The Socioeconomic Impact of Irritable Bowel Syndrome: An Analysis of Direct and Indirect Health Care Costs.

BACKGROUND & AIMS: Irritable bowel syndrome (IBS) is associated with substantial costs to society. Extensive data on direct costs (health care consumption) and indirect costs (health-related productivity loss) are lacking. Hence, we examined the socioeconomic costs of IBS and assessed which patient characteristics are associated with higher costs. METHODS: Cross-sectional data from 3 Rome-defined Dutch IBS patient cohorts (n = 419) were collected. Bootstrapped mean direct and indirect costs were evaluated per patient with IBS using validated questionnaires (ie, medical cost questionnaire and productivity cost questionnaire, respectively). Multivariable regression analyses were performed to identify variables associated with higher costs. RESULTS: Quarterly mean total costs per patient were €2.156 (95% confidence interval (CI), €1793-€2541 [$2444]), consisting of €802 (95% CI, €625-€1010 [$909]) direct costs and €1.354 (95% CI, €1072-€1670 [$1535]) indirect costs. Direct costs consisted primarily of health care professional consultations, with costs related to gastrointestinal clinic visits accounting for 6% and costs related to mental health care visits for 20%. Higher direct costs were significantly associated with older age (P = .007), unemployment (P = .001), IBS subtypes other than constipation (P = .033), lower disease-specific quality of life (P = .027), and more severe depressive symptoms (P = .001). Indirect costs consisted of absenteeism (45%), presenteeism (42%), and productivity loss related to unpaid labor (13%) and were significantly associated with the male sex (P = .014) and more severe depressive symptoms (P = .047). CONCLUSIONS: Productivity loss is the main contributor to the socioeconomic burden of IBS. Direct costs were not predominantly related to gastrointestinal care, but rather to mental health care. Awareness of the nature of costs and contributing patient factors should lead to significant socioeconomic benefits for society.

Satisfaction With Life in IBS Is Associated With Psychological Burden Rather than Gastrointestinal Symptom Severity.

INTRODUCTION: Irritable bowel syndrome (IBS) has a major impact on emotional, social, and professional life. This study aimed to evaluate general life satisfaction, a subjective measure of well-being, in IBS patients, and to determine which factors are associated with higher life satisfaction. METHODS: IBS patients (n = 195, mean age 51.4 ± 16.5 years, 73.8% female) recruited from primary and secondary/tertiary care completed questionnaires regarding gastrointestinal symptoms, quality of life, psychological factors, and life satisfaction (Satisfaction With Life Scale, 5 items, range 5-35). A finite mixture model analysis was performed to identify latent classes. Multivariable linear regression was used to identify variables associated with life satisfaction. RESULTS: Overall, 71.3% of the patients were satisfied about their life (Satisfaction With Life Scale-score ≥21). Three latent subgroups could be identified with significantly higher life satisfaction in the subgroup with higher mental quality of life, fewer anxiety and depressive symptoms, lower gastrointestinal specific anxiety, and lower gastrointestinal symptom severity, compared with the other 2 groups. Multivariable linear regression showed that higher physical quality of life (B0.168, P < 0.001) and higher mental quality of life (B0.199, P < 0.001) were associated with higher life satisfaction. Using multivariable regression, no significant association was found between gastrointestinal symptom severity and life satisfaction. DISCUSSION: Higher physical and mental quality of life, but not gastrointestinal symptom severity, were independently associated with higher general life satisfaction in IBS. These findings reinforce the clinical need in IBS treatment to focus on the full extent of the disorder and not merely on gastrointestinal symptom improvement. ClinicalTrials.gov Identifier: NCT00775060.

Efficacy and Safety of Peppermint Oil in a Randomized, Double-Blind Trial of Patients With Irritable Bowel Syndrome.

BACKGROUND & AIMS: Peppermint oil is frequently used to treat irritable bowel syndrome (IBS), despite a lack of evidence for efficacy from high-quality controlled trials. We studied the efficacy and safety of small-intestinal-release peppermint oil in patients with IBS and explored the effects of targeted ileocolonic-release peppermint oil. METHODS: We performed a double-blind trial of 190 patients with IBS (according to Rome IV criteria) at 4 hospitals in The Netherlands from August 2016 through March 2018; 189 patients were included in the intent-to-treat analysis (mean age, 34.0 years; 77.8% female; 57.7% in primary care), and 178 completed the study. Patients were randomly assigned to groups given 182 mg small-intestinal-release peppermint oil, 182 mg ileocolonic-release peppermint oil, or placebo for 8 weeks. The primary endpoint was abdominal pain response, as defined by the US Food and Drug Administration: at least a 30% decrease in the weekly average of worst daily abdominal pain compared with baseline in at least 4 weeks. The co-primary endpoint was overall relief of IBS symptoms, as defined by the European Medicines Agency. Secondary endpoints included abdominal pain, discomfort, symptom severity, and adverse events. RESULTS: Abdominal pain response did not differ significantly between the peppermint oil and placebo groups: 29 of 62 patients in the small-intestinal-release peppermint oil group had a response (46.8%, P = .170 vs placebo), 26 of 63 patients in the ileocolonic-release peppermint oil group had a response (41.3%, P = .385 vs placebo), and 22 of 64 patients in the placebo group had a response (34.4%). We did not find differences among the groups in overall relief (9.7%, P = .317 and 1.6%, P = .351 vs 4.7% for placebo). The small intestinal peppermint oil did, however, produce greater improvements than placebo in secondary outcomes of abdominal pain (P = .016), discomfort (P = .020), and IBS severity (P = .020). Adverse events, although mild, were more common in both peppermint oil groups (P < .005). CONCLUSIONS: In a randomized trial of patients with IBS, we found that neither small-intestinal-release nor ileocolonic-release peppermint oil (8 weeks) produced statistically significant reductions in abdominal pain response or overall symptom relief, when using US Food and Drug Administration/European Medicines Agency recommended endpoints. The small-intestinal-release peppermint oil did, however, significantly reduce abdominal pain, discomfort, and IBS severity. These findings do not support further development of ileocolonic-release peppermint oil for treatment of IBS. Clinicaltrials.gov, Number: NCT02716285.

Cost-effectiveness of Telemedicine-directed Specialized vs Standard Care for Patients With Inflammatory Bowel Diseases in a Randomized Trial.

BACKGROUND & AIMS: Telemedicine can be used to monitor determinants and outcomes of patients with chronic diseases, possibly increasing the quality and value of care. Telemedicine was found to reduce outpatient visits and hospital admissions for patients with inflammatory bowel diseases (IBD). We performed a full economic evaluation of telemedicine interventions in patients with IBD, comparing the cost-utility of telemedicine vs standard care. METHODS: We performed a randomized trial of 909 patients with IBD at 2 academic and 2 non-academic hospitals in The Netherlands. Patients were randomly assigned to groups that received telemedicine (myIBDcoach; n = 465) or standard outpatient care (n = 444) and followed for 12 months. Costs were measured from a societal perspective. Direct healthcare costs were based on actual resource use. Indirect costs comprised self-reported hours sick leave from work, intervention costs (annual license fee of €40 per patient [$45]), and utility costs (assessed using EQ5D). Cost-utility and uncertainty were estimated using the non-parametric bootstrapping method. RESULTS: Telemedicine resulted in lower mean annual costs of €547/patient [$612] (95% CI, €1029-2143 [$1150-2393]; mean costs of €9481 [$10,587] for standard care and €8924 [$9965] for telemedicine) without changing quality adjusted life years. At the Dutch threshold of €80,000 [$89,335] per quality adjusted life year, the intervention had increased incremental cost-effectiveness over standard care in 83% of replications and an incremental net monetary benefit of €707/patient [$790] (95% CI, €1241-2544 [$1386-2841]). CONCLUSIONS: Telemedicine with myIBDcoach is cost saving and has a high probability of being cost effective for patients with IBD. This self-management tool enables continuous registration of quality indicators and (patient-reported) outcomes and might help reorganize IBD care toward value-based healthcare. ClinicalTrials.gov no: NCT02173002.

The Role of Brown Adipose Tissue in the Development and Treatment of Nonalcoholic Steatohepatitis: An Exploratory Gene Expression Study in Mice.

Brown adipose tissue (BAT) might be a beneficial mediator in the development and treatment of nonalcoholic steatohepatitis (NASH). We aim to evaluate the gene expression of BAT activity-related genes during the development and the dietary and surgical treatment of NASH. BAT was collected from male C57BL/6J mice that received a high fat-high sucrose diet (HF-HSD) or a normal chow diet (NCD) for 4 and 20 weeks (n=8-9 per dietary group and timepoint) and from mice that underwent dietary intervention (return to NCD) (n=8), roux-en-y gastric bypass (RYGB) (n=6), or sham procedure (n=6) after 12 weeks HF-HSD. Expression of BAT genes involved in lipid metabolism (Cd36 and Cpt1b; p<0.05) and energy expenditure (Ucp1 and Ucp3; p<0.05) were significantly increased after 4 weeks HF-HSD compared with NCD, whereas in the occurrence of NASH after 20 weeks HF-HSD no difference was observed. We observed no differences in gene expression regarding lipid metabolism or energy expenditure at 8 weeks after dietary intervention (no NASH) compared with HF-HSD mice (NASH), nor in mice that underwent RYGB compared with SHAM. However, dietary intervention and RYGB both decreased the BAT gene expression of inflammatory cytokines (Il1b, Tnf-α and MCP-1; p<0.05). Gene expression of the batokine neuregulin 4 was significantly decreased after 20 weeks HF-HSD (p<0.05) compared with NCD, but was restored by dietary intervention and RYGB (p<0.05). In conclusion, BAT is hallmarked by dynamic alterations in the gene expression profile during the development of NASH and can be modulated by dietary intervention and bariatric surgery.

The reproducibility of skeletal muscle signal intensity on routine magnetic resonance imaging in Crohn's disease.

BACKGROUND AND AIM: Myosteatosis is a prognostic factor in cancer and liver cirrhosis. It can be determined noninvasively using computed tomography or, as shown recently, by magnetic resonance (MR) imaging. The primary aim was to analyze the reproducibility of skeletal muscle signal intensity on routine MR-enterographies, as indicator of myosteatosis, in Crohn's disease (CD) and to explore the association between skeletal muscle signal intensity at diagnosis with time to intestinal resection. METHODS: CD patients undergoing MR-enterography within 6 months from diagnosis and having a maximum of 5 years follow-up were included. Skeletal muscle signal intensity was analyzed on T1-weighted fat-saturated post-contrast images. Intra-observer and inter-observer reproducibilities were assessed by intra-class correlation coefficient and Cohen's kappa. Intra-observer and inter-observer variabilities were determined by Pearson correlation coefficient and displayed by Bland-Altman plots. Time to intestinal resection was studied by Kaplan-Meier analysis. RESULTS: Median time between diagnosis and MR-enterography was 5 weeks (inter-quartile range 1-9) in 35 CD patients. Skeletal muscle signal intensity showed good intra-class correlation and substantial agreement (for intra-observer, intraclass correlation coefficient = 0.948, κ = 0.677; and inter-observer reproducibility, intraclass correlation coefficient = 0.858, κ = 0.622). Resection free survival was shorter in the low skeletal muscle signal intensity group (P = 0.037). CONCLUSION: Skeletal muscle signal intensity on routine MR-enterographies is reproducible and was associated with unfavorable disease outcome, indicating potential clinical relevance.

Ambient air quality as risk factor for microscopic colitis - A geographic information system (GIS) study.

BACKGROUND: Microscopic colitis (MC) is considered a multifactorial disease, strongly associated with smoking. However, little is known about the role of environmental factors such as ambient air pollution in MC pathophysiology. There is an overlap in components of cigarette smoke and ambient air pollution. Therefore, the aim of this study was to explore an independent association between ambient air quality and MC. METHODS: A case-control study was performed. MC cases in South Limburg, the Netherlands, diagnosed between 2000 and 2012, were retrieved from the national pathology registry and matched to non-MC controls from the same area based on age (±2 years) and gender. A stable residential address for ≥3 years was required. Residential land use, proximity to major road, and concentrations of air pollution compounds, were determined using a Geographic Information System (GIS). Univariate and multivariable regression analyses were corrected for age, gender and smoking status. RESULTS: In total, 345 MC cases (78.6% female) and 583 matched controls (77.2% female) were included. In the univariate analyses, the percentage of urban green within a 500 m buffer and residential proximity to the nearest highway were associated with MC (both p < 0.10). On the multivariable level only a higher age at diagnosis (OR 1.02, 95%-CI 1.01-1.04) and current smoking at index date (OR 4.30; 95%-CI 3.01-6.14) were significantly associated with MC. CONCLUSION: Based on the current findings, ambient air quality does not seem to be an important risk factor for MC, in contrast to the well-known risk factors age and current smoking.

Telemedicine for management of inflammatory bowel disease (myIBDcoach): a pragmatic, multicentre, randomised controlled trial.

BACKGROUND: Tight and personalised control of inflammatory bowel disease in a traditional setting is challenging because of the disease complexity, high pressure on outpatient clinics, and rising incidence. We compared the effects of self-management with a telemedicine system, which was developed for all subtypes of inflammatory bowel disease, on health-care utilisation and patient-reported quality of care versus standard care. METHODS: We did this pragmatic, randomised trial in two academic and two non-academic hospitals in the Netherlands. Outpatients aged 18-75 years with inflammatory bowel disease and without an ileoanal or ileorectal pouch anastomosis, who had internet access and Dutch proficiency, were randomly assigned (1:1) to care via a telemedicine system (myIBDcoach) that monitors and registers disease activity or standard care and followed up for 12 months. Randomisation was done with a computer-generated sequence and used the minimisation method. Participants, health-care providers, and staff who assessed outcome measures were not masked to treatment allocation. Primary outcomes were the number of outpatient visits and patient-reported quality of care (assessed by visual analogue scale score 0-10). Safety endpoints were the numbers of flares, corticosteroid courses, hospital admissions, emergency visits, and surgeries. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02173002. FINDINGS: Between Sept 9, 2014, and May 18, 2015, 909 patients were randomly assigned to telemedicine (n=465) or standard care (n=444). At 12 months, the mean number of outpatient visits to the gastroenterologist or nurse was significantly lower in the telemedicine group (1·55 [SD 1·50]) than in the standard care group (2·34 [1·64]; difference -0·79 [95% CI -0·98 to -0·59]; p<0·0001), as was the mean number of hospital admissions (0·05 [0·28] vs 0·10 [0·43]; difference -0·05 [-0·10 to 0·00]; p=0·046). At 12 months, both groups reported high mean patient-reported quality of care scores (8·16 [1·37] in the telemedicine group vs 8·27 [1·28] in the standard care group; difference 0·10 [-0·13 to 0·32]; p=0·411). The mean numbers of flares, corticosteroid courses, emergency visits, and surgeries did not differ between groups. INTERPRETATION: Telemedicine was safe and reduced outpatient visits and hospital admissions compared with standard care. This self-management tool might be useful for reorganising care of inflammatory bowel disease towards personalised and value-based health care. FUNDING: Maastricht University Medical Centre and Ferring.

Patient-Reported Outcome Measures for Use in Clinical Trials and Clinical Practice in Inflammatory Bowel Diseases: A Systematic Review.

BACKGROUND & AIMS: Mucosal inflammation must be carefully monitored to improve the long-term outcomes of patients with inflammatory bowel diseases (IBD). Patient-reported outcome measures (PROMs) are used increasingly to monitor disease activity in clinical practice and as endpoints in clinical trials. We performed a systematic review to provide an overview of the available PROMs on IBD activity and to evaluate their diagnostic value. METHODS: A systematic search of the PubMed, Medline, Cochrane library, and Embase databases using defined keywords, identified 973 articles. These were screened by 2 independent reviewers, and 37 articles on development or validation of PROMs to assess IBD activity were identified for further analysis. Based on the recommendations of the Food and Drug Administration (FDA), the following measurement properties were evaluated: content, construct, and criterion validity; reliability; and responsiveness to change. In addition, data on ease of use in clinical practice were collected. RESULTS: Seventeen articles presenting 20 different PROMs were included the final analysis, although none met all the FDA-recommended criteria. Only 2 PROMs (patient-reported Harvey Bradshaw Index and Simple Clinical Colitis Activity Index scores) reported patient involvement during its development. Only 6 PROMs (patient-reported global assessment, patient assessment of disease activity, mobile health index for Crohn's disease, mobile health index for ulcerative colitis, patient-reported outcome derived from the Mayo score, and the 6-point Mayo score) were validated as markers of IBD activity, using findings from endoscopy as the reference standard; these PROMs identified patients with mucosal inflammation with area under the curve values of 0.63-0.82. The mobile health index for CD and UC scores had the best measurement properties for use in clinical practice and in clinical trials. CONCLUSIONS: In a systematic review, we identified more than 20 PROMS that have been developed and tested for their ability to determine IBD activity. Further studies are needed to determine their accuracy and whether they can be used effectively in routine practice, clinical trials, telemedicine systems, and value-based healthcare programs.

Intestinal Fungal Dysbiosis Is Associated With Visceral Hypersensitivity in Patients With Irritable Bowel Syndrome and Rats.

BACKGROUND & AIMS: Visceral hypersensitivity is one feature of irritable bowel syndrome (IBS). Bacterial dysbiosis might be involved in the activation of nociceptive sensory pathways, but there have been few studies of the role of the mycobiome (the fungal microbiome) in the development of IBS. We analyzed intestinal mycobiomes of patients with IBS and a rat model of visceral hypersensitivity. METHODS: We used internal transcribed spacer 1-based metabarcoding to compare fecal mycobiomes of 18 healthy volunteers with those of 39 patients with IBS (with visceral hypersensitivity or normal levels of sensitivity). We also compared the mycobiomes of Long-Evans rats separated from their mothers (hypersensitive) with non-handled (normally sensitive) rats. We investigated whether fungi can cause visceral hypersensitivity using rats exposed to fungicide (fluconazole and nystatin). The functional relevance of the gut mycobiome was confirmed in fecal transplantation experiments: adult maternally separated rats were subjected to water avoidance stress (to induce visceral hypersensitivity), then given fungicide and donor cecum content via oral gavage. Other rats subjected to water avoidance stress were given soluble ß-glucans, which antagonize C-type lectin domain family 7 member A (CLEC7A or DECTIN1) signaling via spleen-associated tyrosine kinase (SYK), a SYK inhibitor to reduce visceral hypersensitivity, or vehicle (control). The sensitivity of mast cells to fungi was tested with mesenteric windows (ex vivo) and the human mast cell line HMC-1. RESULTS: α diversity (Shannon index) and mycobiome signature (stability selection) of both groups of IBS patients differed from healthy volunteers, and the mycobiome signature of hypersensitive patients differed from that of normally sensitive patients. We observed mycobiome dysbiosis in rats that had been separated from their mothers compared with non-handled rats. Administration of fungicide to hypersensitive rats reduced their visceral hypersensitivity to normal levels of sensitivity. Administration of cecal mycobiomes from rats that had been separated from their mothers (but not non-handled mycobiome) restored hypersensitivity to distension. Administration of soluble ß-glucans or a SYK inhibitor reduced visceral hypersensitivity, compared with controls. Particulate ß-glucan (a DECTIN-1 agonist) induced mast cell degranulation in mesenteric windows and HMC-1 cells responded to fungal antigens by release of histamine. CONCLUSIONS: In an analysis of patients with IBS and controls, we associated fungal dysbiosis with IBS. In studies of rats, we found fungi to promote visceral hypersensitivity, which could be reduced by administration of fungicides, soluble ß-glucans, or a SYK inhibitor. The intestinal fungi might therefore be manipulated for treatment of IBS-related visceral hypersensitivity.

Corticosteroid Sparing in Inflammatory Bowel Disease is More Often Achieved in the Immunomodulator and Biological Era-Results from the Dutch Population-Based IBDSL Cohort.

OBJECTIVES: Corticosteroid-free remission is an emerging treatment goal in the management of inflammatory bowel disease (IBD). In the population-based Inflammatory Bowel Disease South Limburg cohort, we studied temporal changes in corticosteroid use and assessed the corticosteroid-sparing effects of immunomodulators and biologicals in real life. METHODS: In total, 2,823 newly diagnosed patients with Crohn's disease (CD) or ulcerative colitis (UC) were included. Corticosteroid exposure and cumulative days of use were compared between patients diagnosed in 1991-1998 (CD: n=316, UC: n=539), 1999-2005 (CD: n=387, UC: n=527), and 2006-2011 (CD: n=459, UC: n=595). Second, the corticosteroid-sparing effects of immunomodulators and biologicals were assessed. RESULTS: Over time, the corticosteroid exposure rate was stable (54.0% in CD and 31.4% in UC), even as the cumulative corticosteroid use in the first disease year (CD: 83 days (interquartile range (IQR) 35-189), UC: 62 days (IQR 0-137)). On the long-term, a gradual decrease in cumulative corticosteroid use was seen in CD (era '91-'98: 366 days (IQR 107-841), era '06-'11: 120 days (IQR 72-211), P<0.01), whereas in UC an initial decrease was observed (era '91-'98: 184 days (IQR 86-443), era '99-'05: 166 days (IQR 74-281), P=0.03), and stabilization thereafter. Immunomodulator and biological users had a lower risk of requiring corticosteroids than matched controls in CD only (33.6% vs. 49.9%, P<0.01, and 25.7% vs. 38.2%, P=0.04, respectively). CONCLUSIONS: In a real-world setting, more recently diagnosed IBD patients used lower amounts of corticosteroids as of the second year of disease. For CD, a significant association was found with the use of immunomodulators and biologicals. These conclusions support the increasing use of these treatment modalities.

Improvements in the Long-Term Outcome of Crohn's Disease Over the Past Two Decades and the Relation to Changes in Medical Management: Results from the Population-Based IBDSL Cohort.

OBJECTIVES: Medical treatment options and strategies for Crohn's disease (CD) have changed over the past decades. To assess its impact, we studied the evolution of the long-term disease outcome in the Dutch Inflammatory Bowel Disease South Limburg (IBDSL) cohort. METHODS: In total, 1,162 CD patients were included. Three eras were distinguished: 1991-1998 (n=316), 1999-2005 (n=387), and 2006-2011 (n=459), and patients were followed until 2014. Medication exposure and the rates of hospitalization, surgery, and phenotype progression were estimated using Kaplan-Meier survival analyses and compared between eras by multivariable Cox regression models. Second, propensity score matching was used to assess the relation between medication use and the long-term outcome. RESULTS: Over time, the immunomodulator exposure rate increased from 30.6% in the era 1991-1998 to 70.8% in the era 2006-2011 at 5 years. Similar, biological exposure increased from 3.1% (era 1991-1998) to 41.2% (era 2006-2011). In parallel, the hospitalization rate attenuated from 65.9% to 44.2% and the surgery rate from 42.9% to 17.4% at 5 years, respectively (both P<0.01). Progression to a complicated phenotype has not changed over time (21.2% in the era 1991-1998 vs. 21.3% in the era 2006-2011, P=0.93). Immunomodulator users had a similar risk of hospitalization, surgery, or phenotype progression as propensity score-matched nonusers (P>0.05 for all analyses). Similar results were found for biological users (P>0.05 for all analyses). CONCLUSIONS: Between 1991 and 2014, the hospitalization and surgery rates decreased, whereas progression to complicated disease is still common in CD. These improvements were not significantly related to the use of immunomodulators and biologicals.

Inflammatory bowel disease, cancer and medication: Cancer risk in the Dutch population-based IBDSL cohort.

The management of inflammatory bowel disease (IBD) has changed since the mid-1990s (e.g., use of thiopurines/anti-TNFα agents, improved surveillance programs), possibly affecting cancer risk. To establish current cancer risk in IBD, updates are warranted from cohorts covering this time span, and detailed enough to study associations with phenotype and medication. We studied intestinal-, extra-intestinal- and overall cancer risk in the Dutch population-based IBDSL cohort. In total, 1,157 Crohn's disease (CD) and 1,644 ulcerative colitis (UC) patients were diagnosed between 1991 and 2011, and followed until 2013. Standardized incidence ratios (SIRs) were calculated for CD and UC separately, as well as for gender-, phenotype-, disease duration-, diagnosis era- and medication groups. We found an increased risk for colorectal cancer in CD patients with colon involvement (SIR 2.97; 95% CI 1.08-6.46), but not in the total CD or UC population. In addition, CD patients were at increased risk for hematologic- (2.41; 1.04-4.76), overall skin- (1.55; 1.06-2.19), skin squamous cell- (SCC; 3.83; 1.83-7.04) and overall cancer (1.28; 1.01-1.60), whereas UC patients had no increased risk for extra-intestinal- and overall cancer. Finally, in a medication analysis on CD and UC together, long-term immunosuppression exposure (>12 months) was associated with an increased risk for hematologic cancer, non-Hodgkin lymphoma, SCC and overall cancer, and this increase was mainly attributed to thiopurines. IBD patients with long-term immunosuppression exposure can be considered as having a higher cancer risk, and our data support the advice in recent IBD guidelines to consider skin cancer screening in these patients.

Is intestinal oxidative stress involved in patients with compensated liver cirrhosis?

BACKGROUND: Liver cirrhosis is associated with intestinal epithelial barrier dysfunction, which may be affected by oxidative stress. Studies in cirrhotic rats provided evidence for intestinal oxidative stress, but studies in cirrhotic patients are scarce. We have shown intestinal barrier dysfunction in patients with compensated cirrhosis. AIM: The present study aimed to investigate whether oxidative stress occurs in the intestinal mucosa of compensated cirrhotic patients and may contribute to barrier dysfunction. MATERIAL AND METHODS: Oxidative stress was studied in duodenal and sigmoid biopsies from 15 cirrhotic patients and 22 controls by analyzing transcription of genes involved in glutathione and uric acid metabolism using quantitative real-time polymerase chain reaction. Protein levels of glutathione and glutathione disulphide were measured and the glutathione/glutathione disulphide ratio was calculated as marker of oxidative stress. In addition, intestinal myeloperoxidase and fecal calprotectin were determined. RESULTS: Gene transcription of glutathione synthetase and glutathione reductase were significantly different in duodenal and sigmoid biopsies of cirrhotic patients vs. controls, but no alterations were found for other genes nor for glutathione, glutathione disulphide, glutathione/glutathione disulphide ratio and intestinal myeloperoxidase and fecal calprotectin concentrations. CONCLUSION: This study did not find indications for oxidative stress and low-grade inflammation in the small and large intestine of stable compensated cirrhotic patients. Although these preliminary findings need further validation, we found intestinal oxidative stress not to be a major mechanism contributing to epithelial barrier dysfunction in patients with compensated cirrhosis.

Intestinal microbiota and diet in IBS: causes, consequences, or epiphenomena?

Irritable bowel syndrome (IBS) is a heterogeneous functional disorder with a multifactorial etiology that involves the interplay of both host and environmental factors. Among environmental factors relevant for IBS etiology, the diet stands out given that the majority of IBS patients report their symptoms to be triggered by meals or specific foods. The diet provides substrates for microbial fermentation, and, as the composition of the intestinal microbiota is disturbed in IBS patients, the link between diet, microbiota composition, and microbial fermentation products might have an essential role in IBS etiology. In this review, we summarize current evidence regarding the impact of diet and the intestinal microbiota on IBS symptoms, as well as the reported interactions between diet and the microbiota composition. On the basis of the existing data, we suggest pathways (mechanisms) by which diet components, via the microbial fermentation, could trigger IBS symptoms. Finally, this review provides recommendations for future studies that would enable elucidation of the role of diet and microbiota and how these factors may be (inter)related in the pathophysiology of IBS.

Large intestine permeability is increased in patients with compensated liver cirrhosis.

Intestinal barrier dysfunction, facilitating translocation of bacteria and bacterial products, plays an important role in the pathophysiology of liver cirrhosis and its complications. Increased intestinal permeability has been found in patients with liver cirrhosis, but data on small and large intestine permeability and tight junctions (TJs) in patients with compensated cirrhosis are scarce. We aimed to investigate both small and large intestine permeability in patients with stable compensated cirrhosis compared with healthy controls and evaluated the expression of TJ proteins in mucosal biopsies at duodenal and sigmoid level. Intestinal permeability was assessed in 26 patients with compensated cirrhosis and 27 matched controls using a multisugar test. Duodenal and sigmoid biopsies were available from a subgroup for analyses of gene transcription and expression of key TJ proteins by qRT-PCR and ELISA, respectively. Median 0-5-h urinary sucrose excretion and lactulose/rhamnose ratio were comparable between patients with compensated cirrhosis and controls, whereas 5-24-h urinary sucralose/erythritol ratio was increased in these patients. Downregulation of gene transcription was found for claudin-3 in duodenal biopsies and claudin-4 in sigmoid biopsies, and at the protein level occludin expression was significantly increased in both duodenal and sigmoid biopsies. This study shows that gastroduodenal and small intestine permeability are not altered, whereas large intestine permeability is increased in patients with stable compensated cirrhosis. Only limited alterations were found regarding the expression of TJ proteins in both the small and large intestine.

Two randomized crossover multicenter studies investigating gastrointestinal symptoms after bread consumption in individuals with noncoeliac wheat sensitivity: do wheat species and fermentation type matter?

BACKGROUND: Many individuals reduce their bread intake because they believe wheat causes their gastrointestinal (GI) symptoms. Different wheat species and processing methods may affect these responses. OBJECTIVES: We investigated the effects of 6 different bread types (prepared from 3 wheat species and 2 fermentation conditions) on GI symptoms in individuals with self-reported noncoeliac wheat sensitivity (NCWS). METHODS: Two parallel, randomized, double-blind, crossover, multicenter studies were conducted. NCWS individuals, in whom coeliac disease and wheat allergy were ruled out, received 5 slices of yeast fermented (YF) (study A, n = 20) or sourdough fermented (SF) (study B, n = 20) bread made of bread wheat, spelt, or emmer in a randomized order on 3 separate test days. Each test day was preceded by a run-in period of 3 d of a symptom-free diet and separated by a wash-out period of ≥7 d. GI symptoms were evaluated by change in symptom score (test day minus average of the 3-d run-in period) on a 0-100 mm visual analogue scale (ΔVAS), comparing medians using the Friedman test. Responders were defined as an increase in ΔVAS of ≥15 mm for overall GI symptoms, abdominal discomfort, abdominal pain, bloating, and/or flatulence. RESULTS: GI symptoms did not differ significantly between breads of different grains [YF bread wheat median ΔVAS 10.4 mm (IQR 0.0-17.8 mm), spelt 4.9 mm (-7.6 to 9.4 mm), emmer 11.0 mm (0.0-21.3 mm), P = 0.267; SF bread wheat 10.5 mm (-3.1 to 31.5 mm), spelt 11.3 mm (0.0-15.3 mm), emmer 4.0 mm (-2.9 to 9.3 mm), P = 0.144]. The number of responders was also comparable for both YF (6 to wheat, 5 to spelt, and 7 to emmer, P = 0.761) and SF breads (9 to wheat, 7 to spelt, and 8 to emmer, P = 0.761). CONCLUSIONS: The majority of NCWS individuals experienced some GI symptoms for ≥1 of the breads, but on a group level, no differences were found between different grains for either YF or SF breads. CLINICAL TRIAL REGISTRY: clinicaltrials.gov, NCT04084470 (https://classic. CLINICALTRIALS: gov/ct2/show/NCT04084470).