Colon length in pediatric health and constipation measured using magnetic resonance imaging and three dimensional skeletonization.

Recent magnetic resonance imaging (MRI) studies showed that colonic volumes in children are different between health and functional constipation. The length of the colon has however been rarely measured and principally using unphysiological colon preparations or cadaver studies. The main objective of this study was to measure the length of the undisturbed colon in children with functional constipation (FC) and healthy controls. Here, the colon of 19 healthy controls (10-18 years old) and 16 children with FC (7-18 years old) was imaged using MRI. Different regions of the colon (ascending, transverse, descending, and sigmoid-rectum) were first segmented manually on the MRI images. Three-dimensional skeletonization image analysis methods were then used to reduce the regions of interest to a central, measurable line. Total colon length (corrected for body surface area) in healthy controls was 56±2 cm/m2 (mean±SEM). Total colon length was significantly longer in children with FC 69±3 cm/m2 compared to controls (p = 0.0037). The colon regions showing the largest differences between groups were the ascending colon (p = 0.0479) and the sigmoid-rectum (p = 0.0003). In a linear regression model, there was a positive significant correlation between total colon length and age (R = 0.45, p = 0.0064), height (R = 0.49, p = 0.0031), weight (R = 0.46, p = 0.0059) and colon volume (R = 0.4543, p = 0.0061). Our findings showed significant differences in colon lengths between healthy controls and children with constipation. A new objective diagnostic imaging endpoint such as colon length may help to improve knowledge of colon morphology and function and, in turn, understanding of colon functional pathology.

Thinking outside the box: a review of gastrointestinal symptoms and complications in cystic fibrosis.

INTRODUCTION: Gastrointestinal (GI)-related symptoms, complications, and comorbidities in cystic fibrosis (CF) are common and research to reduce their burden is a priority for the CF community. To enable future research, this review aimed to summarize the range of GI symptoms, complications and comorbidities seen in CF, the underlying pathophysiology, and treatments. AREAS COVERED: This was a rapid systematic review undertaken using the recommendations from the Cochrane Rapid Reviews Methods Group. We searched databases including PubMed, Embase, Medline and the Cochrane database and identified those studies reporting GI-related symptoms, complications, or comorbidities in CF or their treatment. Our searches identified 2,930 studies and a total 119 studies met our inclusion criteria. Where a prevalence could be determined, GI symptoms were reported in 33.7% of study participants. The range of symptoms reported was broad and the highest median prevalence included flatulence (43.5%), bloating and abdominal distension (36%), and fatty stool (36%). Meconium ileus was reported in 12% and distal intestinal obstruction syndrome in 8.5. EXPERT OPINION: GI-related symptoms, complications, and comorbidities in CF are common. More consistent characterization and recording of these symptoms in clinical studies may help achieve the priority of reducing the burden of GI disease in CF.

MRI tagging of colonic chyme mixing in healthy subjects: Inter-observer variability and reliability of the measurement with time.

BACKGROUND: Magnetic resonance imaging (MRI) tagging techniques have been applied to the GI tract to assess bowel contractions and content mixing. We aimed to evaluate the dependence of a tagging measurement (for assessing chyme mixing) on inter-observer variability in both the ascending colon (AC) and descending colon (DC) and to investigate the temporal variation and hence reliability of the colonic tagging technique by acquiring multiple measurements over time on healthy participants. METHODS: Two independent datasets of healthy adults were used for the retrospective inter-observer variability (Study 1: 13 datasets and Study 2: 31 datasets), and ten participants were scanned for the prospective temporal variation study following a 1 L mannitol oral preparation. All colonic tagging data were acquired on 3 T MRI scanners. The mean and the standard deviation (SD) maps were generated pixel-by-pixel using custom-written software in MATLAB. The colonic regions of interest were defined using MIPAV software. Bland-Altman plots and scatter plots were used for the inter-observer variability. The mean and SD of all repeated measures for each subject were calculated along with a one-way ANOVA to test for variations with time. RESULTS: Scatter plots and Bland-Altman plots showed a large range of data with low variation and small limits of agreements (<5% CoV). The intraclass correlation coefficient of inter-rater reliability was excellent and 0.97 or above for the AC and DC measurements for both datasets. The temporal variation study shows that there was no significant difference found between the multiple measures with time (p = 0.53, one-way repeated measures ANOVA test). CONCLUSIONS: MRI tagging technique can provide an assessment of colonic chyme mixing. The inter-observer study data showed high inter-rater agreement. The temporal variation study showed some individual variations with time suggesting multiple measurements may be needed to increase accuracy.

Randomised, placebo-controlled trial and meta-analysis show benefit of ondansetron for irritable bowel syndrome with diarrhoea: The TRITON trial.

BACKGROUND: Ondansetron may be beneficial in irritable bowel syndrome with diarrhoea (IBS-D). AIM: To conduct a 12-week parallel group, randomised, double-blind, placebo-controlled trial of ondansetron 4 mg o.d. (titrated up to 8 mg t.d.s.) in 400 IBS-D patients. PRIMARY ENDPOINT: % responders using the Food and Drug Administration (FDA) composite endpoint. Secondary and mechanistic endpoints included stool consistency (Bristol Stool Form Scale) and whole gut transit time (WGTT). After literature review, results were pooled with other placebo-controlled trials in a meta-analysis to estimate relative risks (RR), 95% confidence intervals (CIs) and number needed to treat (NNT). RESULTS: Eighty patients were randomised. On intention-to-treat analysis, 15/37 (40.5%; 95% CI 24.7%-56.4%) met the primary endpoint on ondansetron versus 12/43 (27.9%; 95% CI 14.5%-41.3%) on placebo (p = 0.19). Ondansetron improved stool consistency compared with placebo (adjusted mean difference - 0.7; 95% CI -1.0 to-0.3, p < 0.001). Ondansetron increased WGTT between baseline and week 12 (mean (SD) difference 3.8 (9.1) hours, versus placebo -2.2 (10.3) hours, p = 0.01). Meta-analysis of 327 patients from this, and two similar trials, demonstrated ondansetron was superior to placebo for the FDA composite endpoint (RR of symptoms not responding = 0.86; 95% CI 0.75-0.98, NNT = 9) and stool response (RR = 0.65; 95% CI 0.52-0.82, NNT = 5), but not abdominal pain response (RR = 0.95; 95% CI 0.74-1.20). CONCLUSIONS: Although small numbers meant the primary endpoint was not met in this trial, when pooled with other similar trials meta-analysis suggests ondansetron improves stool consistency and reduces days with loose stool and urgency. Trial registration - http://www.isrctn.com/ISRCTN17508514.

Postinfective bowel dysfunction following Campylobacter enteritis is characterised by reduced microbiota diversity and impaired microbiota recovery.

OBJECTIVES: Persistent bowel dysfunction following gastroenteritis (postinfectious (PI)-BD) is well recognised, but the associated changes in microbiota remain unclear. Our aim was to define these changes after gastroenteritis caused by a single organism, Campylobacter jejuni, examining the dynamic changes in the microbiota and the impact of antibiotics. DESIGN: A single-centre cohort study of 155 patients infected with Campylobacter jejuni. Features of the initial illness as well as current bowel symptoms and the intestinal microbiota composition were recorded soon after infection (visit 1, <40 days) as well as 40-60 days and >80 days later (visits 2 and 3). Microbiota were assessed using 16S rRNA sequencing. RESULTS: PI-BD was found in 22 of the 99 patients who completed the trial. The cases reported significantly looser stools, with more somatic and gastrointestinal symptoms. Microbiota were assessed in 22 cases who had significantly lower diversity and altered microbiota composition compared with the 44 age-matched and sex-matched controls. Moreover 60 days after infection, cases showed a significantly lower abundance of 23 taxa including phylum Firmicutes, particularly in the order Clostridiales and the family Ruminoccocaceae, increased Proteobacteria abundance and increased levels of Fusobacteria and Gammaproteobacteria. The microbiota changes were linked with diet; higher fibre consumption being associated with lower levels of Gammaproteobacteria. CONCLUSION: The microbiota of PI-BD patients appeared more disturbed by the initial infection compared with the microbiota of those who recovered. The prebiotic effect of high fibre diets may inhibit some of the disturbances seen in PI-BD. TRIAL REGISTRATION NUMBER: NCT02040922.

The serotonin receptor 3E variant is a risk factor for female IBS-D.

Irritable bowel syndrome (IBS) is a gut-brain disorder of multifactorial origin. Evidence of disturbed serotonergic function in IBS accumulated for the 5-HT3 receptor family. 5-HT3Rs are encoded by HTR3 genes and control GI function, and peristalsis and secretion, in particular. Moreover, 5-HT3R antagonists are beneficial in the treatment of diarrhea predominant IBS (IBS-D). We previously reported on functionally relevant SNPs in HTR3A c.-42C > T (rs1062613), HTR3C p.N163K (rs6766410), and HTR3E c.*76G > A (rs56109847 = rs62625044) being associated with IBS-D, and the HTR3B variant p.Y129S (rs1176744) was also described within the context of IBS. We performed a multi-center study to validate previous results and provide further evidence for the relevance of HTR3 genes in IBS pathogenesis. Therefore, genotype data of 2682 IBS patients and 9650 controls from 14 cohorts (Chile, Germany (2), Greece, Ireland, Spain, Sweden (2), the UK (3), and the USA (3)) were taken into account. Subsequent meta-analysis confirmed HTR3E c.*76G > A (rs56109847 = rs62625044) to be associated with female IBS-D (OR = 1.58; 95% CI (1.18, 2.12)). Complementary expression studies of four GI regions (jejunum, ileum, colon, sigmoid colon) of 66 IBS patients and 42 controls revealed only HTR3E to be robustly expressed. On top, HTR3E transcript levels were significantly reduced in the sigma of IBS patients (p = 0.0187); more specifically, in those diagnosed with IBS-D (p = 0.0145). In conclusion, meta-analysis confirmed rs56109847 = rs62625044 as a risk factor for female IBS-D. Expression analysis revealed reduced HTR3E levels in the sigmoid colon of IBS-D patients, which underlines the relevance of HTR3E in the pathogenesis of IBS-D.

Serotonin type 3 receptor subunit gene polymorphisms associated with psychosomatic symptoms in irritable bowel syndrome: A multicenter retrospective study.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) of the serotonin type 3 receptor subunit (HTR3) genes have been associated with psychosomatic symptoms, but it is not clear whether these associations exist in irritable bowel syndrome (IBS). AIM: To assess the association of HTR3 polymorphisms with depressive, anxiety, and somatization symptoms in individuals with IBS. METHODS: In this retrospective study, 623 participants with IBS were recruited from five specialty centers in Germany, Sweden, the United States, the United Kingdom, and Ireland. Depressive, anxiety, and somatization symptoms and sociodemographic characteristics were collected. Four functional SNPs - HTR3A c.-42C>T, HTR3B c.386A>C, HTR3C c.489C>A, and HTR3E c.*76G>A - were genotyped and analyzed using the dominant and recessive models. We also performed separate analyses for sex and IBS subtypes. SNP scores were calculated as the number of minor alleles of the SNPs above. The impact of HTR3C c.489C>A was tested by radioligand-binding and calcium influx assays. RESULTS: Depressive and anxiety symptoms significantly worsened with increasing numbers of minor HTR3C c.489C>A alleles in the dominant model (F depressive = 7.475, P depressive = 0.006; F anxiety = 6.535, P anxiety = 0.011). A higher SNP score (range 0-6) was linked to a worsened depressive symptoms score (F = 7.710, P-linear trend = 0.006) in IBS. The potential relevance of the HTR3C SNP was corroborated, showing changes in the expression level of 5-HT3AC variant receptors. CONCLUSION: We have provided the first evidence that HTR3C c.489C>A is involved in depressive and anxiety symptoms in individuals with IBS. The SNP score indicated that an increasing number of minor alleles is linked to the worsening of depressive symptoms in IBS.

Application of In Vivo MRI Imaging to Track a Coated Capsule and Its Disintegration in the Gastrointestinal Tract in Human Volunteers.

Oral specially coated formulations have the potential to improve treatment outcomes of a range of diseases in distal intestinal tract whilst limiting systemic drug absorption and adverse effects. Their development is challenging, partly because of limited knowledge of the physiological and pathological distal gastrointestinal factors, including colonic chyme fluid distribution and motor function. Recently, non-invasive techniques such as magnetic resonance imaging (MRI) have started to provide novel important insights. In this feasibility study, we formulated a coated capsule consisting of a hydroxypropyl methylcellulose (HPMC) shell, coated with a synthetic polymer based on polymethacrylate-based copolymer (Eudragit®) that can withstand the upper gastrointestinal tract conditions. The capsule was filled with olive oil as MRI-visible marker fluid. This allowed us to test the ability of MRI to track such a coated capsule in the gastrointestinal tract and to assess whether it is possible to image its loss of integrity by exploiting the ability of MRI to image fat and water separately and in combination. Ten healthy participants were administered capsules with varying amounts of coating and underwent MRI imaging of the gastrointestinal tract at 45 min intervals. The results indicate that it is feasible to track the capsules present in the gastrointestinal tract at different locations, as they were detected in all 10 participants. By the 360 min endpoint of the study, in nine participants the capsules were imaged in the small bowel, in eight participants in the terminal ileum, and in four in the colon. Loss of capsule integrity was observed in eight participants, occurring predominantly in distal intestinal regions. The data indicate that the described approach could be applied to assess performance of oral formulations in undisturbed distal gastrointestinal regions, without the need for ionizing radiation or contrast agents.

Psyllium reduces inulin-induced colonic gas production in IBS: MRI and in vitro fermentation studies.

OBJECTIVE: Health-promoting dietary fibre including inulin often triggers gastrointestinal symptoms in patients with IBS, limiting their intake. Our aim was to test if coadministering psyllium with inulin would reduce gas production. DESIGN: A randomised, four-period, four-treatment, placebo-controlled, crossover trial in 19 patients with IBS. Subjects ingested a 500 mL test drink containing either inulin 20 g, psyllium 20 g, inulin 20 g+ psyllium 20 g or dextrose 20 g (placebo). Breath hydrogen was measured every 30 min with MRI scans hourly for 6 hours. Faecal samples from a subset of the patients with IBS were tested using an in vitro fermentation model. Primary endpoint was colonic gas assessed by MRI. RESULTS: Colonic gas rose steadily from 0 to 6 hours, with inulin causing the greatest rise, median (IQR) AUC(0-360 min) 3145 (848-6502) mL·min. This was significantly reduced with inulin and psyllium coadministration to 618 (62-2345) mL·min (p=0.02), not significantly different from placebo. Colonic volumes AUC(0-360 min) were significantly larger than placebo for both inulin (p=0.002) and inulin and psyllium coadministration (p=0.005). Breath hydrogen rose significantly from 120 min after inulin but not psyllium; coadministration of psyllium with inulin delayed and reduced the maximum increase, AUC(0-360 min) from 7230 (3255-17910) ppm·hour to 1035 (360-4320) ppm·hour, p=0.007.Fermentation in vitro produced more gas with inulin than psyllium. Combining psyllium with inulin did not reduce gas production. CONCLUSIONS: Psyllium reduced inulin-related gas production in patients with IBS but does not directly inhibit fermentation. Whether coadministration with psyllium increases the tolerability of prebiotics in IBS warrants further study. TRIAL REGISTRATION NUMBER: NCT03265002.

Small bowel water content assessed by MRI in health and disease: a collation of single-centre studies.

BACKGROUND: New developments in MRI have allowed the non-invasive, accurate measurement of the small bowel water content (SBWC). AIMS: To collate studies measuring SBWC following ingestion of a range of foods in both health and disease to provide data for adequately powering future studies in this area. METHODS: This collation brings together 29 studies including 954 participants (530 healthy, 54 diverticulosis, 255 IBS, 53 functional constipation, 12 cystic fibrosis, 15 Crohn's disease, 20 coeliac disease, 15 scleroderma) which have been carried out in a single centre using comparable study designs. RESULTS: Fasting SBWC (mean 82 [SD 65] mL) shows high variability with a small decline with advancing age (healthy volunteers only; individual patient data). Fasting values are increased in untreated coeliac disease (202 [290] mL, P = 0.004). Post-prandial SBWC shows less intra-individual variability than fasting values in healthy volunteers. SBWC is increased by eating, most markedly by high fat meals but also by fibre, both viscous and particulate. Indigestible residue accumulates in late post-prandial period but empties soon after ingestion of a high calorie meal which produces a significant drop (by 50 [52] mL) in healthy volunteers. The associated fall in SBWC is abnormal in people with cystic fibrosis (SBWC reduced by 10 [121] mL, P = 0.002) and in people with irritable bowel syndrome with diarrhoea (SBWC reduced by 17 [43] mL, P = 0.007). CONCLUSIONS: SBWC as assessed by MRI is a valuable biomarker indicating the balance of secretion and absorption in health and disease and the impact of treatments.

Magnetic resonance imaging of the gastrointestinal tract shows reduced small bowel motility and altered chyme in cystic fibrosis compared to controls.

People with cystic fibrosis (CF) experience digestive symptoms but the mechanisms are incompletely understood. Here we explore causes and consequences of slower gastrointestinal transit using magnetic resonance imaging (MRI). Twelve people with CF and 12 healthy controls, matched for age and gender, underwent MRI scans, both fasted and after standardised meals, over 6.5 h. Fasted small bowel motility scores were lower in CF than in controls. No difference in ascending colon chyme T1 was detected. The difference in texture between small bowel and colon contents, seen in health, was diminished in CF. The ascending colon in CF participants had an abnormal appearance compared to controls. MRI offers unique potential to evaluate gut luminal content, colonic mucosa and intestinal motor activity. These new data support the theoretical cycle of desiccation, dysmotility and delayed transit as a cause of gastrointestinal symptoms in CF.

Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders.

Irritable bowel syndrome (IBS) results from disordered brain-gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6. The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression (rg > 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brain-gut interactions underlying IBS.

Colonic Volume Changes in Paediatric Constipation Compared to Normal Values Measured Using MRI.

BACKGROUND: Functional constipation in children is common. Management of this condition can be challenging and is often based on symptom reports. Increased, objective knowledge of colonic volume changes in constipation compared to health could provide additional information. However, very little data on paediatric colonic volume is available except from methods that are invasive or require unphysiological colonic preparations. OBJECTIVES: (1) To measure volumes of the undisturbed colon in children with functional constipation (FC) using magnetic resonance imaging (MRI) and provide initial normal range values for healthy controls, and (2) to investigate possible correlation of colonic volume with whole gut transit time (WGTT). METHODS: Total and regional (ascending, transverse, descending, sigmoid, and rectum) colon volumes were measured from MRI images of 35 participants aged 7-18 years (16 with FC and 19 healthy controls), and corrected for body surface area. Linear regression was used to explore the relationship between total colon volume and WGTT. RESULTS: Total colonic volume was significantly higher, with a median (interquartile range) of 309 mL (243-384 mL) for the FC group than for the healthy controls of 227 mL (180-263 mL). The largest increase between patients and controls was in the sigmoid colon-rectum region. In a linear regression model, there was a positive significant correlation between total colonic volume and WGTT (R = 0.56, p = 0.0005). CONCLUSIONS: This initial study shows increased volumes of the colon in children with FC, in a physiological state, without use of any bowel preparation. Increased knowledge of colonic morphology may improve understanding of FC in this age group and help to direct treatment.

The alternative serotonin transporter promoter P2 impacts gene function in females with irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a gut-brain disorder in which symptoms are shaped by serotonin acting centrally and peripherally. The serotonin transporter gene SLC6A4 has been implicated in IBS pathophysiology, but the underlying genetic mechanisms remain unclear. We sequenced the alternative P2 promoter driving intestinal SLC6A4 expression and identified single nucleotide polymorphisms (SNPs) that were associated with IBS in a discovery sample. Identified SNPs built different haplotypes, and the tagging SNP rs2020938 seems to associate with constipation-predominant IBS (IBS-C) in females. rs2020938 validation was performed in 1978 additional IBS patients and 6,038 controls from eight countries. Meta-analysis on data from 2,175 IBS patients and 6,128 controls confirmed the association with female IBS-C. Expression analyses revealed that the P2 promoter drives SLC6A4 expression primarily in the small intestine. Gene reporter assays showed a functional impact of SNPs in the P2 region. In silico analysis of the polymorphic promoter indicated differential expression regulation. Further follow-up revealed that the major allele of the tagging SNP rs2020938 correlates with differential SLC6A4 expression in the jejunum and with stool consistency, indicating functional relevance. Our data consolidate rs2020938 as a functional SNP associated with IBS-C risk in females, underlining the relevance of SLC6A4 in IBS pathogenesis.

Colonic Gene Expression and Fecal Microbiota in Diarrhea-predominant Irritable Bowel Syndrome: Increased Toll-like Receptor 4 but Minimal Inflammation and no Response to Mesalazine.

BACKGROUND/AIMS: Diarrhea-predominant irritable bowel syndrome (IBS-D) has been previously associated with evidence of immune activation and altered microbiota. Our aim is to assess the effect of the anti-inflammatory agent, mesalazine, on inflammatory gene expression and microbiota composition in IBS-D. METHODS: We studied a subset of patients (n = 43) from a previously published 12-week radomized placebo-controlled trial of mesalazine. Mucosal biopsies were assessed by immunohistochemistry and reverse transcription-polymerase chain reaction for a range of markers of inflammation, altered permeability, and sensory receptors including Toll-like receptors (TLRs) at randomization after treatment. All biopsy data were compared to 21 healthy controls. Patient's stool microbiota composition was analysed through 16S ribosomal RNA sequencing. RESULTS: We found no evidence of increased immune activation compared to healthy controls. However, we did find increased expression of receptors in both sensory pathways and innate immune response including TLR4. Higher TLR4 expression was associated with greater urgency. TLR4 expression correlated strongly with the expression of the receptors bradykinin receptor B2, chemerin chemokine-like receptor 1, and transient receptor potential cation channel, subfamily A, member 1 as well as TLR4's downstream adaptor myeloid differentiation factor 88. Mesalazine had minimal effect on either gene expression or microbiota composition. CONCLUSIONS: Biopsies from a well-characterized IBS-D cohort showed no substantial inflammation. Mesalazine has little effect on gene expression and its previous reported effect on fecal microbiota associated with much greater inflammation found in inflammatory bowel diseases is likely secondary to reduced inflammation. Increased expression of TLR4 and correlated receptors in IBS may mediate a general increase in sensitivity to external stimuli, particularly those that signal via the TLR system.

Pain Severity Correlates With Biopsy-Mediated Colonic Afferent Activation But Not Psychological Scores in Patients With IBS-D.

INTRODUCTION: Despite heterogeneity, an increased prevalence of psychological comorbidity and an altered pronociceptive gut microenvironment have repeatedly emerged as causative pathophysiology in patients with irritable bowel syndrome (IBS). Our aim was to study these phenomena by comparing gut-related symptoms, psychological scores, and biopsy samples generated from a detailed diarrhea-predominant IBS patient (IBS-D) cohort before their entry into a previously reported clinical trial. METHODS: Data were generated from 42 patients with IBS-D who completed a daily 2-week bowel symptom diary, the Hospital Anxiety and Depression score, and the Patient Health Questionnaire-12 Somatic Symptom score and underwent unprepared flexible sigmoidoscopy. Sigmoid mucosal biopsies were separately evaluated using immunohistochemistry and culture supernatants to determine cellularity, mediator levels, and ability to stimulate colonic afferent activity. RESULTS: Pain severity scores significantly correlated with the daily duration of pain (r = 0.67, P < 0.00001), urgency (r = 0.57, P < 0.0005), and bloating (r = 0.39, P < 0.05), but not with psychological symptom scores for anxiety, depression, or somatization. Furthermore, pain severity scores from individual patients with IBS-D were significantly correlated (r = 0.40, P < 0.008) with stimulation of colonic afferent activation mediated by their biopsy supernatant, but not with biopsy cell counts nor measured mediator levels. DISCUSSION: Peripheral pronociceptive changes in the bowel seem more important than psychological factors in determining pain severity within a tightly phenotyped cohort of patients with IBS-D. No individual mediator was identified as the cause of this pronociceptive change, suggesting that nerve targeting therapeutic approaches may be more successful than mediator-driven approaches for the treatment of pain in IBS-D.

Chronic constipation in adults: Contemporary perspectives and clinical challenges. 2: Conservative, behavioural, medical and surgical treatment.

BACKGROUND: Chronic constipation is a prevalent disorder that affects quality of life of patients and consumes resources in healthcare systems worldwide. In clinical practice, it is still considered a challenge as clinicians frequently are unsure as to which treatments to use and when. Over a decade ago, a Neurogastroenterology and Motility journal supplement devoted to the investigation and management of constipation was published (Neurogastroenterol Motil 2009;21(Suppl 2):1). In October 2018, the 3rd London Masterclass, entitled "Contemporary management of constipation" was held. The faculty members of this symposium were invited to write two reviews to present a collective synthesis of talks presented and discussions held during this meeting. The first review addresses epidemiology, diagnosis, clinical associations, pathophysiology, and investigation. PURPOSE: The present is the second of these reviews, providing contemporary perspectives and clinical challenges regarding behavioral, conservative, medical, and surgical treatments for patients presenting with constipation. It includes a management algorithm to guide clinical practice.

Impact of Diet on Symptoms of the Irritable Bowel Syndrome.

Irritable bowel syndrome (IBS), with its key features of abdominal pain and disturbed bowel habit, is thought by both patients and clinicians to be strongly influenced by diet. However, the complexities of diet have made identifying specific food intolerances difficult. Eating disorders can masquerade as IBS and may need specialist treatment. While typical food allergy is readily distinguished from IBS, the mechanisms of gut-specific adverse reactions to food are only just being defined. These may include gut-specific mast cell activation as well as non-specific activation by stressors and certain foods. Visceral hypersensitivity, in some cases mediated by mast cell activation, plays a key part in making otherwise innocuous gut stimuli painful. Rapidly fermented poorly absorbed carbohydrates produce gaseous distension as well as short-chain fatty acids and lowering of colonic pH which may cause symptoms in IBS patients. Limiting intake of these in low FODMAP and related diets has proven popular and apparently successful in many patients. Existing diet, colonic microbiota and their metabolic products may be helpful in predicting who will respond. Wheat intolerance may reflect the fact that wheat is often a major source of dietary FODMAPs. It may also be either a forme fruste of coeliac disease or non-specific immune activation. Wheat exclusion can be successful in some of these patients. More research is needed to fully understand the mechanisms of food intolerances and how to best ameliorate them in a personalised medicine approach to diet in IBS.