The effect of expectancy versus actual gluten intake on gastrointestinal and extra-intestinal symptoms in non-coeliac gluten sensitivity: a randomised, double-blind, placebo-controlled, international, multicentre study.

BACKGROUND: Many individuals without coeliac disease or wheat allergy reduce their gluten intake because they believe that gluten causes their gastrointestinal symptoms. Symptoms could be affected by negative expectancy. Therefore, we aimed to investigate the effects of expectancy versus actual gluten intake on symptoms in people with non-coeliac gluten sensitivity (NCGS). METHODS: This randomised, double-blind, placebo-controlled, international, multicentre study was done at the University of Leeds (Leeds, UK), Maastricht University (Maastricht, the Netherlands), and Wageningen University and Research (Wageningen, the Netherlands). People aged 18-70 years with self-reported NCGS (ie, gastrointestinal symptoms within 8 h of gluten consumption) without coeliac disease and wheat allergy were recruited. Participants had to follow a gluten-free or gluten-restricted diet for at least 1 week before (and throughout) study participation and had to be asymptomatic or mildly symptomatic (overall gastrointestinal symptom score ≤30 mm on the Visual Analogue Scale [VAS]) while on the diet. Participants were randomly assigned (1:1:1:1; blocks of eight; stratified by site and gender) to one of four groups based on the expectation to consume gluten-containing (E+) or gluten-free (E-) oat bread for breakfast and lunch (two slices each) and actual intake of gluten-containing (G+) or gluten-free (G-) oat bread. Participants, investigators, and those assessing outcomes were masked to the actual gluten assignment, and participants were also masked to the expectancy part of the study. The primary outcome was overall gastrointestinal symptom score on the VAS, which was measured at and corrected for baseline (before breakfast) and hourly for 8 h, with lunch served after 4 h, and analysed per-protocol. Safety analysis included all participants incorporated in the per-protocol analysis. The study is registered at ClinicalTrials.gov, NCT05779358, and has ended. FINDINGS: Between Oct 19, 2018, and Feb 14, 2022, 165 people were screened and 84 were randomly assigned to E+G+ (n=21), E+G- (n=21), E-G+ (n=20), or E-G- (n=22). One person in the E+G+ group was excluded due to not following test day instructions, leaving 83 participants in the per-protocol analysis. Median age was 27·0 years (IQR 21·0-45·0), 71 (86%) of 83 people were women, and 12 (14%) were men. Mean overall gastrointestinal symptom score was significantly higher for E+G+ (16·6 mm [95% CI 13·1 to 20·0]) than for E-G+ (6·9 mm [3·5 to 10·4]; difference 9·6 mm [95% CI 3·0 to 16·2], p=0·0010) and E-G- (7·4 mm [4·2 to 10·7]; difference 9·1 mm [2·7 to 15·6], p=0·0016), but not for E+G- (11·7 mm [8·3 to 15·1]; difference 4·9 mm [-1·7 to 11·5], p=0·28). There was no difference between E+G- and E-G+ (difference 4·7 mm [-1·8 to 11·3], p=0·33), E+G- and E-G- (difference 4·2 mm [-2·2 to 10·7], p=0·47), and E-G+ and E-G- (difference -0·5 mm [-7·0 to 5·9], p=1·0). Adverse events were reported by two participants in the E+G- group (itching jaw [n=1]; feeling lightheaded and stomach rumbling [n=1]) and one participant in the E-G+ group (vomiting). INTERPRETATION: The combination of expectancy and actual gluten intake had the largest effect on gastrointestinal symptoms, reflecting a nocebo effect, although an additional effect of gluten cannot be ruled out. Our results necessitate further research into the possible involvement of the gut-brain interaction in NCGS. FUNDING: Government of the Netherlands Topsector Agri & Food Top Consortium for Knowledge and Innovation, AB Mauri Global Bakery Ingredients, Baking Industry Research Trust, Borgesius-Albert Heijn, CSM Innovation Centre, the International Maize and Wheat Improvement Center (CIMMYT), DSM Food Specialties, Fazer, Healthgrain Forum, the International Association for Cereal Science and Technology, the International Wheat Gluten Association, Lantmännen, Mondelez International, Nederlands Bakkerij Centrum, Nutrition & Santé, Puratos, Rademaker, Sonneveld Group, and Zeelandia HJ Doeleman.

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.

Diet Quality and Dietary Inflammatory Index in Dutch Inflammatory Bowel Disease and Irritable Bowel Syndrome Patients.

Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) share common culprit foods and potential pathophysiological factors. However, how diet may contribute to disease course and whether this differs between both entities is unclear. We therefore investigated the association of dietary indices with intestinal inflammation and gastrointestinal symptoms in both IBD and IBS patients. Food frequency questionnaires from 238 IBD, 261 IBS and 195 healthy controls (HC) were available to calculate the overall diet quality by the Dutch Healthy Diet-Index 2015 (DHD-2015) and its inflammatory potential by the Adapted Dietary Inflammatory Index (ADII). Intestinal inflammation and symptoms were evaluated by faecal calprotectin and the Gastrointestinal Symptom Rating Scale, respectively. The DHD-2015 was lower in IBD and IBS versus HC (p < 0.001), being associated with calprotectin levels in IBD (b = −4.009, p = 0.006), and with abdominal pain (b = −0.012, p = 0.023) and reflux syndrome (b = −0.016, p = 0.004) in IBS. ADII scores were comparable between groups and were only associated with abdominal pain in IBD (b = 0.194, p = 0.004). In this side-by-side comparison, we found a lower diet quality that was differentially associated with disease characteristics in IBD versus IBS patients. Longitudinal studies are needed to further investigate the role of dietary factors in the development of flares and predominant symptoms.

Examining the optimal cutoff values of HADS, PHQ-9 and GAD-7 as screening instruments for depression and anxiety in irritable bowel syndrome.

BACKGROUND: Self-rating scales are frequently used to screen for anxiety and depression in patients with irritable bowel syndrome (IBS). Different cutoff values are recommended in literature, and guidelines have suggested the use of other screening instruments over time. The aim of this study was to assess the correlation between the most commonly used psychological screening instruments for anxiety and depression in IBS and to compare custom cutoff scores for these instruments. METHODS: Irritable bowel syndrome patients (n = 192) completed several questionnaires including the Hospital Anxiety and Depression Scale (HADS, HADS-A and HADS-D subscale), Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7). Agreement at different cutoff points, for depressive and anxiety disorder, was assessed by use of the Gwet AC1 coefficient. KEY RESULTS: Hospital Anxiety and Depression Scale (HADS)-D and PHQ-9 scores, and HADS-A and GAD-7 scores showed high correlations (rs  = 0.735 and rs  = 0.805, respectively). For depressive disorder, a Gwet AC1 value of 0.829 was found when recommended cutoff points from literature were compared (PHQ-9 cutoff ≥10, HADS-D cutoff ≥8). For anxiety disorder, a Gwet AC1 value of 0.806 was found when recommended cutoff points from literature were compared (GAD-7 cutoff ≥10, HADS-A cutoff ≥8). Even higher agreements were found when higher HADS cutoff values were chosen, with impact on sensitivity and specificity. CONCLUSIONS & INFERENCES: Custom cutoff values deem the HADS subscales (HADS-D and HADS-A) concordant to PHQ-9 and GAD-7 scores. The choice of a cutoff value has substantial impact on sensitivity/specificity and is dependent on patient population, setting, and the purpose of use.

Reduction in IBS symptom severity is not paralleled by improvement in quality of life in patients with irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is a brain-gut disorder, of which the natural course varies between patients and is difficult to predict. This study aimed to evaluate symptom evolution over a 5-year follow-up period and to identify baseline predictors for symptom severity and quality of life (QoL) at follow-up. METHODS: Maastricht IBS cohort participants completed questionnaires upon inclusion regarding demographics and lifestyle, gastrointestinal (GI) symptoms, anxiety and depression, and QoL. The same questionnaires, in addition to others, were completed after 5 years. Rome criteria were confirmed face-to-face at initial enrollment and through telephonic interviews at follow-up. KEY RESULTS: At a mean follow-up of 4.7 years, 379 patients were approached of whom 203 (53.7%) responded. Of these, 161 were reached by telephone and analyzed; 49 (30.4%) did not fulfill the Rome III criteria at follow-up and had lower levels of GI symptoms and GI-specific anxiety compared to those remaining Rome III-positive (P < 0.001). However, Rome III-negative patients had comparable levels of QoL and life satisfaction, comorbid anxiety and depression, work absenteeism, and impaired productivity. No baseline predictors were found for being Rome III-positive or Rome III-negative. However, greater age and lower baseline physical QoL predicted lower physical QoL at follow-up (P < 0.005 and P < 0.01, respectively), while lower baseline mental QoL predicted lower mental QoL at follow-up (P = 0.005). Additionally, higher anxiety and depression scores at follow-up were associated with lower QoL and life satisfaction at follow-up (P < 0.001). CONCLUSIONS AND INFERENCES: Long-term QoL and general well-being might depend on concurrent psychological symptoms, rather than GI symptom improvement.

The Experience Sampling Method-Evaluation of treatment effect of escitalopram in IBS with comorbid panic disorder.

BACKGROUND: Confirming treatment response in clinical trials for irritable bowel syndrome (IBS) is challenging, due to the lack of biomarkers and limitations of the currently available symptom assessment tools. The Experience Sampling Method (ESM) might overcome these limitations by collecting digital assessments randomly and repeatedly during daily life. This study evaluated differences in change in abdominal pain between real-time (ie, ESM) and retrospective (ie, Gastrointestinal Symptom Rating Scale [GSRS] and an end-of-day symptom diary) measurements, using data of an RCT on escitalopram vs placebo in patients with IBS and comorbid panic disorder. METHODS: Twenty-nine IBS patients with comorbid panic disorder were included in a 6-month RCT. The GSRS, diary, and ESM were completed at baseline (t = 0) and after 3 (t = 3) and 6 months (t = 6). Linear mixed models were used. KEY RESULTS: Experience Sampling Method analyses revealed a significant interaction between escitalopram and time, and ESM abdominal pain scores were 1.4 points lower in the escitalopram group compared to placebo at t = 6 (on a 1-to-7 scale; P = 0.021). When including the interaction with momentary anxiety, the reduction in abdominal pain scores in escitalopram vs placebo was even more pronounced for higher levels of anxiety. Average GSRS- and end-of-day abdominal pain scores were not significantly different between escitalopram and placebo at t = 3 and 6. CONCLUSIONS & INFERENCES: Real-time ESM has the potential to capture treatment response more sensitively compared to a retrospective end-of-day GI symptom diary and the GSRS, by taking into account day-to-day symptom variability as well as momentary factors that might moderate treatment effect, such as anxiety.