Efficacy and Findings of a Blinded Randomized Reintroduction Phase for the Low FODMAP Diet in Irritable Bowel Syndrome.

BACKGROUND AND AIMS: The efficacy of a low fermentable oligo-, di-, monosaccharides and polyols (FODMAP) diet in irritable bowel syndrome (IBS) is well established. After the elimination period, a reintroduction phase aims to identify triggers. We studied the impact of a blinded reintroduction using FODMAP powders to objectively identify triggers and evaluated the effect on symptoms, quality of life, and psychosocial comorbidities. METHODS: Responders to a 6-week low FODMAP diet, defined by a drop in IBS symptom severity score (IBS-SSS) compared with baseline, entered a 9-week blinded randomized reintroduction phase with 6 FODMAP powders (fructans, fructose, galacto-oligosaccharides, lactose, mannitol, sorbitol) or control (glucose). A rise in IBS-SSS (≥50 points) defined a FODMAP trigger. Patients completed daily symptom diaries and questionnaires for quality of life and psychosocial comorbidities. RESULTS: In 117 recruited patients with IBS, IBS-SSS improved significantly after the elimination period compared with baseline (150 ± 116 vs 301 ± 97, P < .0001, 80% responders). Symptom recurrence was triggered in 85% of the FODMAP powders, by an average of 2.5 ± 2 FODMAPs/patient. The most prevalent triggers were fructans (56%) and mannitol (54%), followed by galacto-oligosaccharides, lactose, fructose, sorbitol, and glucose (respectively 35%, 28%, 27%, 23%, and 26%) with a significant increase in abdominal pain at day 1 for sorbitol/mannitol, day 2 for fructans/galacto-oligosaccharides, and day 3 for lactose. CONCLUSION: We confirmed the significant benefit of the low FODMAP diet in tertiary-care IBS. A blinded reintroduction revealed a personalized pattern of symptom recurrence, with fructans and mannitol as the most prevalent, and allows the most objective identification of individual FODMAP triggers. Ethical commission University hospital of Leuven reference number: s63629; Clinicaltrials.gov number: NCT04373304.

The Effects of Corticotropin-Releasing Hormone on Gastric Electrical Activity and Sensorimotor Function in Healthy Volunteers: A Double-blinded Crossover Study.

Biopsychosocial factors are associated with disorders of gut brain interaction and exacerbate gastrointestinal symptoms. The mechanisms underlying pathophysiological alterations of stress remain unclear. Corticotropin-releasing hormone (CRH) is a central regulator of the hormonal stress response and has diverse impact on different organ systems. The aim of the present study was to investigate the effects of peripheral CRH infusion on meal-related gastrointestinal symptoms, gastric electrical activity and gastric sensorimotor function in healthy volunteers (HVs). In a randomized, double-blinded, placebo-controlled, crossover study, we evaluated the effects of CRH on gastric motility and sensitivity. HVs were randomized to receive either peripheral administered CRH (100 µg bolus + 1 µg/kg/hr) or placebo (saline), followed by at least a 7-day washout period and assignment to the opposite treatment. Tests encompassed saliva samples, gastric emptying (GE) testing, body surface gastric mapping (BSGM, Gastric Alimetry®; Alimetry) to assess gastric myoelectrical activity with real-time symptom profiling, and a gastric barostat study to assess gastric sensitivity to distention and accommodation. 20 HVs (13 women, mean age 29.2±5.3 years, BMI 23.3±3.8 kg/m2) completed GE tests, of which 18 also underwent BSGM measurements during the GE tests. The GE half time decreased significantly after CRH exposure (65.2±17.4 vs 78.8±24.5 minutes, p=0.02) with significantly increased gastric amplitude (49.7 (34.7-55.6) vs 31.7 (25.7-51.0) µV, p<0.01), saliva cortisol levels and postprandial symptom severity. Eleven HVs also underwent gastric barostat studies on a separate day. However, the thresholds for discomfort during isobaric distensions, gastric compliance, and accommodation did not differ between CRH and placebo.

Mechanisms underlying food-related symptoms in disorders of gut-brain interaction: Course ahead in research and clinical practice.

A subgroup of patients with a disorder of gut-brain interaction (DGBI) report symptoms such as abdominal pain, gas-related symptoms, dyspeptic symptoms and loose stool or urgency after meal intake. Therefore, the effect of several dietary therapies including fibre-rich or restrictive diets have already been studied in patients with irritable bowel syndrome, functional abdominal bloating or distention, and functional dyspepsia. However, there is a paucity of studies in the literature on the mechanisms underlying food-related symptoms. Therefore, this review focuses on these potential mechanisms and explains the role of nutrient sensing and tasting, physical considerations, malabsorption or allergy-like reaction to food and its interaction with microbiota. In addition, it emphasizes the importance of future research and clinical practice regarding food-related symptoms in patients with a DGBI.

Prevalence of delayed gastric emptying in patients with gastroparesis-like symptoms.

BACKGROUND: The European consensus defined gastroparesis as a condition characterised by delayed gastric emptying (GE) in the absence of mechanical obstruction, with a symptom pattern of predominant nausea and/or vomiting and overlapping postprandial distress syndrome (PDS). The distinction between patients with gastroparesis and those with functional dyspepsia (FD), another gastrointestinal condition characterised by predominant PDS or epigastric pain syndrome symptoms, is ongoing. AIM: To investigate the extent that symptom patterns may differentiate gastroparesis from FD. METHODS: This retrospective study included 637 patients from Leuven University Hospital in 2006-2021 who had upper gastrointestinal symptoms, underwent a GE test, and completed the Dyspepsia Symptom Severity (DSS) questionnaire. Patients were identified as with gastroparesis-like symptoms (GPLS; i.e., moderate to severe nausea with moderate to severe PDS) or FD symptoms (not fitting GPLS). We excluded patients aged <18 years, and those with diabetes, organic gastrointestinal disease or a history of abdominal surgeries. Demographic and clinical variables were compared. RESULTS: Among 545 patients, 238 reported GPLS and 307 reported FD symptoms. Those with GPLS had a significantly higher prevalence of delayed GE (half emptying time (T1/2) ≥109 min) and lower body mass index than those with FD (33.2% vs 17.6%, p < 0.01; 19.9 vs 21.2, p < 0.01, respectively). Among GPLS patients, those with delayed GE had higher DSS than those without (13.0 vs 12.0, p < 0.01). CONCLUSIONS: In tertiary care patients who reported gastroparesis or FD symptoms, the presence of delayed GE was associated with GPLS. In patients with GPLS, delayed GE was associated with higher symptom severity.

Worldwide prevalence and burden of gastroparesis-like symptoms as defined by the United European Gastroenterology (UEG) and European Society for Neurogastroenterology and Motility (ESNM) consensus on gastroparesis.

BACKGROUND/OBJECTIVES: The global epidemiology of gastroparesis is unknown. The European UEG and European Society for Neurogastroenterology and motility consensus defines Gastroparesis as a condition characterized by delayed gastric emptying in the absence of mechanical obstruction, with a symptom pattern of nausea and/or vomiting and overlapping postprandial distress syndrome (PDS). Real-world evidence of this gastroparesis-like symptom pattern is a crucial step in understanding the epidemiology of gastroparesis. METHODS: In the Rome Foundation Global Epidemiology Study, 54,127 respondents from 26 countries completed the Rome IV Diagnostic Questionnaire and variables associated with disorders of gut-brain interaction via Internet. We selected subjects with gastroparesis-like symptoms (GPLS) (nausea and/or vomiting ≥1 day/week and simultaneous PDS). Patients reporting organic gastrointestinal disease, or fulfilling criteria for self-induced vomiting, cyclic vomiting or cannabinoid hyperemesis syndrome were excluded. We determined prevalence, associated comorbidities, quality of life (QoL) (PROMIS Global-10), symptoms of anxiety and depression (PHQ-4), somatic symptoms (PHQ-12), and healthcare utilization. RESULTS: The global prevalence of GPLS was 0.9% overall and 1.3% among diabetic individuals. Subjects with GPLS showed frequent overlapping of epigastric pain syndrome and irritable bowel syndrome. Subjects with GPLS had significantly lower body mass index, QoL, more non-gastrointestinal somatic complaints, symptoms of anxiety and depression, higher medication usage and doctor visits in the overall and diabetic population, compared to subjects without these symptoms. CONCLUSIONS: GPLS are common worldwide and more common in diabetic patients. The symptom complex is associated with multiple aspects of illness and an increased healthcare consumption.

Mechanisms Underlying Food-Triggered Symptoms in Disorders of Gut-Brain Interactions.

There has been a dramatic increase in clinical studies examining the relationship between disorders of gut-brain interactions and symptoms evoked by food ingestion in the upper and lower gastrointestinal tract, but study design is challenging to verify valid endpoints. Consequently, mechanistic studies demonstrating biological relevance, biomarkers and novel therapeutic targets are greatly needed. This review highlights emerging mechanisms related to nutrient sensing and tasting, maldigestion, physical effects with underlying visceral hypersensitivity, allergy and immune mechanisms, food-microbiota interactions and gut-brain signaling, with a focus on patients with functional dyspepsia and irritable bowel syndrome. Many patients suffering from disorders of gut-brain interactions exhibit these mechanism(s) but which ones and which specific properties may vary widely from patient to patient. Thus, in addition to identifying these mechanisms and the need for further studies, biomarkers and novel therapeutic targets are identified that could enable enriched patient groups to be studied in future clinical trials examining the role of food in the generation of gut and non-gut symptoms.

Diet or medication in primary care patients with IBS: the DOMINO study - a randomised trial supported by the Belgian Health Care Knowledge Centre (KCE Trials Programme) and the Rome Foundation Research Institute.

BACKGROUND: In Europe, IBS is commonly treated with musculotropic spasmolytics (eg, otilonium bromide, OB). In tertiary care, a low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet provides significant improvement. Yet, dietary treatment remains to be explored in primary care. We evaluated the effect of a smartphone FODMAP-lowering diet application versus OB on symptoms in primary care IBS. METHODS: IBS patients, recruited by primary care physicians, were randomised to 8 weeks of OB (40 mg three times a day) or diet and followed for 24 weeks. We compared IBS Symptom Severity Score and the proportion of responders (improvement ≥50 points) in all patients and the subgroup fulfilling Rome IV criteria (Rome+). We also evaluated treatment efficacy, quality of life, anxiety, depression, somatic symptom severity (Patient Health Questionnaire (PHQ15, PHQ9)) and treatment adherence and analysed predictors of response. RESULTS: 459 primary care IBS patients (41±15 years, 76% female, 70% Rome+) were randomised. The responder rate after 8 weeks was significantly higher with diet compared with OB (71% (155/218) vs 61% (133/217), p=0.03) and more pronounced in Rome+ (77% (118/153) vs 62% (98/158), p=0.004). Patients allocated to diet (199/212) were 94% adherent compared with 73% with OB (148/202) (p<0.001). The significantly higher response rate with diet was already observed after 4 weeks (62% (132/213) vs 51% (110/215), p=0.02) and a high symptom response persisted during follow-up. Predictors of response were female gender (OR=2.08, p=0.04) for diet and PHQ15 (OR=1.10, p=0.02) for OB. CONCLUSION: In primary care IBS patients, a FODMAP-lowering diet application was superior to a spasmolytic agent in improving IBS symptoms. A FODMAP-lowering diet should be considered the first-line treatment for IBS in primary care. TRIAL REGISTRATION NUMBER: NCT04270487.

Postinfectious onset in functional dyspepsia is a risk factor for weight loss.

BACKGROUND: Functional dyspepsia (FD) is differentiated into two subgroups: the postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS). Acute gastroenteritis and Helicobacter pylori (HP) infection have been identified as risk factors for FD. It is unclear how these risk factors relate to Rome IV subgroups and their clinical impact. We aimed to study the association of postinfectious FD (PI-FD) and HP status with clinical profiles and weight loss. METHODS: Consecutive FD patients were assessed for symptom frequency and severity. Patients were identified as PDS, EPS or the overlap group according to severity scores. Additionally, PI history and HP status were determined. RESULTS: In a cohort of 459 FD-patients, 36% were characterized as having PDS, 9% as having EPS and 55% showed overlap. PI onset and positive HP status were reported by, respectively, 20% and 14% of patients, not significantly differing between subgroups (respectively, p = 0.31 and p = 0.40). Weight loss was reported by 63% in PDS, 36% in EPS and 56% in overlap patients (p = 0.011). Only early satiety severity correlated with more severe weight loss in the PDS (r 0.31, p < 0.0001) and overlap group (r 0.38, p < 0.0001). PI-FD patients were more likely to experience weight loss (OR 2.27, p = 0.0013). HP status was not significantly associated with weight loss (p = 0.90). CONCLUSION: In this cohort, PI onset of FD symptoms emerged as a risk factor for weight loss, but was not associated with the symptom patterns of PDS, EPS or overlap subgroups. Patients with HP infection were not more likely to experience important weight loss.

Relationship Between Gastric Emptying Rate and Simultaneously Assessed Symptoms in Functional Dyspepsia.

METHODS: During a GE test (breath test with 13C-octanoic acid labelled 250 kcal solid meal), the severity of 6 symptoms (postprandial fullness, epigastric pain and burning, bloating, nausea and belching) was assessed, every 15 min, before meal-intake and 4h postprandially. The sum of individual symptom scores generated the meal-related symptoms score; the sum of all symptoms generated overall meal-related symptom severity (OSS). Data were compared in patients with normal and delayed GE (cut-off T1/2≥ 109 min). Data are shown as mean±SEM. RESULTS: 504 patients were included, of which 382 patients (67% female, age 43.8±0.8 years, BMI 23.3±0.2 kg/m2) had normal and 122 patients (77% female, age 42.7±1.5 years, BMI 23.2±0.6 kg/m2) had delayed GE. OSS tended to be higher in patients with delayed GE (81.8±3.4 vs. 99.5±7.1, p=.05). Only nausea was significantly higher in patients with delayed GE (11±0.8 vs. 16±1.6, p=.01). No correlations were observed between GE rate and any of the symptoms (OSS: r=0.06, p=.2; nausea: r=0.06, p=.1). The symptom severity time course showed a significant difference only for nausea, with increased severity ratings 90 min after the meal (p<.01) in delayed GE compared to normal GE patients. CONCLUSION: The severity of symptoms in functional dyspepsia and idiopathic gastroparesis, even when assessed during the GE test meal, is not correlated to gastric emptying rate. (Ethics committee University Hospital of Leuven study number S55426).

The gastrointestinal tract in hunger and satiety signalling.

BACKGROUND: Different peripheral pathways are implicated in the regulation of the food ingestion-digestion cycle. METHODS: Narrative review on gastrointestinal mechanisms involved in satiety and hunger signalling. RESULTS: Combined mechano- and chemoreceptors, peripherally released peptide hormones and neural pathways provide feedback to the brain to determine sensations of hunger (increase energy intake) or satiation (cessation of energy intake) and regulate the human metabolism. The gastric accommodation reflex, which consists of a transient relaxation of the proximal stomach during food intake, has been identified as a major determinant of meal volume, through activation of tension-sensitive gastric mechanoreceptors. Motilin, whose release is the trigger of gastric Phase 3, has been identified as the major determinant of return of hunger after a meal. In addition, the release of several peptide hormones such as glucagon-like peptide 1 (GLP-1), cholecystokinin as well as motilin and ghrelin contributes to gut-brain signalling with relevance to control of hunger and satiety. A number of nutrients, such as bitter tastants, as well as pharmacological agents, such as endocannabinoid receptor antagonists and GLP-1 analogues act on these pathways to influence hunger, satiation and food intake. CONCLUSION: Gastrointestinal mechanisms such as gastric accommodation and motilin release are key determinants of satiety and hunger.

Nutrient Drinking Test as Biomarker in Functional Dyspepsia.

INTRODUCTION: Functional dyspepsia (FD) is a prevalent condition with multifactorial pathophysiology, including impaired gastric accommodation (GA), hypersensitivity to gastric distention, and delayed gastric emptying. Drink tests (DT) have been proposed as a potential biomarker for the presence and severity of gastric sensorimotor dysfunction. Thus, we aimed to summarize the state of knowledge on different DT and their potential as a biomarker for FD. METHODS: A PubMed and MEDLINE search was conducted for English language articles, reviews, meta-analyses, case series, and randomized controlled trials, including also published meeting abstracts. RESULTS: Several DT have been described in literature (e.g., different type of liquid, number of calories used, pace of drinking, and subject's awareness of the amount of liquid drunk). FD patients ingest significantly less volume in the different variants of the tests. The slow nutrient ("satiety drinking") test (SDT) studies show the most consistent separation between health and FD and correlation with GA. However, sensitivity to distention may be correlated with rapid DT. SDTs were used to evaluate the effect of several pharmacological agents, often showing concordance between their effects on GA and tolerated nutrient volume. This correlation was not found mainly for agents with central actions. DISCUSSION: An SDT is a potential diagnostic biomarker in FD, reflecting GA. Additional studies are required to confirm its role as a predictive biomarker for treatment outcome in FD.

Effects of Rome IV Definitions of Functional Dyspepsia Subgroups in Secondary Care.

BACKGROUND & AIMS: Functional dyspepsia (FD) is subdivided into postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS) according to the Rome III consensus. In clinical practice, there is a major overlap between these subgroups. The Rome IV criteria included postprandially occurring symptoms in the PDS subgroup. We aimed to analyze the effects of the Rome IV criteria, compared with Rome III, on FD subgroups in patients recruited from secondary care. METHODS: Patients with FD (n = 224; mean age, 43 ± 1 y; 77% women) were recruited from secondary-care units in Belgium and filled out symptom questionnaires, allowing subdivision according to Rome III and Rome IV criteria and identification of postprandial symptoms. Symptom patterns and demographics were compared between the subgroups. Statistical analysis was performed using the t test and the Fisher exact test. RESULTS: According to the Rome III criteria, 25% of participants had PDS, 8% had EPS, and 67% had an overlap. Postprandial fullness, early satiation, and bloating were present in significantly more patients in the PDS and overlap groups than the EPS group (P < .0001). A higher proportion of patients in the overlap group showed symptoms such as postprandial epigastric pain and nausea than in the EPS group (both P ≤ .02). With the Rome IV criteria, the overlap group was reduced to 35%; 57% of patients were considered to have PDS and 8% to have EPS. Postprandial pain was significantly more prevalent in the PDS than in the EPS group (P ≤ .002), and postprandial nausea was significantly more prevalent in the PDS group than the overlap group (P = .007). CONCLUSIONS: Compared with Rome III criteria, the Rome IV criteria significantly reduces the overlap between PDS and EPS groups. Studies are needed to determine if Rome IV subgroups are associated differently with psychological comorbidities and treatment responses.

Paradigm Shift: Functional Dyspepsia-A "Leaky Gut" Disorder?

ABSTRACT: For up to 2 decades, pathophysiological research in functional dyspepsia focused on gastric sensorimotor dysfunction underlying symptom generation. Recent pathophysiological research has focused on low-grade inflammation in the duodenal mucosa. Emerging evidence confirms a loss of mucosal integrity in the duodenum in functional dyspepsia, and this is confirmed in a confocal laser endomicroscopy study demonstrating altered mucosal barrier function and pyroptosis. This technique may help to establish underlying mechanisms and evaluate novel therapeutic approaches to functional dyspepsia.

Recent advances in diagnosis and management of irritable bowel syndrome.

PURPOSE OF REVIEW: This review summarizes recent progress in the diagnosis and management of irritable bowel syndrome, with a focus on dietary and microbiota aspects. RECENT FINDINGS: From a pathophysiological point of view, IBS is a multifactorial condition with both peripheral (transit) as central (visceral hypersensitivity, anxiety, depression) contribution in a cumulative fashion to the symptom pattern and severity. More recently, the focus has shifted to diet and microbiota. The number of dietary options that can be used for IBS and the understanding of determinants of their efficacy is rapidly increasing. Several studies have confirmed the efficacy of the low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet. Sucrose-isomaltase deficiency has emerged as pathogenetic mechanisms in a subset of patients, who do not respond to low FODMAP diet but may respond to starch and sucrose elimination. Herbal remedies, probiotics and secretagogues have been the topic of additional treatment trials. The efficacy of fecal microbiota transplantation in IBS is variable across studies, but donor selection is emerging as a critical factor. SUMMARY: Irritable bowel syndrome has evolved into a disorder of interaction between dietary factors and gut microbiota, with impact on bowel symptoms as well as extra-intestinal, central, symptoms. Dietary adjustments and treatments targeting the gut microbiota are areas of active research and clinical progress.

A survey on the impact of the COVID-19 pandemic on motility and functional investigations in Europe and considerations for recommencing activities in the early recovery phase.

BACKGROUND: The COVID-19 pandemic, declared by WHO on March 13, 2020, had a major global impact on the healthcare system and services. In the acute phase, the presence of the SARS-CoV-2 virus in the aerodigestive tract limited activities in the gastroenterology clinic and procedures to emergencies only. Motility and function testing was interrupted and as we enter the recovery phase, restarting these procedures requires a safety-focused approach with adequate infection prevention for patients and healthcare professionals. METHODS: We summarized knowledge on the presence of the SARS-CoV-2 virus in the aerodigestive tract and the risk of spread with motility and functional testing. We surveyed 39 European centers documenting how the pandemic affected activities and which measures they are considering for restarting these measurements. We propose recommendations based on current knowledge as applied in our center. RESULTS: Positioning of catheters for gastrointestinal motility tests carries a concern for aerosol-borne infection of healthcare workers. The risk is low with breath tests. The surveyed centers stopped almost all motility and function tests from the second half of March. The speed of restarting and the safety measures taken varied highly. CONCLUSIONS AND INFERENCES: Based on these findings, we provided recommendations and practical relevant information for motility and function test procedures in the COVID-19 pandemic era, to guarantee a high-quality patient care with adequate infection prevention.

The Role of GI Peptides in Functional Dyspepsia and Gastroparesis: A Systematic Review.

Functional dyspepsia (FD) and gastroparesis (GP) are common disorders of the upper gastrointestinal tract. The pathophysiology of these conditions is likely to be heterogenous, and factors such as altered motility, sensitivity and response to nutrition have been identified as putative underlying mechanisms. Motility, sensitivity as well as responses to nutrition can be influenced or mediated by peptide hormones and serotonin released from the gastrointestinal mucosa. This review summarizes the role of GI peptides in functional dyspepsia and gastroparesis. In most studies, the levels of somatostatin, ghrelin, and motilin did not differ between healthy volunteers and FD or GP patients, but higher symptom burden was often correlated with higher peptide levels. Ghrelin and motilin receptor agonists showed promising results in improvement of the gastric emptying, but the link with improvement of symptoms is less predictable. Serotonin agonists have a potential to improve symptoms in both FD and idiopathic gastroparesis. Drugs acting on the GLP-1 and on the PYY receptors deserve further investigation. There is a need for systematic large scale studies.

Mast cell-nerve interactions correlate with bloating and abdominal pain severity in patients with non-celiac gluten / wheat sensitivity.

BACKGROUND: Gastrointestinal (GI) and extra-GI symptoms/manifestations represent key clinical features of patients with non-celiac gluten/wheat sensitivity (NCG/WS). This study aimed to investigate neuro-immune (focusing on mast cells, MCs) interactions in the duodenal submucosa of patients with NCG/WS. METHODS: Submucosal whole mounts from duodenal biopsies of 34 patients with self-reported NCG/WS, 28 with celiac disease (CD), 13 with functional dyspepsia (FD), and 24 healthy controls (HC) were analyzed by immunohistochemistry. Quantitative data on neuronal and MCs density and the percentage of MCs in close vicinity to nerves were obtained, and correlations among neurons, MC density and MC-nerve distance (D), and symptoms were assessed in the three groups. KEY RESULTS: The number of submucosal neurons was not different among groups. In NCG/WS, MC density was not different from HC, while it was slightly increased vs. CD (P = .07) and significantly decreased vs. FD (P < .05). The percentage of MCs close to nerves (D < 15 µm) was similarly increased in all three pathological groups vs. HC (P < .001). In NCG/WS, MC infiltration correlated with bloating (P = .001) and abdominal pain severity (P = .03) and the percentage of MCs in proximity to neurons correlated with the number of GI symptoms (D < 5 µm; P = .05), bloating and abdominal pain severity (D < 15um; P = .01). CONCLUSIONS AND INFERENCES: Submucosal MC infiltration and the close (within 15 µm) MC-to-nerve proximity in the duodenum of NCG/WS patients are features providing a histopathological basis to better understand GI symptoms in this condition.