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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

BACKGROUND Functional gastrointestinal disorders (FGIDs) are diagnosed according to expert consensus criteria based on recall of symptoms over periods of 3 months or longer. Whether the expert opinion concords with underlying disease process and whether individual recall is accurate are both in doubt. This study aimed to identify naturally occurring clusters of individuals with respect to symptom pattern, evaluate their significance, compare cluster profiles with expert opinion and evaluate their temporal stability. METHODS As part of a random population study of FGID-related symptoms, we first explored the use of prospective stool and symptom diaries combined with empirical grouping of individuals into clusters using nonhierarchical cluster analysis. RESULTS The analysis identified two clusters of individuals, one of which was characterized by elevated scores on all domains of symptoms (26% of the sample) and one that was low to average on all domains (74% of the sample). Cluster membership was found to be stable over a long interval. Clusters were found to differ on most domains of quality-of-life (d = 0.46-0.74), self-rated health (d = -0.42) and depression (d = -0.42) but not anxiety. Prevalence of clinically diagnosed irritable bowel syndrome (IBS) was higher in the more impacted cluster (33%) compared with the healthy cluster (13%; P

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.

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.

We present an application, and its development process, for interactive visual analysis of brain imaging data and clinical measurements. The application targets neuroscientists interested in understanding the correlations between active brain regions and physiological or psychological factors. The application has been developed in a participatory design process and has subsequently been released as the free software VisualNeuro. From initial observations of the neuroscientists workflow, we concluded that while existing tools provide powerful analysis options, they lack effective interactive exploration requiring the use of many tools side by side. Consequently, our application has been designed to simplify the workflow combining statistical analysis with interactive visual exploration. The resulting environment comprises parallel coordinates for effective overview and selection, Welchs t-test to filter out brain regions with statistically significant differences and multiple visualizations for comparison between brain regions and clinical parameters. These exploration concepts enable neuroscientists to interactively explore the complex bidirectional interplay between clinical and brain measurements and easily compare different patient groups. A qualitative user study has been performed with three neuroscientists from different domains. The study shows that the developed environment supports simultaneous analysis of more parameters, provides rapid pathways to insights and is an effective tool for hypothesis formation. Funding Agencies|grants Seeing Organ Function from the Knut and Alice Wallenberg Foundation (KAW) [2013-0076]; Swedish research councilSwedish Research Council [2015-05462]; SeRC (Swedish e-Science Research Centre); ELLIIT environment for strategic research in Sweden; Center for Medical Image science and Visualization (CMIV) at Linkoping University

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; Magnus Bergvall Foundation [2018-02604]; Bengt Ihre Foundation [SLS-788111, SLS-882561]; Ruth and Richard Julin Foundation [2017-00350, 2019-00347]; County Council of Ostergotland [Lio-934618]; Mucosa 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

Clinical understanding of gastrointestinal symptoms is commonly based on patient reports of symptom experience. For diagnosis and treatment choices to be appropriate, symptom reports need to be accurate. We examined the agreement between questionnaire recall and prospective diary enumeration of symptoms relevant to the irritable bowel syndrome.Data are reported from a randomly selected general population sample (n=238) and also a primary healthcare centre (PHC) sample (n=503, 10 PHCs). All the patients completed the questionnaires, which included Rome III-qualifying irritable bowel syndrome items and a stool and symptom diary over either 7 or 14 days. Agreement between retrospective questionnaire reports and prospective diaries was evaluated.Concordance between questionnaires and diaries was highest for the simple construct of the occurrence of abdominal pain, although after adjusting for possible chance, agreement was only moderate in the general population sample. More complex constructs, such as pain relieved by defecation, yielded poorer concordance. In general, concordance was stronger among PHC respondents than in the general population sample.Concordance between questionnaires and diaries was generally poor and related to the complexity of the symptom construct and the type of respondent. The information used to classify individuals based on patient self-report may be unreliable, and therefore, more effort is needed to develop data collection instruments.

Contains fulltext : 231681.pdf (Publisher’s version ) (Closed access) To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P

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, pFDR = 0.02) and right lateral orbitofrontal cortex (OFC; t(33) = 2.9, pFDR = 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.

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]

Irritable bowel syndrome (IBS) is a symptom-based disorder of gut-brain interactions generating abdominal pain. It is also associated with a vulnerability to develop extraintestinal symptoms, with fatigue often reported as one of the most disturbing. Fatigue is related to brain function and inflammation in several disorders, however, the mechanisms of such relations in IBS remain elusive. This study aimed to elucidate fatigue and its association with a resting state network of mesocorticolimbic regions of known importance in fatigue, and to explore the possible role of circulating TNF-α levels in IBS and healthy controls (HC). Resting state functional magnetic resonance imaging (fMRI) was conducted in 88 IBS patients and 47 HC of similar age and gender to investigate functional connectivity between mesocorticolimbic regions. Further, fatigue impact on daily life and plasma levels of the proinflammatory cytokine tumor necrosis factor-α (TNF-α), of known relevance to immune activation in IBS, were also measured. The selected mesocorticolimbic regions indeed formed a functionally connected network in all participants. The nucleus accumbens (NAc), in particular, exhibited functional connectivity to all other regions of interest. In IBS, fatigue impact on daily life was negatively correlated with the connectivity between NAc and dorsolateral prefrontal cortex bilaterally (left p = 0.019; right p = 0.038, corrected for multiple comparisons), while in HC, fatigue impact on daily life was positively correlated to the connectivity between the right NAc and anterior middle insula in both hemispheres (left p = 0.009; right p = 0.011). We found significantly higher levels of TNF-α in IBS patients compared to HC (p = 0.001) as well as a positive correlation between TNF-α and fatigue impact on daily life in IBS patients (rho = 0.25, p = 0.02) but not in HC (rho = −0.13, p = 0.37). There was no association between functional connectivity in the mesocorticolimbic network and plasma levels of TNF-α in either group In summary, this novel multimodal study provides the first evidence that the vulnerability to fatigue in IBS is associated with connectivity within a mesocorticolimbic network as well as immune activation. These findings warrant further investigation, both peripherally and potentially with measurements of central immune activation as well. Additional funding agencies: Lions forskningsfond mot folksjukdomar (AKN; LIU-2019-01190).

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.

Summary Gut dysmotility is associated with constipation, diarrhea, and functional gastrointestinal disorders like irritable bowel syndrome (IBS), although its molecular underpinnings are poorly characterized. We studied stool frequency (defined by the number of bowel movements per day, based on questionnaire data) as a proxy for gut motility in a GWAS meta-analysis including 167,875 individuals from UK Biobank and four smaller population-based cohorts. We identify 14 loci associated with stool frequency (p ≤ 5.0 × 10−8). Gene set and pathway analyses detected enrichment for genes involved in neurotransmitter/neuropeptide signaling and preferentially expressed in enteric motor neurons controlling peristalsis. PheWAS identified pleiotropic associations with dysmotility syndromes and the response to their pharmacological treatment. The genetic architecture of stool frequency correlates with that of IBS, and UK Biobank participants from the top 1% of stool frequency polygenic score distribution were associated with 5× higher risk of IBS with diarrhea. These findings pave the way for the identification of actionable pathological mechanisms in IBS and the dysmotility syndromes., Graphical abstract, Highlights Genetics of gut motility via data on stool frequency in 167,875 individuals GWAS identifies 14 loci associated with stool frequency Candidate genes enriched in neurotransmitter signaling and enteric motor neurons Polygenic scores predict increased risk of irritable bowel syndrome, Bonfiglio et al. investigate the genetics of human gut motility using genotype and questionnaire data on stool frequency in 167,875 individuals from the UK Biobank and four other cohorts. They identify 14 loci associated with stool frequency as well as candidate genes enriched in neurotransmitter signaling and preferentially expressed in enteric neurons controlling peristalsis. The genetic architecture of stool frequency correlates with that of irritable bowel syndrome (IBS), and stool frequency polygenic scores were predictive of IBS risk.

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 out of 410 genera were detected in more than 95% samples. A genome-wide association study (GWAS) of host genetic variation in relation to microbial taxa identified 31 loci affecting microbiome at a genome-wide significant (P−8) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (GWAS signal P=1.28×10−20), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95×10−10−8) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome has causal effects in ulcerative colitis and rheumatoid arthritis.

ObjectiveGut dysmotility is associated with constipation, diarrhea, and functional gastrointestinal disorders (FGID) like irritable bowel syndrome (IBS). Its molecular underpinnings, and their anomalies in FGID disorders are poorly characterized, hence we sought to gain mechanistic insight through a large-scale genetic investigation.DesignWe used stool frequency (STL-FRQ) as a (surrogate) quantitative trait to study the genetics of gut motility, exploiting questionnaire and genotype data from UK Biobank and four smaller population-based cohorts (LifeLines-Deep, Genes for Good, Flemish Gut Flora Project and PopCol), in a GWAS meta-analysis spanning 8,817,117 high-quality SNP markers and 167,875 individuals of European descent.ResultsWe identify 13 genome-wide significant loci (P≤5.0×10−8) harboring prioritized genes that are: i) involved in sensory perception and neurotransmitter/neuropeptide signaling; ii) enriched for their expression in enteric motor neurons associated with the control of peristalsis (P=7.0×10−8) iii) previously linked to other traits and conditions, including GI motility and dysmotility syndromes, and the response to their pharmacological treatment. The genetic architecture of STL-FRQ most strongly correlates with that of IBS (rg=0.42; P=1.1×10−3). In UK Biobank, the risk of IBS with diarrhea was 4x higher in individuals from the top 1% of the distribution of polygenic scores (PGS) computed based on STL-FRQ GWAS summary statistics (ORs=4.14; P=1.2×10−97).ConclusionWe identify loci harboring genes with a plausible role in GI motility, possibly acting via neurotransmission and similar pathways in specialized enteric neurons. The demonstrated relevance of these findings to IBS warrants further study for the identification of actionable pathomechanisms in the dysmotility syndromes.

The cause of irritable bowel syndrome (IBS), a chronic disorder characterized by abdominal pain and disturbed bowel habits, is largely unknown. It is believed to be related to physical properties in the gut, central mechanisms in the brain, psychological factors, or a combination of these. To understand the relationships within the gut-brain axis with respect to IBS, large numbers of measurements ranging from stool samples to functional magnetic resonance imaging are collected from patients with IBS and healthy controls. As such, IBS is a typical example in medical research where research turns into a big data analysis challenge. In this chapter we demonstrate the power of interactive visual data analysis and exploration to generate an environment for scientific reasoning and hypothesis formulation for data from multiple sources with different character. Three case studies are presented to show the utility of the presented work.

n/a Funding Agencies|Region Ostergotland; Bengt-Ihre Fond

Supplemental Digital Content is Available in the Text. Quantitative magnetic resonance spectroscopy of anterior insula reveals decreased glutamatergic neurotransmitter concentrations in patients with irritable bowel syndrome and hemisphere-specific associations with pain severity and pain-related coping., Irritable bowel syndrome (IBS) is a visceral pain condition with psychological comorbidity. Brain imaging studies in IBS demonstrate altered function in anterior insula (aINS), a key hub for integration of interoceptive, affective, and cognitive processes. However, alterations in aINS excitatory and inhibitory neurotransmission as putative biochemical underpinnings of these functional changes remain elusive. Using quantitative magnetic resonance spectroscopy, we compared women with IBS and healthy women (healthy controls [HC]) with respect to aINS glutamate + glutamine (Glx) and γ-aminobutyric acid (GABA+) concentrations and addressed possible associations with symptoms. Thirty-nine women with IBS and 21 HC underwent quantitative magnetic resonance spectroscopy of bilateral aINS to assess Glx and GABA+ concentrations. Questionnaire data from all participants and prospective symptom-diary data from patients were obtained for regression analyses of neurotransmitter concentrations with IBS-related and psychological parameters. Concentrations of Glx were lower in IBS compared with HC (left aINS P < 0.05, right aINS P < 0.001), whereas no group differences were detected for GABA+ concentrations. Lower right-lateralized Glx concentrations in patients were substantially predicted by longer pain duration, while less frequent use of adaptive pain‐coping predicted lower Glx in left aINS. Our findings provide first evidence for reduced excitatory but unaltered inhibitory neurotransmitter levels in aINS in IBS. The results also indicate a functional lateralization of aINS with a stronger involvement of the right hemisphere in perception of abdominal pain and of the left aINS in cognitive pain regulation. Our findings suggest that glutaminergic deficiency may play a role in pain processing in IBS.

Altered neural mechanisms are well-acknowledged in irritable bowel syndrome (IBS), a disorder of brain-gut-communication highly comorbid with anxiety and depression. As a key hub in corticolimbic inhibition, medial prefrontal cortex (mPFC) may be involved in disturbed emotion regulation in IBS. However, aberrant mPFC excitatory and inhibitory neurotransmission potentially contributing to psychological symptoms in IBS remains unknown. Using quantitative magnetic resonance spectroscopy (qMRS), we compared mPFC glutamate + glutamine (Glx) and gamma-aminobutyric acid (GABA+) concentrations in 64 women with IBS and 32 age-matched healthy women (HCs) and investigated their association with anxiety and depression in correlational and subgroup analyses. Applying functional magnetic resonance imaging (fMRI), we explored whether altered neurotransmission was paralleled by aberrant mPFC resting-state functional connectivity (FC). IBS patients did not differ from HCs with respect to mPFC GABA+ or Glx levels. Anxiety was positively associated with mPFC GABA+ concentrations in IBS, whereas Glx was unrelated to psychological or gastrointestinal symptoms. Subgroup comparisons of patients with high or low anxiety symptom severity and HCs revealed increased GABA+ in patients with high symptom severity, and lower mPFC FC with adjacent anterior cingulate cortex (ACC), a crucial region of emotion modulation. Our findings provide novel evidence that altered prefrontal inhibitory neurotransmission may be linked to anxiety in IBS. Funding Agencies|Martinos Center for Biomedical Imaging, MGH (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [P41-RR14075, R01 RR16594-01A1, R01 NS052585-01]; Child and Adolescent Neuropsychiatric Research Program, Cambridge Health Alliance (NIH) [K08 MH01573, K01 MH01798]; County Council of Ostergotland; AFA research foundation; Bengt-Ihre fund; Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)German Research Foundation (DFG) [IC 81/1-1, 316803389 - SFB 1280]; Kurt and Helena Widens Research Fund; Seeing Organ Function project - Knut and Alice Wallenberg Foundation; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [P41 015909, R01 016089]

The cause of irritable bowel syndrome (IBS), a chronic disorder characterized by abdominal pain and disturbed bowel habits, is largely unknown. It is believed to be related to physical properties in the gut, central mechanisms in the brain, psychological factors, or a combination of these. To understand the relationships within the gut-brain axis with respect to IBS, large numbers of measurements ranging from stool samples to functional magnetic resonance imaging are collected from patients with IBS and healthy controls. As such, IBS is a typical example in medical research where research turns into a big data analysis challenge. In this chapter we demonstrate the power of interactive visual data analysis and exploration to generate an environment for scientific reasoning and hypothesis formulation for data from multiple sources with different character. Three case studies are presented to show the utility of the presented work.

Stool consistency and frequency patterns are complex traits that are often altered in GI disease, and recent studies published in Gut highlight the importance of stool frequency in relation to gut microbiota composition and the efficacy of pharmacological and dietary treatments in IBS.1–3 Despite reported heritability in invertebrates4 and similar evidence from open-field defaecation models in rats,5 the genetics of stool frequency has not been explored in humans. We undertook a genome-wide association study (GWAS) in two well-characterised population-based cohorts with genotype and defaecation data available: LifeLines-Deep (LLD) from the Netherlands (N=1546; 58% females; mean age 44 years (range 18–86)) and PopCol (PC) from Sweden (N=284; 60% females; mean age 54 years (range 22–71)).6 ,7 The average number of bowel movements per day (BM/d) was extracted from daily records kept by both populations and did not differ between cohorts (LLD=1.39±0.64SD; PC=1.42±0.74SD). Available CytoChip+Immunochip (LLD) and HumanOmniExpressExome (PC) Illumina single-nucleotide polymorphism (SNP) genotype data were imputed using IMPUTE2 (https://mathgen.stats.ox.ac.uk/impute/impute_v2.html) with the Genome of the Netherlands (http://www.nlgenome.nl/) as reference. SNPs were filtered on minor allele frequency >0.05 and Hardy–Weinberg equilibrium p>1E-04, samples were filtered on infoscore ≥0.8 and population outliers …

BACKGROUND & AIMS: Genetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants. METHODS: We studied 7,287,191 high-quality single nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; n = 9576) compared to the remainder of the cohort (controls; n = 336,499) (mean age of study subjects, 40-69 years). Genome-wide significant findings were further investigated in 2045 patients with IBS from tertiary centers and 7955 population controls from Europe and the United States, and a small general population sample from Sweden (n = 249). Functional annotation of GWAS results was carried out by integrating data from multiple biorepositories to obtain biological insights from the observed associations. RESULTS: We identified a genome-wide significant association on chromosome 9q31.2 (single nucleotide polymorphism rs10512344; P = 3.57 × 10-8) in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P < 5.0×10-6). Sex-stratified analyses revealed that the variants at 9q31.2 affect risk of IBS in women only (P = 4.29 × 10-10 in UK Biobank) and also associate with constipation-predominant IBS in women (P = .015 in the tertiary cohort) and harder stools in women (P = .0012 in the population-based sample). Functional annotation of the 9q31.2 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKBKAP), which is mutated in patients with familial dysautonomia. CONCLUSIONS: In a sufficiently powered GWAS of IBS, we associated variants at the locus 9q31.2 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS. ispartof: GASTROENTEROLOGY vol:155 issue:1 pages:168-179 ispartof: location:United States status: published

Changes in brain-gut interactions have been implicated in the pathophysiology of chronic visceral pain in irritable bowel syndrome (IBS). Different mechanisms of sensitization of visceral afferent pathways may contribute to the chronic visceral pain reports and associated brain changes that characterize IBS. They include increased gut permeability and gut associated immune system activation, and an imbalance in descending pain inhibitory and facilitatory mechanisms. In order to study the involvement of these mechanisms, correlations between gut epithelial permeability and live bacterial passage, and structural and functional brain connectivity were measured in women with moderate-to-severe IBS and healthy women. The relationships between gut permeability and functional and anatomical connectivity were significantly altered in IBS compared with the healthy women. IBS participants with lower epithelial permeability reported increased IBS symptoms, which was associated with increased functional and structural connectivity in endogenous pain facilitation regions. The findings suggest that relationships between gut permeability and the brain are significantly altered in IBS and suggest the existence of IBS subtypes based on these interactions., Highlights • Brain-gut interactions are significantly altered in irritable bowel syndrome. • Brain-gut interactions engage pain modulation brain regions in healthy women. • Normal levels of gut permeability in IBS are linked with endogenous pain facilitation.

Patients with irritable bowel syndrome (IBS) often associate their symptoms to certain foods. In congenital sucrase-isomaltase deficiency (CSID), recessive mutations in the SI gene (coding for the disaccharidase digesting sucrose and 60% of dietary starch)1 cause clinical features of IBS through colonic accumulation of undigested carbohydrates, triggering bowel symptoms.2 Hence, in a previous study,3 we hypothesized that CSID variants reducing SI enzymatic activity may contribute to development of IBS symptoms. We detected association with increased risk of IBS for 4 rare loss-of-function variants typically found in (homozygous) CSID patients, because carriers (heterozygous) of these rare variants were more common in patients than in controls.1,4 Through a 2-step computational and experimental strategy, the present study aimed to determine whether other (dys-)functional SI variants are associated with risk of IBS in addition to known CSID mutations. We first aimed to identify all SI rare pathogenic variants (SI-RPVs) on the basis of integrated Mendelian Clinically Applicable Pathogenicity (M-CAP) and Combined Annotation Dependent Depletion (CADD) predictive (clinically relevant) scores; next, we inspected genotype data currently available for 2207 IBS patients from a large ongoing project to compare SI-RPV case frequencies with ethnically matched population frequencies from the Exome Aggregation Consortium (ExAC). ispartof: CLINICAL GASTROENTEROLOGY AND HEPATOLOGY vol:16 issue:10 pages:1673-1676 ispartof: location:United States status: published

ObjectiveIBS 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.DesignWe 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.ResultsCSID 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 (pConclusionsSI 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.

Objective. Biofeedback and medical treatments have been extensively used for moderate fecal incontinence (FI). There is limited data comparing and combining these two treatments. The objective of this study was to evaluate the effect of biofeedback and medical treatments, separately and in combination. Material and methods. Sixty-four consecutive female patients, referred to a tertiary centre for FI, were included. The patients were randomized to start with either biofeedback (4-6 months) or medical treatment with loperamide and stool-bulking agents (2 months). Both groups continued with a combination of treatments, i.e. medical treatment was added to biofeedback and vice versa. A two-week prospective bowel symptom diary and anorectal physiology were evaluated at baseline, after single-and combination treatments. Results. Fifty-seven patients completed the study. Median number of leakage episodes during two weeks decreased from 6 to 3 (p less than 0.0001) from baseline to completion. The patients showed a significant (1) decrease in number of leakages without forewarning (p = 0.04); (2) decrease in number of stools with urgency (p = 0.001); (3) decrease in number of loose stool consistency; and (4) an increase in rectal sensory thresholds, both for maximum tolerable rectal pressure and first sensation (less than 0.01). The combination treatment was superior to both single treatments in terms of symptoms and functions. There was no significant difference between the two groups at any time point. Conclusions. The combination therapy with biofeedback and medical treatment is effective for symptom relief in FI. The symptom improvement was associated with improved fecal consistency, reduced urgency, and increased rectal sensory thresholds. Funding Agencies|County Council of Ostergotland

Recently in Gut , genetic variation affecting ion channels activity has been highlighted in relation to bowel function and the biology of stool frequency.1 It is also known that 2% of patients with IBS carry functional missense mutations in the voltage-gated channel NaV1.5 ( SCN5A gene).2 Hence, channelopathies represent potential abnormalities underlying GI dysfunction and IBS. We inspected data from our previous genome-wide association study (GWAS) of IBS,3 in relation to 27 genes whose ion channel products contribute to GI sensorimotor development and function, visceral sensation and GI motility (see online supplementary table S1). Significant (uncorrected) results were detected for four genes (calcium voltage-gated channels CACNA1A and CACNA1E , and transient receptor potential channels TRPV3 and TRPM8 ; see online supplementary figure S1), which were selected for replication analyses in an independent set of IBS cases (N=386) and controls (N=357) (see online supplementary material methods). A sex-adjusted logistic regression analysis of genotype data from this cohort (see online supplementary material methods) detected significant associations for …

Gut-directed hypnotherapy can reduce IBS symptoms, but the mechanisms underlying this therapeutic effect remain unknown.To determine the effect of hypnotherapy and educational intervention on brain responses to cued rectal distensions in IBS patients.Forty-four women with moderate-to-severe IBS and 20 healthy controls (HCs) were included. Blood oxygen level dependent (BOLD) signals were measured by functional Magnetic Resonance Imaging (fMRI) during expectation and delivery of high- (45 mmHg) and low-intensity (15 mmHg) rectal distensions. Twenty-five patients were assigned to hypnotherapy (HYP) and 16 to educational intervention (EDU). Thirty-one patients completed treatments and posttreatment fMRI.Similar symptom reduction was achieved in both groups. Clinically successful treatment (all responders) was associated with significant BOLD attenuation during high-intensity distension in the dorsal and ventral anterior insula (cluster size 142, P = 0.006, and cluster size 101, P = 0.005 respectively). Moreover HYP responders demonstrated a pre-post treatment BOLD attenuation in posterior insula (cluster sizes 59, P = 0.05) while EDU responders had a BOLD attenuation in prefrontal cortex (cluster size 60, P = 0.05). Pre-post differences for expectation conditions were almost exclusively seen in the HYP group. Following treatment, the brain response to distension was similar to that observed in HCs, suggesting that the treatment had a normalising effect on the central processing abnormality of visceral signals in IBS.The abnormal processing and enhanced perception of visceral stimuli in IBS can be normalised by psychological interventions. Symptom improvement in the treatment groups may be mediated by different brain mechanisms.NCT01815164.

Stress is an important component in the pathophysiology of irritable bowel syndrome (IBS). Long term Hypothalamus Pituitary Adrenal (HPA)-axis activity can be studied by measuring hair cortisol concentrations (HCC). Some previous studies have indicated a dysregulated HPA-axis in IBS patients, but cortisol levels in hair have not yet been studied. We investigated whether HCC and self-reported stress differentiate IBS patients from controls.In a cross-sectional study within 10 Swedish Primary Health Care Centers we compared patients in working age with active IBS to patients without GI complaints. The participants donated hair samples and completed questionnaires including a scale of self-reported perceived stress (PSS). 169 Rome III-fulfilling IBS patients and 316 non-IBS patients were available for final analyses.IBS patients had significantly lower HCC, median=16.3pg/mg, IQR=26.9pg/mg, compared to non-IBS patients, median=22.8pg/mg, IQR=29.1pg/mg. There was also a difference in the distribution of HCC quintiles between the two groups, with 30.2% IBS patients and 14.2% of non-IBS patients in the lowest quintile of HCC. PSS was higher among IBS patients with a mean (SD) total score of 25.3 (8.0) compared to controls 21.4, (7.5). Quintiles of HCC and PSS stayed significantly but very weakly related to IBS (B=-0.332, Std error=0.146, p0.005) in multivariable analyses.This study suggests a possible suppression of the HPA-axis activity in a considerable portion of IBS patients.

Objectives. The association between abdominal symptoms, disease severity of fecal incontinence (FI), and quality of life (QoL) is not yet clear. We hypothesized that it would become clearer by prospective diary data. We also aimed to compare QoL of FI patients with ulcerative colitis (UC) patients in relapse and remission. Material and methods. Sixty-five consecutive female patients with FI recorded bowel symptoms prospectively on diary cards. QoL was evaluated with the disease specific short health scale questionnaire (SHS). Patients with UC in remission and relapse were used as a reference group regarding SHS. Results. FI patients had median 3.5 leakage episodes/week. In all, 48% of bowel movements were associated with urgency. Urgency was correlated to decreased QoL according to SHS domains: symptoms (Rho = 0.54, p = 0.0002), function (Rho = 0.48, p = 0.0008), and disease related worry (Rho = 0.32, p = 0.027). Abdominal pain and bloating, reported by nearly half of patients, correlated to deceased QoL but not to number of leakages. QoL of patients with FI compared to UC in active phase (n = 35) was similar. FI patients had decreased QoL compared to UC in remission (n = 94) in all dimensions of SHS: symptoms (p < 0.0001), function (p < 0.0001), disease related worry (p < 0.0001), and general well being (p = 0.03). Conclusion. Urgency and irritable bowel syndrome (IBS)-like symptoms were associated with decreased QoL in FI. Therefore, IBS should be considered as an important confounding factor in FI QoL studies. QoL in patients with FI was considerably decreased, in a similar extent as in patients with UC in relapse.

Defining normal stool habit is important when evaluating diarrhoea or constipation, but common confounders such as irritable bowel syndrome (IBS) or the intake of medications with gastrointestinal side effects have not been considered in earlier population based studies defining what is normal. We hypothesized that the exclusion of subjects with common confounders would help to better understand what are "normal bowel habits". We aimed to prospectively study bowel habits in a carefully studied random sample of the general population.Two hundred and sixty-eight randomly selected subjects between 18 and 70 years completed symptom diaries for one week and were clinically evaluated by a gastroenterologist. They also had a colonoscopy and laboratory investigations to exclude organic disease.One hundred and twenty-four subjects had no organic gastrointestinal abnormality, IBS, or relevant medication; 98% of them had between three stools per day and three per week. Seventy-seven percent of all stools were normal, 12% hard, and 10% loose in consistency. Urgency was reported by 36%; straining by 47% and incomplete defecation by 46%. After the exclusion of subjects with organic abnormalities, women had significantly more symptoms than men in terms of abdominal pain, bloating, constipation, urgency, and feeling of incomplete evacuation but these gender differences disappeared after excluding subjects with IBS.This study confirms that normal stool frequency is between three per week and three per day. We could not demonstrate any gender or age differences in terms of stool frequency, defecatory symptoms or abdominal bloating. Some degree of urgency, straining, and incomplete evacuation should be considered normal.

Knowledge about the neural underpinnings of the negative blood oxygen level dependent (BOLD) responses in functional magnetic resonance imaging (fMRI) is still limited. We hypothesized that pharmacological GABAergic modulation attenuates BOLD responses, and that blood concentrations of a positive allosteric modulator of GABA correlate inversely with BOLD responses in the cingulate cortex. We investigated whether or not pure task-related negative BOLD responses were co-localized with pharmacologically modulated BOLD responses. Twenty healthy adults received either 5 mg diazepam or placebo in a double blind, randomized design. During fMRI the subjects performed a working memory task. Results showed that BOLD responses in the cingulate cortex were inversely correlated with diazepam blood concentrations; that is, the higher the blood diazepam concentration, the lower the BOLD response. This inverse correlation was most pronounced in the pregenual anterior cingulate cortex and the anterior mid-cingulate cortex. For subjects with diazepam plasma concentration > 0.1 mg/L we observed negative BOLD responses with respect to fixation baseline. There was minor overlap between cingulate regions with task-related negative BOLD responses and regions where the BOLD responses were inversely correlated with diazepam concentration. We interpret that the inverse correlation between the BOLD response and diazepam was caused by GABA-related neural inhibition. Thus, this study supports the hypothesis that GABA attenuates BOLD responses in fMRI. The minimal overlap between task-related negative BOLD responses and responses attenuated by diazepam suggests that these responses might be caused by different mechanisms. Funding agencies: Linkoping University; County Council of Ostergotland

Aim: To investigate how individuals fulfilling the Rome II criteria for irritable bowel syndrome (IBS) spontaneously described their symptoms. Method: From a general population, 1,244 randomly sampled adults were asked to describe their gastrointestinal symptoms (if any) verbally, in their own words, at a semi-structured interview. Their own descriptions were sorted into five symptom clusters. The participants independently completed a written questionnaire (the Rome II Modular Questionnaire (RMIIMQ)). Results: A total of 601 participants reported at least one gastrointestinal symptom, and 128 had IBS according to the RMIIMQ. After exclusion of organic causes, previously diagnosed IBS, or additional gastrointestinal diagnosis, 81 participants with IBS according to RMIIMQ remained. Five participants (6%) described symptoms included in the full definition of IBS, but none fulfilled the Rome II criteria completely. Abdominal pain or other IBS-related symptoms were reported by 64 (79%), and 12 (15%) did not report any IBS-like symptom. Conclusion: Previously undiagnosed individuals, who fulfil criteria for Rome II-IBS, often express their complaints in words that do not fit into the current diagnostic criteria.

none 44 si IBS shows genetic predisposition, but adequately powered gene-hunting efforts have been scarce so far. We sought to identify true IBS genetic risk factors by means of genome-wide association (GWA) and independent replication studies. open Ek, Weronica E; Reznichenko, Anna; Ripke, Stephan; Niesler, Beate; Zucchelli, Marco; Rivera, Natalia V; Schmidt, Peter T; Pedersen, Nancy L; Magnusson, Patrik; Talley, Nicholas J; Holliday, Elizabeth G; Houghton, Lesley; Gazouli, Maria; Karamanolis, George; Rappold, Gudrun; Burwinkel, Barbara; Surowy, Harald; Rafter, Joseph; Assadi, Ghazaleh; Li, Ling; Papadaki, Evangelia; Gambaccini, Dario; Marchi, Santino; Colucci, Rocchina; Blandizzi, Corrado; Barbaro, Raffaella; Karling, Pontus; Walter, Susanna; Ohlsson, Bodil; Tornblom, Hans; Bresso, Francesca; Andreasson, Anna; Dlugosz, Aldona; Simren, Magnus; Agreus, Lars; Lindberg, Greger; Boeckxstaens, Guy; Bellini, Massimo; Stanghellini, Vincenzo; Barbara, Giovanni; Daly, Mark J; Camilleri, Michael; Wouters, Mira M; D'Amato, Mauro Ek, Weronica E; Reznichenko, Anna; Ripke, Stephan; Niesler, Beate; Zucchelli, Marco; Rivera, Natalia V; Schmidt, Peter T; Pedersen, Nancy L; Magnusson, Patrik; Talley, Nicholas J; Holliday, Elizabeth G; Houghton, Lesley; Gazouli, Maria; Karamanolis, George; Rappold, Gudrun; Burwinkel, Barbara; Surowy, Harald; Rafter, Joseph; Assadi, Ghazaleh; Li, Ling; Papadaki, Evangelia; Gambaccini, Dario; Marchi, Santino; Colucci, Rocchina; Blandizzi, Corrado; Barbaro, Raffaella; Karling, Pontus; Walter, Susanna; Ohlsson, Bodil; Tornblom, Hans; Bresso, Francesca; Andreasson, Anna; Dlugosz, Aldona; Simren, Magnus; Agreus, Lars; Lindberg, Greger; Boeckxstaens, Guy; Bellini, Massimo; Stanghellini, Vincenzo; Barbara, Giovanni; Daly, Mark J; Camilleri, Michael; Wouters, Mira M; D'Amato, Mauro

We read with great interest the two recent communications by Vandeputte et al 1 and Tigchelaar et al ,2 which reported an association between stool consistency and gut microbiota composition. Both studies focused on stool consistency, based on the Bristol Stool Scale (BSS) as the main trait, due to its reported correlation with colonic transit time (CTT) that is of clinical relevance for several GI conditions. However, stool frequency, another feature of human bowel function that is easy to measure and record, has also been shown to correlate with CTT,3 ,4 although to a lesser extent than stool form, and has not yet been investigated in relation to microbiota composition. We examined the association between gut microbiota and stool frequency in the Population-based Colonoscopy study, a general population-based cohort from Stockholm, Sweden, previously described in detail.5 Sixty-nine individuals (21 males and 48 females, aged 55.6±10.33) with available frozen faecal samples and daily recordings of defaecation …

To determine whether there is a postprandial increase of rectal pressure in patients with spinal cord injury (SCI) and to compare their rectal pressures with those of healthy volunteers.A before-after trial comparing SCI and control subjects.Patients were recruited from the register of an SCI unit at a rehabilitation medicine department, and the study took place at the university hospital laboratory in Sweden.Ten patients with high traumatic SCI and 9 healthy volunteers. Eight patients had a lesion above level T5.Continuous anorectal manometry was performed. Rectal activity was calculated before and at regular time intervals after a 1000-cal test meal.Rectal activity measured as area under the pressure curve.There was a significant increase in rectal activity of 46% after 10 minutes in the patients but of 72% after 5 minutes in the volunteers. There was no difference in fasting rectal activity, but patients had a stronger mean rectal postprandial response during 60 minutes compared with volunteers.These results support the theory that the colonic response to food is preserved in patients with high SCI.

Irritable bowel syndrome (IBS) is associated with intestinal dysbiosis and symptoms of IBS develop following gastroenteritis. We aimed to study the passage of live bacteria through the colonic epithelium, and determine the role of mast cells (MCs) and vasoactive intestinal polypeptide (VIP) in barrier regulation in IBS and healthy individuals.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 MCs. Levels of VIP and tryptase were measured in plasma and biopsy lysates. Number of MCs and MCs 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.In colon biopsies from patients with IBS, larger numbers of E coli HS and S typhimurium 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 MCs. 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 MCs, and a higher percentage of MCs 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.We found that colonic epithelium tissues from patients with IBS have increased translocation of commensal and pathogenic live bacteria compared with controls. The mechanisms of increased translocation include MCs and VIP.

We read with great interest the recent communication by Simren et al ,1 reporting a correlation between visceral hypersensitivity and GI symptom severity in functional GI disorders (FGID). Previously, it has been shown that visceral hypersensitivity can be modulated or even induced in animal models, by altering the composition of their gut microbiota with antibiotics or faecal transplantation from IBS donors.2 3 Hence, while a direct link between gut microbiota composition and visceral pain may need to be conclusively established, this holds great potential for translational exploitation in the treatment of IBS and other FGID. Thus far, the potential association between microbiota and abdominal pain in humans has only been investigated in one study that included 15 individuals.4 For this purpose, we studied 159 individuals (average age 59.1, 39.6% men) from the Swedish Population-based Colonoscopy (PopCol) cohort, previously described and with faecal microbiota 16S sequencing data and daily recordings of abdominal pain (number of episodes, duration and intensity) collected over the same period (7.41±7.91 days).5–7 Among these, 52 individuals (assigned to the case group) reported at least one episode …

Background and aimsIrritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by abdominal pain and altered bowel habits. The societal costs of the disorder are significant, as are its negative effects on quality of life. Medical treatment options are limited, but psychological treatments such as hypnotherapy have proven to be effective. Important pathophysiological mechanisms include disturbances in brain processing of visceral sensation and expectation of visceral sensation. Increased sensation of stimuli (hypersensitivity) is present in a subset of IBS patients to distensions in the lower part of the gastrointestinal tract, indicating a probable important pathophysiological mechanism in IBS. The overall aim of the thesis was to further study the central pathophysiological mechanisms involved in IBS. Specifically, we aimed to identify differences in brain response to standardized repeated rectal distensions and expectation of these stimuli between IBS patients (with or without perceptual rectal hypersensitivity), and healthy controls. Furthermore, we aimed to investigate IBS patients´ brain responses to standardized rectal distensions and expectation of these stimuli after either a successful course hypnotherapy or educational intervention.MethodsFunctional magnetic resonance imaging (fMRI) data were acquired and analyzed from 15 IBS patients with visceral hypersensitivity, and 18 IBS patients with normal visceral sensitivity (papers I and II). In paper III, fMRI data were analyzed from IBS patients who reported significant symptom reduction after either a course of hypnotherapy, or an educational intervention. FMRI data from IBS patients and healthy controls were also compared.ResultsThe findings reported in papers I and II suggest, that the differences in brain response between IBS patients with and without rectal hypersensitivity, can be explained by changes in brain response during the course of the experiment. Even though the brain responses were similar between groups during the early phase of the experiment, they became substantially different during the late phase. The IBS patients with rectal hypersensitivity demonstrated increased brain response in several brain regions and networks involved in visceral sensation and processing. In contrast, IBS patients with normal rectal sensitivity exhibited reduced brain response during the late phase of the experiment. As reported in paper III, similar symptom reduction was achieved for both treatments. The symptomatic improvement was associated with a reduction of response in the anterior insula, indicating an attenuated awareness of the stimuli. The hypnotherapy group had a reduction of response in the posterior insula, indicating less input to the brain, possibly due to changed activity in endogenous pain modulatory systems. In patients who reported significant symptom reduction following treatment, the brain response to rectal distension got more similar to that observed in healthy controls.ConclusionsThe results from papers I and II indicate that a subpopulation of IBS patients lacks the ability to habituate to repeated rectal distensions and expectation of these stimuli. Results from paper III indicate that the abnormal processing of visceral stimuli in IBS can be altered, and that the treatments probably had a normalizing effect on the central processing abnormality of visceral signals in IBS.

Background Irritable Bowel Syndrome (IBS) is a chronic, relapsing gastrointestinal disorder,that affects approximately 10% of the general population and the majority are diagnosed in primary care. IBS has been reported to be associated with altered psychological and cognitive functioning such as mood disturbances, somatization, catastrophizing or altered visceral interoception by negative emotions and stress. The aim was to investigate the psychosocial constructs of self-esteem and sense of coherence among IBS patients compared to non-IBS patients in primary care. Methods A case–control study in primary care setting among IBS patients meeting the ROME III criteria (n = 140) compared to controls i.e. non-IBS patients (n = 213) without any present or previous gastrointestinal complaints. The data were collected through self-reportedquestionnaires of psychosocial factors. Results IBS-patients reported significantly more negative self-esteem (p < 0.001), lower scores for positive self-esteem (p < 0.001), and lower sense of coherence (p < 0.001) than the controls. The IBS-cases were also less likely to report ‘good’ health status (p < 0.001) and less likely to report a positive belief in the future (p < 0.001). After controlling for relevant confounding factors in multiple regressions, the elevation in negative self-esteem among IBS patients remained statistically significant (p =0.02), as did the lower scores for sense of coherence among IBS cases (p = 0.04). Conclusions The more frequently reported negative self-esteem and inferior coping strategies among IBS patients found in this study suggest the possibility that psychological therapies might be helpful for these patients. However these data do not indicate the causal direction of the observed associations. More research is therefore warranted to determine whether these psychosocial constructs are more frequent in IBS patients. Funding Agencies|FORSS (Research fund in South of Sweden)