS-M) were treated with enema containing ReFerm (R) or placebo. The patients underwent sigmoidoscopy with biopsies obtained from the distal colon at baseline and after 14 days of treatment with ReFerm (R) or placebo twice daily. The biopsies were mounted in Ussing chambers, and paracellular and transcellular permeabilities were measured for 120 min. In addition, the effects of ReFerm (R) or placebo on the epithelial barrier were investigated in vitro using Caco-2 cells.Results: ReFerm (R) reduced paracellular permeability (p < 0.05) and increased transepithelial resistance (TER) over time (p < 0.01), whereas the placebo had no significant effect in patients. In ReFerm (R)-treated Caco-2 cells, paracellular and transcellular permeabilities were decreased compared to the control (p < 0.05) and placebo (p < 0.01). TER was increased in Caco-2 ReFerm (R)-treated cells, and normalised TER was increased in ReFerm (R)-treated Caco-2 cells compared to control (p < 0.05) and placebo-treated (p < 0.05) cells.Conclusion: ReFerm (R) significantly reduced paracellular permeability and improved TER in colonic biopsies collected from patients with IBS and in a Caco-2 cell model. Our results offer new insights into the potential benefits of ReFerm (R) in IBS management. Further studies are needed to identify the molecular mechanisms underlying the barrier-protective properties of ReFerm (R)., Funding Agencies|P. Hakanssons Stiftelse, Esloev, Sweden; ALF Grants, Region OEstergoetland; Region OEstergoetland [LIO-938303, ROE-960493]; Bengt Ihre Foundation [ROE-969343]; Ruth and Richard Julin Foundation; Mucosa Infection and Inflammation Center-MIIC [2022-00270]; Nordic Rebalance

Background Enteric glial cells (EGC) and mast cells (MC) are intimately associated with gastrointestinal physiological functions. We aimed to investigate EGC-MC interaction in irritable bowel syndrome (IBS), a gut-brain disorder linked to increased intestinal permeability, and MC. Methods Parallel approaches were used to quantify EGC markers in colonic biopsies from healthy controls (HC) and patients with IBS. Data were correlated with MC, vasoactive intestinal polypeptide (VIP) and VIP receptors (VPAC1/VPAC2) expressions, and bacterial translocation through biopsies mounted in Ussing chambers. In addition, we investigated the effects of EGC mediators on colonic permeability and the pharmacological-induced responses of EGC and MC cell lines. Key Results Immunofluorescence of IBS colonic mucosa, as well as Western blotting and ELISA of IBS biopsy lysates, revealed increased glial fibrillary intermediate filament (GFAP) expression, indicating EGC activation. Mucosal GFAP correlated with increased MC and VPAC1(+)MC numbers and decreased VIP+MC, which seemed to control bacterial translocation in HC. In the contrary, EGC activation in IBS correlated with less MC and VPAC1(+) MC numbers, and more VIP+ MC. In vitro, MC and EGC cell lines showed intracellular calcium responses to each others mediators. Furthermore, EGC mediators prevented VIP-induced MC degranulation, while MC mediators induced a reactive EGC phenotype. In Ussing chambers, EGC mediators decreased paracellular passage through healthy colonic biopsies. Conclusions & Inferences Findings suggest the involvement of EGC and MC in the control of barrier function in the human colon and indicate a potential EGC-MC interaction that seems altered in IBS, with detrimental consequences to colonic permeability. Altogether, results suggest that imbalanced EGC-MC communication contributes to the pathophysiology of IBS., Funding Agencies|Apotekare Hedberg Foundation; Magnus Bergwall Foundation [2018-02604]; Bengt Ihre Foundation [SLS-788111, SLS-882561]; Ruth and Richard Julin Foundation [2017-00350, 2019-00347]; Mucosa Infection and Inflammation Center-MIIC; AFA Insurance Research Foundation; County Council of Ostergotland [Lio-934618, Lio-902661]

Objectives Gastrointestinal (GI) symptoms are intimately related to our wellbeing. The Short Health Scale for GI symptoms (SHS-GI) is a simple questionnaire to measure the impact of GI inconvenience and symptoms on quality of life. The aim was to validate the SHS-GI in a general population sample and to compare it with SHS-data across different patient groups. Method A subsample of 170 participants from a population-based colonoscopy study completed the Rome II questionnaire, GI diaries, psychological questionnaire (hospital anxiety and depression scale) and SHS-GI at follow-up investigation. Psychometric properties of SHS-GI as an overall score were determined by performing a confirmatory factor analysis (CFA). Spearman correlation between SHS total score and symptoms was calculated in the general population sample. SHS-GI data was compared with SHS data from patients with inflammatory bowel disease (IBD) and fecal incontinence (FI). Results As expected, the general population rated their impact of GI inconvenience on quality of life as better than the patient populations in terms of all aspects of the SHS-GI. The CFA showed a good model fit meeting all fit criteria in the general population. Cronbach's alpha for the total scale was 0.80 in the general population sample and ranged from 0.72 in the FI sample to 0.88 and 0.89 in the IBD samples. Conclusions SHS-GI demonstrated appropriate psychometric properties in a sample of the normal population. We suggest that SHS-GI is a valid simple questionnaire suitable for measuring the impact of GI symptoms and inconvenience on quality of life in both general and patient populations.

Vasoactive intestinal polypeptide (VIP) is a neuroendocrine peptide distributed throughout the human body, including the CNS, where it is particularly abundant in brain regions associated with anxiety and depression. Based on earlier studies indicating that peripheral VIP may cross through the blood-brain barrier, we hypothesized plasma VIP levels to be associated with symptoms of anxiety and depression, as well as brain volume and resting-state functional connectivity in the amygdala, hippocampus, parahippocampus, and orbitofrontal cortex. Plasma VIP concentrations and anxiety/depression symptoms were measured in 37 healthy females. Functional and structural magnetic resonance imaging were used to evaluate functional connectivity and brain volume respectively, and their associations with VIP concentrations within brain regions associated with anxiety and depression. Negative correlations were found between VIP levels and symptoms of anxiety (r=- 0.44, p=0.002) and depression (r=- 0.50, p=0.001). Functional connectivity demonstrated significant VIP-dependent positive associations between the amygdala seed region with both the right parahippocampus (t((33))=3.1, p(FDR)=0.02) and right lateral orbitofrontal cortex (OFC; t((33))=2.9, p(FDR)=0.02). Moreover, VIP concentrations were significantly, positively correlated with brain volume in the left amygdala (r=0.28, p=0.007) and left lateral OFC (r=0.29, p=0.004). The present findings highlight a potential role for VIP in the neurobiology of affective symptoms., Funding Agencies|Linkoping University Library

Objective: The mechanism of action of intragastric balloons in the treatment of obesity is not fully understood. One of the hypotheses is that balloons might have an effect on the fundus, the area of ghrelin production. Methods: Participants were randomized to a 13-week period of sham or balloon treatment followed by a 13-week period of balloon therapy in everyone. Blood samples for ghrelin levels were taken in the fasting state and after a breakfast at the start, after 13 and 26 weeks. Biopsies for ghrelin cell immunohistochemistry were taken from the fundus at endoscopy. Results: Seven participants entered the balloon-balloon (BB) group and 11 the sham-balloon (SB) group. Despite a considerable weight loss, a median -17.9 kg (interquartile ranges -23.8 to -0.5) in the BB group and -18.3 kg (-22.7 to -14.7) in the SB group, fasting ghrelin and meal-induced ghrelin response did not change. In the SB group, the number of ghrelin cells increased significantly (p 0.001) from 110.6 (83.6-118.9) to 160.2 (128.5-223.0) while on sham treatment and returned to initial levels, 116.3 (91.7-146.9) (p 0.001), when they received their first balloon. No significant changes in ghrelin cell numbers were observed in the BB group. Conclusion: In participants without a balloon, weight loss induced an increase in ghrelin cell numbers in the fundus, which was annulled by the subsequent placement of a balloon. The effect of a balloon might be explained by effects on ghrelin cell numbers or ghrelin cell activity.

Magnetotactic bacteria (MTB), ubiquitous in soil and fresh and saltwater sources have been identified in the microbiome of humans and many animals. MTB endogenously produce magnetic nanocrystals enabling them to orient and navigate along geomagnetic fields. Similar magnetite deposits have been found throughout the tissues of the human brain, including brain regions associated with orientation such as the cerebellum and hippocampus, the origins of which remain unknown. Speculation over the role and source of MTB in humans, as well as any association with the brain, remain unanswered. We performed a metagenomic analysis of the gut microbiome of 34 healthy females as well as grey matter volume analysis in magnetite-rich brain regions associated with orientation and navigation with the goal of identifying specific MTB that could be associated with brain structure in orientation and navigation regions. We identified seven MTB in the human gut microbiome: Magnetococcus marinus, Magnetospira sp. QH-2, Magnetospirillum magneticum, Magnetospirillum sp. ME-1, Magnetospirillum sp. XM-1, Magnetospirillum gryphiswaldense, and Desulfovibrio magneticus. Our preliminary results show significant negative associations between multiple MTB with bilateral flocculonodular lobes of the cerebellum and hippocampus (adjusted for total intracranial volume, uncorrected P<0.05). These findings indicate that MTB in the gut are associated with grey matter volume in magnetite-rich brain regions related to orientation and navigation. These preliminary findings support MTB as a potential biogenic source for brain magnetite in humans. Further studies will be necessary to validate and elucidate the relationship between these bacteria, magnetite concentrations, and brain function., Funded by: The AFA Insurance Research Foundation, the County Council of Östergotland, a Bengt Ihre Research Fellowship and the Ruth and Richard Julin Foundation. DAB was supported by the US National Science Foundation (No. EAR-1423939)

Objective Irritable bowel syndrome (IBS) is a gut-brain disorder associated with increased gut permeability. Zonulin has been suggested to regulate the gut barrier and claimed to be pre-haptoglobin 2 (pre-HP2) and circulating zonulin is often used as a proxy for gastrointestinal permeability. This study investigated the correlation between colonic paracellular permeability and levels of circulating zonulin and pre-HP2. Materials and Methods Colonic biopsies from 32 patients with IBS and 15 healthy controls (HC) were used to measure permeability in Ussing chambers and levels of zonulin (Cusabio ELISA). Zonulin was also measured in blood samples from 40 HC, 78 patients with IBS and 20 patients with celiac disease (CeD), before and after a gluten-free diet. In addition, we verified HP genotype and circulating pre-HP2 using a monoclonal pre-HP2 antibody (Bio-Rad) by ELISA. Results Increased colonic paracellular permeability correlated positively with zonulin levels in IBS biopsies, but negatively with plasma zonulin. We found no agreement between circulating zonulin and pre-HP2. Genotyping revealed non-specificity of the zonulin kit, as all pre-HP2 non-producers presented detectable levels. Patients with CeD displayed higher pre-HP2 and zonulin levels compared to HC. A gluten-free diet in patients with CeD led to lower serum zonulin and pre-HP2 concentrations. Conclusions Our study suggests that neither circulating zonulin nor pre-HP2 mirror colonic permeability. Our data corroborate previous reports showing the inability of the Cusabio zonulin kit to target zonulin and highlights that the results of studies using this kit must be re-examined with caution., Funding Agencies|Mucosa Infection and Inflammation Center-MIIC; AFA research foundation; County Council of Ostergotland; Swedish Research Council (Vetenskapsradet) (VR-Medicine and Health) [2014-02537, 2017-02475]

Background: Enteric glial cells (EGC) and mast cells (MC) are intimately associated with gastrointestinal physiological functions. We aimed to investigate EGC-MC interaction in irritable bowel syndrome (IBS), a gut-brain disorder linked to increased intestinal permeability, and MC. Methods: Parallel approaches were used to quantify EGC markers in colonic biopsies from healthy controls (HC) and patients with IBS. Data were correlated with MC, vasoactive intestinal polypeptide (VIP) and VIP receptors (VPAC1/VPAC2) expressions, and bacterial translocation through biopsies mounted in Ussing chambers. In addition, we investigated the effects of EGC mediators on colonic permeability and the pharmacological-induced responses of EGC and MC cell lines. Key Results: Immunofluorescence of IBS colonic mucosa, as well as Western blotting and ELISA of IBS biopsy lysates, revealed increased glial fibrillary intermediate filament (GFAP) expression, indicating EGC activation. Mucosal GFAP correlated with increased MC and VPAC1(+)MC numbers and decreased VIP+MC, which seemed to control bacterial translocation in HC. In the contrary, EGC activation in IBS correlated with less MC and VPAC1(+) MC numbers, and more VIP+ MC. In vitro, MC and EGC cell lines showed intracellular calcium responses to each other's mediators. Furthermore, EGC mediators prevented VIP-induced MC degranulation, while MC mediators induced a reactive EGC phenotype. In Ussing chambers, EGC mediators decreased paracellular passage through healthy colonic biopsies. Conclusions & Inferences: Findings suggest the involvement of EGC and MC in the control of barrier function in the human colon and indicate a potential EGC-MC interaction that seems altered in IBS, with detrimental consequences to colonic permeability. Altogether, results suggest that imbalanced EGC-MC communication contributes to the pathophysiology of IBS., Funding Agencies:Apotekare Hedberg Foundation Bengt Ihre Foundation SLS-788111 SLS-882561Ruth and Richard Julin Foundation 2017-00350 2019-00347Mucosa Infection and Inflammation Center-MIIC AFA Insurance Research Foundation County Council of Östergötland Lio-934618 Lio-902661