Publications by authors named "Jan Tack"

484 Publications

Duodenal Dysbiosis and Relation to the Efficacy of Proton Pump Inhibitors in Functional Dyspepsia.

Int J Mol Sci 2021 Dec 19;22(24). Epub 2021 Dec 19.

VIB Center for Microbiology, 3000 Leuven, Belgium.

Proton pump inhibitors (PPI) may improve symptoms in functional dyspepsia (FD) through duodenal eosinophil-reducing effects. However, the contribution of the microbiome to FD symptoms and its interaction with PPI remains elusive. Aseptic duodenal brushings and biopsies were performed before and after PPI intake (4 weeks Pantoprazole 40 mg daily, FD-starters and controls) or withdrawal (2 months, FD-stoppers) for 16S-rRNA sequencing. Between- and within-group changes in genera or diversity and associations with symptoms or duodenal factors were analyzed. In total, 30 controls, 28 FD-starters and 19 FD-stoppers were followed. Mucus-associated was lower in FD-starters vs. controls and correlated with symptoms in FD and duodenal eosinophils in both groups, while correlated with eosinophils in controls. Although clinical and eosinophil-reducing effects of PPI therapy were unrelated to microbiota changes in FD-starters, increased was associated with duodenal PPI effects in controls and remained higher despite withdrawal of long-term PPI therapy in FD-stoppers. Thus, duodenal microbiome analysis demonstrated differential mucus-associated genera, with a potential role of in FD pathophysiology. While beneficial effects of short-term PPI therapy were not associated with microbial changes in FD-starters, increased and its association with PPIeffects in controls suggest a role for duodenal dysbiosis after long-term PPI therapy.
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http://dx.doi.org/10.3390/ijms222413609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8708077PMC
December 2021

High-resolution colonic manometry interobserver analysis trial.

Neurogastroenterol Motil 2022 01 29;34(1):e14285. Epub 2021 Nov 29.

Translational Research Center for Gastrointestinal Disorders (TARGID), KULeuven, Belgium.

Introduction: Colonic high-resolution manometry (HRM) is a novel, not widely used diagnostic method used in the final workup of chronic constipation before surgery. Since its introduction, different motor patterns have been defined. However, it remains to be established whether these patterns are easily and reproducibly identified by different investigators.

Methods: The primary aim of this study was to determine agreement for motor pattern identification with HRM. To calculate the interobserver agreement (IOA), the Fleiss's kappa statistic for multiple observers was used. Seven participants analyzed 106 one-min time frames, derived from five measurements in healthy volunteers and five in patients with chronic constipation. The time frames were chosen to show a variety and combination of motor patterns consisting of short antegrade, short retrograde, cyclic anterograde, cyclic retrograde, long antegrade, long retrograde, slow retrograde motor pattern, high-amplitude propagating motor patterns, and pancolonic pressurizations. All of the measurements were performed with a solid-state colonic HRM catheter, comprising 40 pressure sensors spaced 2.5 cm apart.

Results: A median of 10.25 h (range 6-20) were required to analyze all time frames. High-amplitude propagating contractions achieved an almost perfect level of agreement (k = 0.91). Several motor patterns achieved substantial agreement; these included the short antegrade (k = 0.63), long antegrade (k = 0.68), cyclic retrograde (k = 0.70), slow retrograde motor pattern (k = 0.80), and abdominal pressure or movement artifacts (k = 0.67). Moderate agreement was found for short retrograde (k = 0.57), cyclic anterograde (k = 0.59), long retrograde motor patterns (k = 0.59) and simultaneous pressure waves (k = 0.59).

Conclusion: For the majority of motor patterns, the overall IOA for colonic manometry was substantial or high. This high level of agreement supports the use of colonic manometry application in clinical and research settings. Harmonization has the potential to improve agreement for long anterograde motor patterns with high amplitudes and for mixed direction patterns.
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http://dx.doi.org/10.1111/nmo.14285DOI Listing
January 2022

Rome Foundation Clinical Diagnostic Criteria for Disorders of Gut-Brain Interaction.

Gastroenterology 2021 Nov 19. Epub 2021 Nov 19.

Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium; Rome Foundation, Raleigh North Carolina.

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http://dx.doi.org/10.1053/j.gastro.2021.11.019DOI Listing
November 2021

Human intestinal bitter taste receptors regulate innate immune responses and metabolic regulators in obesity.

J Clin Invest 2021 Nov 16. Epub 2021 Nov 16.

Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium.

Bitter taste receptors (TAS2R) serve as warning sensors in the lingual system against ingestion of potential poisonous food. Here, we investigated the functional role of TAS2Rs in the human gut and focused on their potential to trigger an additional host defense pathway in the intestine. Human jejunal crypts, especially from obese subjects, responded to bitter agonists by inducing the release of antimicrobial peptides (α-defensin 5 and REG3A) but also regulated the expression of other innate immune factors (mucins, chemokines) that affected E. coli growth. The effect of aloin on E. coli growth and on the release of the mucus glycoprotein CLCA1, identified via proteomics, was affected by TAS2R43 amino acid/deletion polymorphisms and thus confirmed a role for TAS2R43. RNA sequencing uncovered that denatonium benzoate induced an NRF2-mediated nutrient stress response and an unfolded protein response that increased the expression of the mitokine GDF15 but also ADM2 and the LDLR, genes that are involved in anorectic signaling and lipid homeostasis. To conclude, TAS2Rs in the intestine provide a promising target for treating diseases that involve disturbances in the innate immune system and in body weight control. Polymorphisms in TAS2Rs may be valuable genetic markers to predict therapeutic responses.
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http://dx.doi.org/10.1172/JCI144828DOI Listing
November 2021

Global Prevalence and Impact of Rumination Syndrome.

Gastroenterology 2021 Nov 11. Epub 2021 Nov 11.

Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background And Aims: Rumination syndrome is a Disorder of Gut-Brain Interaction (DGBI) of unknown etiology. We aimed to assess its global prevalence and potential associations with other medical conditions.

Methods: Data were collected via the Internet in 26 countries. Subjects were evenly distributed by country, sex, and age groups and were invited for a "health survey" using the Rome IV diagnostic questionnaire and a supplementary questionnaire addressing factors potentially associated with DGBI.

Results: In all, 54,127 subjects completed the survey (51% male; mean age, 44.3 years). The overall prevalence of rumination syndrome was 3.1% (95% confidence interval [CI], 3.0-3.3%). It was highest in Brazil (5.5% CI, 4.5-6.5) and lowest in Singapore (1.7% CI, 1.1-2.2). The mean age of people with rumination syndrome was 44.5 years (standard deviation, 15.6) and it was more common in females (54.5% vs 45.5%). Factors independently associated with rumination syndrome were depression (odds ratio [OR], 1.46), anxiety (OR, 1.8), body mass index (OR, 1.04), and female sex (OR, 1.19). Subjects with multiple DGBI were at increased risk of having rumination syndrome, with the highest risk in subjects with 4 gastrointestinal regions with DGBI (OR, 15.9 compared with none). Quality of life (QoL) was lower in subjects with rumination syndrome compared with the rest of the cohort (PROMIS-10 score: physical QoL mean 12.9 vs 14.5; mental QoL mean 12.0 vs 13.6).

Conclusions: The prevalence of rumination syndrome is higher than reported in most previous population studies and is likely underdiagnosed in clinical practice. Awareness of rumination syndrome should be raised among clinicians to improve care for these patients.
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http://dx.doi.org/10.1053/j.gastro.2021.11.008DOI Listing
November 2021

Live Imaging of Primary Neurons in Long-Term Cryopreserved Human Nerve Tissue.

eNeuro 2021 Nov-Dec;8(6). Epub 2021 Dec 1.

Laboratory for Enteric Neuroscience (LENS), Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases and Metabolism, Katholieke Universiteit Leuven, Leuven 3000, Belgium

Tissue cryopreservation provides a convenient solution for tackling one of the major problems in neuroscience research, namely, the scarce availability of human nerve tissues, especially if needed alive. While brain tissue can be used only postmortem, live nerve tissue can reasonably well be harvested from the periphery. A valuable source of primary neurons is the intestine, which compared with brain has the advantage to be safely accessible via endoscopy. The nerve tissue innervating the intestine (the enteric nervous system; ENS) can be sampled with regular endoscopic biopsy forceps and remains viable for multiple physiological and immunohistochemical tests, as previously demonstrated. Here, we present a method to preserve, over longer periods of time, human primary neurons contained in these biopsies. The use of a cryoprotective agent and the application of controlled cooling revealed to be crucial to properly store the nerve tissue and to enable functional measurements after thawing. These primary neurons were evaluated for functionality (live imaging) and morphology (histology) up to one year after cryopreservation. Calcium (Ca) imaging indicated that human primary neurons remained viable and responded to selective stimulations (serotonergic and nicotinic agonists) after cryopreservation. Additionally, immunohistochemistry performed with specific neuronal markers showed that nerve structure and neuronal morphology were retained, with no signs of cellular damage. In this study, we demonstrate that the human ENS is a realistic source of primary neurons, which can be successfully preserved over long times and as such can be exploited both for gastrointestinal-specific as well as for general neuroscience research.
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http://dx.doi.org/10.1523/ENEURO.0388-21.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8638677PMC
December 2021

AGA Clinical Practice Update on Management of Medically Refractory Gastroparesis: Expert Review.

Clin Gastroenterol Hepatol 2021 Oct 29. Epub 2021 Oct 29.

Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri. Electronic address:

Description: Delayed gastric emptying on objective testing defines gastroparesis, but symptoms overlap with functional dyspepsia and do not correlate well with gastric emptying delay. This review outlines a strategy for defining, diagnosing, and managing refractory gastroparesis.

Methods: The Best Practice Advice statements presented here were developed from review of existing literature combined with expert opinion to provide practical advice. Because this was not a systematic review, formal rating of the quality of evidence or strength of recommendations was not performed. BEST PRACTICE ADVICE.
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http://dx.doi.org/10.1016/j.cgh.2021.10.038DOI Listing
October 2021

Transient hypopharyngeal intrabolus pressurization patterns: Clinically relevant or normal variant?

Neurogastroenterol Motil 2021 Oct 4:e14276. Epub 2021 Oct 4.

Flinders Health and Medical Research Institute (FHMRI) & College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia.

Introduction: In oropharyngeal dysphagia, impaired pharyngoesophageal junction (PEJ) opening is reflected by an elevated hypopharyngeal intrabolus pressure (IBP), quantifiable using pharyngeal high-resolution manometry with impedance (P-HRM-I). Transient intrabolus pressurization (TP) phenomena are not sustained and last for only a brief period. We hypothesized that TP patterns reflect impaired coordination between timing of hypopharyngeal bolus arrival and PEJ relaxation.

Methods: A retrospective audit was conducted of P-HRM-I datasets; 93 asymptomatic Controls and 214 Patients with differing etiological/clinical backgrounds were included. TP patterns were examined during 10ml liquid swallows. TP was defined by a simultaneous, non-sustained, pressurization wave spanning from the velo-/meso-pharynx to PEJ. The coordination between deglutitive pharyngeal bolus distension and PEJ relaxation timing was assessed using timing variables; (i) Distention-Contraction Latency (DCL, s) and (ii) PEJ Relaxation Time (RT, s). Resultant flow resistance was quantified (IBP, mmHg).

Results: TP swallows were observed in 87 (28%) cases. DCL was not significantly different in relation to TP, while PEJ relaxation time was shorter, and IBP was higher during TP swallows. In Patients RT-DCL time difference correlated with IBP (r -0.368, p < 0.01).

Conclusion: Bolus distension and PEJ relaxation were miss-timed during TP swallows, impeding bolus flow and leading to a brief period of pressurization of the pharyngeal chamber by muscular propulsive forces. While TP swallows were identified in both Controls and Patients, increased IBPs were most apparent for Patient swallows indicating that the extent of IBP increase may differentiate pathological TP swallows.
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http://dx.doi.org/10.1111/nmo.14276DOI Listing
October 2021

United European Gastroenterology (UEG) and European Society for Neurogastroenterology and Motility (ESNM) consensus on functional dyspepsia.

Neurogastroenterol Motil 2021 09;33(9):e14238

Gastroenterology Unit, Departmento of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.

Background: Functional dyspepsia (FD) is one of the most common conditions in clinical practice. In spite of its prevalence, FD is associated with major uncertainties in terms of its definition, underlying pathophysiology, diagnosis, treatment, and prognosis.

Methods: A Delphi consensus was initiated with 41 experts from 22 European countries who conducted a literature summary and voting process on 87 statements. Quality of evidence was evaluated using the grading of recommendations, assessment, development, and evaluation (GRADE) criteria. Consensus (defined as >80% agreement) was reached for 36 statements.

Results: The panel agreed with the definition in terms of its cardinal symptoms (early satiation, postprandial fullness, epigastric pain, and epigastric burning), its subdivision into epigastric pain syndrome and postprandial distress syndrome, and the presence of accessory symptoms (upper abdominal bloating, nausea, belching), and overlapping conditions. Also, well accepted are the female predominance of FD, its impact on quality of life and health costs, and acute gastrointestinal infections, and anxiety as risk factors. In terms of pathophysiological mechanisms, the consensus supports a role for impaired gastric accommodation, delayed gastric emptying, hypersensitivity to gastric distention, Helicobacter pylori infection, and altered central processing of signals from the gastroduodenal region. There is consensus that endoscopy is mandatory for establishing a firm diagnosis of FD, but that in primary care, patients without alarm symptoms or risk factors can be managed without endoscopy. There is consensus that H. pylori status should be determined in every patient with dyspeptic symptoms and H. pylori positive patients should receive eradication therapy. Also, proton pump inhibitor therapy is considered an effective therapy for FD, but no other treatment approach reached a consensus. The long-term prognosis and life expectancy are favorable.

Conclusions And Inferences: A multinational group of European experts summarized the current state of consensus on the definition, diagnosis and management of FD.
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http://dx.doi.org/10.1111/nmo.14238DOI Listing
September 2021

Efficacy of pinaverium bromide in the treatment of irritable bowel syndrome: a systematic review and meta-analysis.

Therap Adv Gastroenterol 2021 15;14:17562848211033740. Epub 2021 Sep 15.

TARGID, University of Leuven, Leuven, Belgium.

Background: Spasmolytic agents are an attractive first line treatment option for irritable bowel syndrome (IBS). Pinaverium bromide (pinaverium) has antispasmodic effects on gastrointestinal smooth muscle and can relieve major IBS symptoms, but an up-to-date meta-analysis comparing the efficacy of pinaverium with placebo is lacking. The aim is to perform a systematic review and meta-analysis to assess the efficacy of pinaverium compared with placebo for IBS treatment.

Methods: All placebo-controlled trials evaluating pinaverium for IBS treatment were included, up to October 2019. Treatment efficacy was evaluated by overall patient IBS symptoms. Individual symptoms were also evaluated. The effect of pinaverium placebo was expressed as standardized mean difference (SMD) and risk ratio (RR). Odds ratio (OR) and number needed to treat (NNT) were also calculated.

Results: Eight studies were included for analysis. Pinaverium treatment had a beneficial effect on overall IBS symptom relief with a positive SMD of 0.64 [95% confidence interval (CI) 0.45-0.82,  < 0.0001] and a positive RR of 1.75 (1.26-2.43,  < 0.0008). No significant difference was found by publication year, gender, age, methodological quality score (MQS), or sample size. No publication bias was detected. OR was 3.43 (2.00-5.88,  < 0.0001), and NNT was 4. Pinaverium also demonstrated a beneficial treatment effect for abdominal pain, stool change, and bloating improvement or resolution.

Conclusion: Pinaverium is superior to placebo for the treatment of IBS symptoms, irrespective of patient age or gender, study publication year, sample size, or MQS. The NNT in this meta-analysis is amongst the lowest for studies and meta-analyses of antispasmodics placebo in IBS.
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http://dx.doi.org/10.1177/17562848211033740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447090PMC
September 2021

The Role of Intestinal Permeability in Gastrointestinal Disorders and Current Methods of Evaluation.

Front Nutr 2021 26;8:717925. Epub 2021 Aug 26.

Department of Chronic Diseases, Translational Research Center for Gastrointestinal Disorders, Metabolism and Ageing, Catholic University Leuven, Leuven, Belgium.

An increased intestinal permeability has been described in various gastrointestinal and non-gastrointestinal disorders. Nevertheless, the concept and definition of intestinal permeability is relatively broad and includes not only an altered paracellular route, regulated by tight junction proteins, but also the transcellular route involving membrane transporters and channels, and endocytic mechanisms. Paracellular intestinal permeability can be assessed by using different molecules (e.g., sugars, polyethylene glycols, Cr-EDTA) and in Ussing chambers combining electrophysiology and probes of different molecular sizes. The latter is still the gold standard technique for assessing the epithelial barrier function, whereas techniques, including putative blood biomarkers such as intestinal fatty acid-binding protein and zonulin, are broadly used despite limitations. In the second part of the review, the current evidence of the role of impaired barrier function in the pathophysiology of selected gastrointestinal and liver diseases is discussed. Celiac disease is one of the conditions with the best evidence for impaired barrier function playing a crucial role with zonulin as its proposed regulator. Increased permeability is clearly present in inflammatory bowel disease, but the question of whether this is a primary event or a consequence of inflammation remains unsolved. The gut-liver axis with a crucial role in impaired intestinal barrier function is increasingly recognized in chronic alcoholic and metabolic liver disease. Finally, the current evidence does not support an important role for increased permeability in bile acid diarrhea.
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http://dx.doi.org/10.3389/fnut.2021.717925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427160PMC
August 2021

Supraphysiological effects of pancreatic polypeptide on gastric motor function and nutrient tolerance in humans.

Physiol Rep 2021 09;9(17):e15002

Translational Research Center for Gastrointestinal Disorders, KULeuven, Belgium.

Pancreatic polypeptide (PP) is known to affect food intake. In this exploratory study, we set out to investigate its supraphysiological effect on food tolerance, gastric accommodation, and emptying. In 12 healthy volunteers, 0, 3, or 10 pmol*kg *min PP was administered intravenously (PP0, PP3 or PP10). Thirty minutes thereafter, nutrient drink infusion (60 ml*min ) through a nasogastric feeding tube was started until maximum satiation. Gastric accommodation was assessed by measuring the intragastric pressure (IGP; nasogastric manometry). In a separate test, the effect of PP0 or PP10 on gastric emptying was tested in 10 healthy volunteers and assessed using the C breath test. Results are presented as mean ± SEM, and p < 0.05 was considered significant. For the IGP test, PP increased ingested nutrient volume: 886 ± 93, 1059 ± 124, and 1025 ± 125 ml for PP0, PP3, and PP10, respectively (p = 0.048). In all groups, Nadir IGP values were reached upon food intake (transformed values: 1.5 ± 0.2, 1.7 ± 0.3, and 1.6 ± 0.3 mmHg for PP0, PP3, and PP10, respectively; NS) to return to baseline thereafter. For the gastric emptying study, volunteers ingested a similar nutrient volume: 802 ± 119 and 1089 ± 128 ml (p = 0.016), and gastric half-emptying time was 281 ± 52 and 249 ± 37 min for PP0 and PP10, respectively (NS). No significant correlation between tolerated nutrient volume and IGP drop (R² < 0.01; p = 0.88 for PP0 vs. PP3 and R² =0.07; p = 0.40 for PP0 vs. PP10, respectively) or gastric half-emptying time (R² = 0.12; p = 0.32) was found. A supraphysiological PP dose enhances food tolerance; however, this effect is not mediated through gastric motility. CLINICAL TRIAL REGISTRY NUMBER: NCT03854708 is obtained from clinicaltrials.gov.
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http://dx.doi.org/10.14814/phy2.15002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387790PMC
September 2021

United European Gastroenterology (UEG) and European Society for Neurogastroenterology and Motility (ESNM) consensus on gastroparesis.

Neurogastroenterol Motil 2021 08;33(8):e14237

Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium.

Background: Gastroparesis is a condition characterized by epigastric symptoms and delayed gastric emptying (GE) rate in the absence of any mechanical obstruction. The condition is challenging in clinical practice by the lack of guidance concerning diagnosis and management of gastroparesis.

Methods: A Delphi consensus was undertaken by 40 experts from 19 European countries who conducted a literature summary and voting process on 89 statements. Quality of evidence was evaluated using grading of recommendations assessment, development, and evaluation criteria. Consensus (defined as ≥80% agreement) was reached for 25 statements.

Results: The European consensus defined gastroparesis as the presence of symptoms associated with delayed GE in the absence of mechanical obstruction. Nausea and vomiting were identified as cardinal symptoms, with often coexisting postprandial distress syndrome symptoms of dyspepsia. The true epidemiology of gastroparesis is not known in detail, but diabetes, gastric surgery, certain neurological and connective tissue diseases, and the use of certain drugs recognized as risk factors. While the panel agreed that severely impaired gastric motor function is present in these patients, there was no consensus on underlying pathophysiology. The panel agreed that an upper endoscopy and a GE test are required for diagnosis. Only dietary therapy, dopamine-2 antagonists and 5-HT receptor agonists were considered appropriate therapies, in addition to nutritional support in case of severe weight loss. No consensus was reached on the use of proton pump inhibitors, other classes of antiemetics or prokinetics, neuromodulators, complimentary, psychological, or more invasive therapies. Finally, there was consensus that gastroparesis adversely impacts on quality of life and healthcare costs and that the long-term prognosis of gastroparesis depends on the cause.

Conclusions And Inferences: A multinational group of European experts summarized the current state of consensus on definition, symptom characteristics, pathophysiology, diagnosis, and management of gastroparesis.
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http://dx.doi.org/10.1111/nmo.14237DOI Listing
August 2021

A survey of functional dyspepsia in 361,360 individuals: Phenotypic and genetic cross-disease analyses.

Neurogastroenterol Motil 2021 Aug 11:e14236. Epub 2021 Aug 11.

Department of Gastrointestinal and Liver Diseases, Biodonostia Health Research Institute, San Sebastian, Spain.

Background: Functional dyspepsia (FD) is a common gastrointestinal condition of poorly understood pathophysiology. While symptoms' overlap with other conditions may indicate common pathogenetic mechanisms, genetic predisposition is suspected but has not been adequately investigated.

Methods: Using healthcare, questionnaire, and genetic data from three large population-based biobanks (UK Biobank, EGCUT, and MGI), we surveyed FD comorbidities, heritability, and genetic correlations across a wide spectrum of conditions and traits in 10,078 cases and 351,282 non-FD controls of European ancestry.

Key Results: In UK Biobank, 281 diagnoses were detected at increased prevalence in FD, based on healthcare records. Among these, gastrointestinal conditions (OR = 4.0, p < 1.0 × 10 ), anxiety disorders (OR = 2.3, p < 1.4 × 10 ), ischemic heart disease (OR = 2.2, p < 2.3 × 10 ), and infectious and parasitic diseases (OR = 2.1, p = 1.5 × 10 ) showed strongest association with FD. Similar results were obtained in an analysis of self-reported conditions and use of medications from questionnaire data. Based on a genome-wide association meta-analysis of genotypes across all cohorts, FD heritability was estimated close to 5% (  = 0.047, p = 0.014). Genetic correlations indicate FD predisposition is shared with several other diseases and traits (r  > 0.344), mostly overlapping with those also enriched in FD patients. Suggestive (p < 5.0 × 10 ) association with FD risk was detected for 13 loci, with 2 showing nominal replication (p < 0.05) in an independent cohort of 192 FD patients.

Conclusions & Inferences: FD has a weak heritable component that shows commonalities with multiple conditions across a wide spectrum of pathophysiological domains. This new knowledge contributes to a better understanding of FD etiology and may have implications for improving its treatment.
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http://dx.doi.org/10.1111/nmo.14236DOI Listing
August 2021

Effect of slow, deep breathing on visceral pain perception and its underlying psychophysiological mechanisms.

Neurogastroenterol Motil 2021 Aug 11:e14242. Epub 2021 Aug 11.

Laboratory for Brain-Gut Axis Studies (LaBGAS), Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium.

Background: Studies using somatic pain models have shown the hypoalgesic effects of slow, deep breathing. We evaluated the effect of slow, deep breathing on visceral pain and explored putative mediating mechanisms including autonomic and emotional responses.

Methods: Fifty-seven healthy volunteers (36 females, mean age = 22.0 years) performed controlled, deep breathing at a slow frequency (6 breaths per minute), controlled breathing at a normal frequency (14 breaths per minute; active control), and uncontrolled breathing (no-treatment control) in randomized order. Moderate painful stimuli were given during each condition by delivering electrical stimulation in the distal esophagus. Participants rated pain intensity after each stimulation. Heart rate variability and self-reported arousal were measured during each condition.

Key Results: Compared to uncontrolled breathing, pain intensity was lower during slow, deep breathing (Cohen's d = 0.40) and normal controlled breathing (d = 0.47), but not different between slow, deep breathing and normal controlled breathing. Arousal was lower (d = 0.53, 0.55) and heart rate variability was higher (d = 0.70, 0.86) during slow, deep breathing compared to the two control conditions. The effect of slow, deep breathing on pain was not mediated by alterations in heart rate variability or arousal but was moderated by pain catastrophizing.

Conclusions And Inferences: Slow, deep breathing can reduce visceral pain intensity. However, the effect is not specific to the slow breathing frequency and is not mediated by autonomic or emotional responses, suggesting other underlying mechanisms (notably distraction). Whether a long-term practice of slow, deep breathing can influence (clinical) visceral pain warrants to be investigated.
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http://dx.doi.org/10.1111/nmo.14242DOI Listing
August 2021

Naldemedine is effective in the treatment of opioid-induced constipation in patients with chronic non-cancer pain who had a poor response to laxatives.

Therap Adv Gastroenterol 2021 31;14:17562848211032320. Epub 2021 Jul 31.

Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Denmark.

Background: Two studies demonstrated the efficacy and safety of naldemedine in adult patients with chronic non-cancer pain and opioid-induced constipation (OIC). However, no studies have compared the efficacy of peripherally acting µ-opioid receptor antagonists in patients with adequate and inadequate responses to prior OIC therapy with laxatives. This analysis of integrated data from the two previous studies compared the efficacy of naldemedine in patients who were unsuccessfully treated with laxatives [poor laxative responders (PLRs)] with those who either did not receive laxatives >30 days prior to screening or those who only received rescue laxative at or after screening (non-PLRs).

Methods: Patients with OIC were randomized to once-daily treatment with naldemedine 0.2 mg or placebo. The primary efficacy endpoint was the proportion of responders [⩾3 spontaneous bowel movements (SBMs)/week and an increase from baseline of ⩾1 SBM/week for ⩾9 weeks of the 12-week treatment period and ⩾3 weeks of the final 4 weeks of the 12-week treatment period]. Additional endpoints included change in SBM frequency, change in frequency of SBMs without straining, proportion of complete SBM (CSBM) responders, change in CSBM frequency, and time to first SBM. Treatment-emergent adverse events (TEAEs) were assessed.

Results: The analysis included 538 (317 PLRs, 221 non-PLRs) and 537 (311 PLRs, 226 non-PLRs) patients in the naldemedine and placebo arms, respectively. There were significantly more responders in the naldemedine PLR (46.4%;  < 0.0001) and non-PLR (54.3%;  = 0.0009) subgroups the placebo groups (30.2% and 38.9%, respectively). In both the PLR and non-PLR subgroups, naldemedine treatment was superior to placebo on all additional endpoints. Overall incidence of TEAEs in the PLR subgroups treated with naldemedine or placebo was similar.

Conclusion: This integrated analysis further supports the efficacy and tolerability of naldemedine in the treatment of OIC and demonstrates a consistent effect in both PLR and non-PLR subgroups.[ClinicalTrials.gov identifier: NCT01965158 and NCT01993940].
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http://dx.doi.org/10.1177/17562848211032320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326612PMC
July 2021

Efficacy and safety of spore-forming probiotics in the treatment of functional dyspepsia: a pilot randomised, double-blind, placebo-controlled trial.

Lancet Gastroenterol Hepatol 2021 10 3;6(10):784-792. Epub 2021 Aug 3.

Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium; Translational Research in Gastrointestinal Disorders, KU Leuven, Leuven, Belgium. Electronic address:

Background: Current treatments for functional dyspepsia have limited efficacy or present safety issues. We aimed to assess spore-forming probiotics in functional dyspepsia as monotherapy or add-on therapy to long-term treatment with proton-pump inhibitors.

Methods: In this single-centre, randomised, double-blind, placebo-controlled pilot trial that took place at University Hospitals Leuven (Leuven, Belgium), adult patients (≥18 years) with functional dyspepsia (as defined by Rome IV criteria, on proton-pump inhibitors or off proton-pump inhibitors) were randomly assigned (1:1) via computer-generated blocked lists, stratified by proton-pump inhibitor status, to receive 8 weeks of treatment with probiotics (Bacillus coagulans MY01 and Bacillus subtilis MY02, 2·5 × 10 colony-forming units per capsule) or placebo consumed twice per day, followed by an open-label extension phase of 8 weeks. Individuals with a history of abdominal surgery, diabetes, coeliac or inflammatory bowel disease, active psychiatric conditions, and use of immunosuppressant drugs, antibiotics, or probiotics in the past 3 months were excluded. All patients and on-site study personnel were masked to treatment allocation in the first 8 weeks. Symptoms, immune activation, and faecal microbiota were assessed and recorded. The primary endpoint was a decrease of at least 0·7 in the postprandial distress syndrome (PDS) score of the Leuven Postprandial Distress Scale in patients with a baseline PDS score of 1 or greater (at least mild symptoms), assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT04030780.

Findings: Between June 3, 2019, and March 11, 2020, of 93 individuals assessed for eligibility, we included 68 patients with functional dyspepsia (51 [75%] women, mean age 40·1 years [SD 14·4], 34 [50%] on proton-pump inhibitors). We randomly assigned 32 participants to probiotics and 36 to placebo. The proportion of clinical responders was higher with probiotics (12 [48%] of 25) than placebo (six [20%] of 30; relative risk 1·95 [95% CI 1·07-4·11]; p=0·028). The number of patients with adverse events was similar with probiotics (five [16%] of 32) and placebo (12 [33%] of 36). Two serious adverse events occurring during the open-label phase (appendicitis and syncope in two separate patients) were assessed as unlikely to be related to the study product.

Interpretation: In this exploratory study, B coagulans MY01 and B subtilis MY02 were efficacious and safe in the treatment of functional dyspepsia. Participants had potentially beneficial immune and microbial changes, which could provide insights into possible underlying mechanisms as future predictors or treatment targets.

Funding: MY HEALTH.
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http://dx.doi.org/10.1016/S2468-1253(21)00226-0DOI Listing
October 2021

The Role of Gasotransmitters in Gut Peptide Actions.

Front Pharmacol 2021 20;12:720703. Epub 2021 Jul 20.

Departement of Endocrinology, University Medical Center Groningen, Groningen, Netherlands.

Although gasotransmitters nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (HS) receive a bad connotation; in low concentrations these play a major governing role in local and systemic blood flow, stomach acid release, smooth muscles relaxations, anti-inflammatory behavior, protective effect and more. Many of these physiological processes are upstream regulated by gut peptides, for instance gastrin, cholecystokinin, secretin, motilin, ghrelin, glucagon-like peptide 1 and 2. The relationship between gasotransmitters and gut hormones is poorly understood. In this review, we discuss the role of NO, CO and HS on gut peptide release and functioning, and whether manipulation by gasotransmitter substrates or specific blockers leads to physiological alterations.
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http://dx.doi.org/10.3389/fphar.2021.720703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329365PMC
July 2021

The effect of an air purifier on aerosol generation measurements during clinical motility testing.

Neurogastroenterol Motil 2021 Aug 2:e14227. Epub 2021 Aug 2.

Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium.

Background: Aerosol spread is key to interpret the risk of viral contamination during clinical procedures such as esophageal high-resolution manometry (HRM). Installing an air purifier seems a legitimate strategy, but this has recently been questioned.

Methods: Patients undergoing an HRM procedure at the Leuven University Hospital were included in this clinical study. All subjects had to wear a surgical mask which was only lowered beneath the nose during the placement and removal of the nasogastric catheter. The number of aerosol particles was measured by a Lasair II Particle Counter to obtain data about different particles sizes: 0.3; 0.5; 1.0; 3.0; 5.0; and 10.0 µm. Measurements were done immediately before the placement and the removal of the HRM catheter, and one and 5 min after. A portable air purifier with high-efficiency particle air filters was installed in the hospital room.

Key Results: Thirteen patients underwent a manometry examination. The amount of 0.3 µm-sized particles was unaffected during the whole procedure. The larger particle sizes (1.0; 3.0; 5.0; and 10.0 µm) decreased when the catheter was positioned, but not 0.5 µm. During the HRM measurements itself, these numbers decreased further. Yet, 1 min after catheter removal a significant elevation of particles was seen, which did not recover within 5 min.

Conclusions & Interferences: Based on this study, there is no evidence that filtration systems reduce aerosol particles properly during a clinical investigation.
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http://dx.doi.org/10.1111/nmo.14227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420584PMC
August 2021

Systematic review: duodenogastroesophageal (biliary) reflux prevalence, symptoms, oesophageal lesions and treatment.

Aliment Pharmacol Ther 2021 09 27;54(6):755-778. Epub 2021 Jul 27.

Department of Chronic Diseases, Metabolism and Ageing (ChroMetA), Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium.

Background: The prevalence of duodenogastroesophageal reflux (DGER) and its effect on symptoms and oesophageal lesions in gastroesophageal reflux disease (GERD) is unclear.

Aims: To conduct a systematic review to determine the prevalence of DGER among patients with GERD, the effect of DGER on symptoms and oesophageal lesions, and the treatment of DGER.

Methods: We searched Pubmed and MEDLINE for full text, English language articles until October 2020 that evaluated DGER prevalence among patients with GERD, the effect of DGER on symptoms and oesophageal lesions, and the treatment of DGER.

Results: We identified 3891 reports and included 35 which analysed DGER prevalence in GERD, 15 which evaluated its effect in non-erosive reflux disease (NERD), 17 on erosive oesophagitis, 23 in Barrett's, and 13 which evaluated the treatment of DGER. The prevalence of DGER, when evaluated by Bilitec, among all GERD patients ranged from 10% to 97%, in NERD 10%-63%, in erosive oesophagitis 22%-80% and in Barrett's 50%-100%. There were no differences in the presence or degree of DGER among patients who were asymptomatic or symptomatic on proton pump inhibitors (PPI). The most commonly evaluated treatments for DGER were PPIs and DGER reduced post-PPI therapy in all studies.

Conclusions: The prevalence of DGER increased with more advanced oesophageal lesions and did not explain persisting symptoms among patients taking PPI therapy. PPIs appear to be effective in the treatment of DGER. DGER remains an important consideration in patients with GERD and future therapies deserve more study.
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http://dx.doi.org/10.1111/apt.16533DOI Listing
September 2021

Naldemedine Improves Patient-Reported Outcomes of Opioid-Induced Constipation in Patients with Chronic Non-Cancer Pain in the COMPOSE Phase 3 Studies.

J Pain Res 2021 16;14:2179-2189. Epub 2021 Jul 16.

Upstate Clinical Research Associates, Williamsville, NY, USA.

Objective: Opioid-induced constipation is among the most common side effects associated with opioid use in patients with chronic non-cancer pain, and it can have a significant negative impact on health-related quality of life (QOL). This analysis evaluated the effect of naldemedine 0.2 mg on patient-reported outcomes in three phase 3 clinical studies.

Methods: COMPOSE-1 and COMPOSE-2 were identical randomized, double-blind, placebo-controlled, parallel-group studies of 12 weeks' duration, allowing data to be integrated (n=1095). COMPOSE-3 was similar in design, but of 52 weeks' duration (n=1241). Patients were adults with chronic non-cancer pain who had been treated with opioid analgesics for ≥3 months and experiencing opioid-induced constipation. Patient-reported outcomes included Patient Assessment of Constipation Symptoms (PAC-SYM; 12 questions assessed on a 5-point Likert scale), PAC-QOL (28 questions assessed on a 5-point Likert scale), and Subject Global Satisfaction (measured on a 7-point Likert scale). The proportion of patients achieving a ≥1.5 improvement in PAC-SYM and PAC-QOL was calculated. The correlation between change in PAC-SYM and PAC-QOL scores and frequency of bowel movements was also explored.

Results: The proportion of PAC-SYM and PAC-QOL responders was significantly higher for naldemedine than for placebo at all assessed time points in COMPOSE-1/COMPOSE-2 (p<0.005 for both) and COMPOSE-3 (p<0.005 and p<0.0001, respectively). There was a statistically significant correlation between improvement in PAC-SYM/PAC-QOL and frequency of bowel movements at all time points (p≤0.0002). The majority of patients treated with naldemedine reported markedly or moderately improved satisfaction with constipation and abdominal symptoms on the Subject Global Satisfaction questionnaire.

Discussion: Naldemedine treatment was associated with a rapid and sustained clinically relevant improvement in patient-reported outcomes, indicating improvement in opioid-induced constipation-related symptoms and QOL.

Clinicaltrialsgov Registration: NCT01965158, NCT01993940, NCT01965652.
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http://dx.doi.org/10.2147/JPR.S282738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8291809PMC
July 2021

The gastrointestinal tract in hunger and satiety signalling.

United European Gastroenterol J 2021 07 21;9(6):727-734. Epub 2021 Jun 21.

Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.

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.
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http://dx.doi.org/10.1002/ueg2.12097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280794PMC
July 2021

Management of Ineffective Esophageal Hypomotility.

Front Pharmacol 2021 26;12:638915. Epub 2021 May 26.

Department of Chronic Diseases, Translational Research Center for Gastrointestinal Disorders (TARGID), Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium.

Esophageal hypomotility in general and especially ineffective esophageal motility according to the Chicago criteria of primary motility disorders of the esophagus, is one of the most frequently diagnosed motility disorders on high resolution manometry and results in a large number of patients visiting gastroenterologists. Most patients with esophageal hypomotility present with gastroesophageal reflux symptoms or dysphagia. The clinical relevance of the motility pattern, however, is not well established but seems to be correlated with disease severity in reflux patients. The correlation with dysphagia is less clear. Prokinetic agents are commonly prescribed as first line pharmacologic intervention to target esophageal smooth muscle contractility and improve esophageal motor functions. However, the beneficial effects of these medications are limited and only confined to some specific drugs. Serotonergic agents, including buspirone, mosapride and prucalopride have been shown to improve parameters of esophageal motility although the effect on symptoms is less clear. Understanding on the complex correlation between esophageal hypomotility and esophageal symptoms as well as the limited evidence of prokinetic agents is necessary for physicians to appropriately manage patients with Ineffective Esophageal Motility (IEM).
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http://dx.doi.org/10.3389/fphar.2021.638915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187940PMC
May 2021

Luminal short-chain fatty acids and 5-HT acutely activate myenteric neurons in the mouse proximal colon.

Neurogastroenterol Motil 2021 12 14;33(12):e14186. Epub 2021 Jun 14.

Laboratory for Enteric NeuroScience (LENS) Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium.

Background: Gastrointestinal (GI) function is critically dependent on the control of the enteric nervous system (ENS), which is situated within the gut wall and organized into two ganglionated nerve plexuses: the submucosal and myenteric plexus. The ENS is optimally positioned and together with the intestinal epithelium, is well-equipped to monitor the luminal contents such as microbial metabolites and to coordinate appropriate responses accordingly. Despite the heightened interest in the gut microbiota and its influence on intestinal physiology and pathophysiology, how they interact with the host ENS remains unclear.

Methods: Using full-thickness proximal colon preparations from transgenic Villin-CreERT2;R26R-GCaMP3 and Wnt1-Cre;R26R-GCaMP3 mice, which express a fluorescent Ca indicator in their intestinal epithelium or in their ENS, respectively, we examined the effects of key luminal microbial metabolites (SCFAs and 5-HT) on the mucosa and underlying enteric neurons.

Key Results: We show that the SCFAs acetate, propionate, and butyrate, as well as 5-HT can, to varying extents, acutely elicit epithelial and neuronal Ca responses. Furthermore, SCFAs exert differential effects on submucosal and myenteric neurons. Additionally, we found that submucosal ganglia are predominantly aligned along the striations of the transverse mucosal folds in the proximal colon.

Conclusions & Inferences: Taken together, our study demonstrates that different microbial metabolites, including SCFAs and 5-HT, can acutely stimulate Ca signaling in the mucosal epithelium and in enteric neurons.
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http://dx.doi.org/10.1111/nmo.14186DOI Listing
December 2021

Greater Overlap of Rome IV Disorders of Gut-Brain Interactions Leads to Increased Disease Severity and Poorer Quality of Life.

Clin Gastroenterol Hepatol 2021 May 27. Epub 2021 May 27.

Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada; Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada.

Background And Aims: Conditions such as irritable bowel syndrome (IBS), functional dyspepsia, and functional constipation are among the prevalent gastrointestinal (GI) disorders classified as disorders of gut-brain interaction (DGBI), which can adversely affect the lives of sufferers. This study aimed to assess the degree and consequences of overlapping DGBI in a large population-based global scale.

Methods: Internet survey data from 54,127 adults (49.1% women) in 26 countries were analyzed by 4 GI anatomic regions (esophageal, gastroduodenal, bowel, and anorectal). The number of DGBI-affected GI regions was assessed, including associations with sex, age, disease severity, quality of life, psychosocial variables, and health care utilization.

Results: A total of 40.3% of surveyed individuals met Rome IV criteria for a DGBI. The percentages with 1-4 DGBI-affected GI regions were 68.3%, 22.3%, 7.1%, and 2.3%, respectively. The IBS symptom severity score increased significantly from 1 (207.6) to 4 (291.6) regions, as did non-GI symptom reporting (somatization), anxiety and depression, concerns and embarrassment about bowel function, doctor visits, medications, and abdominal surgeries (all P < .0001). Quality of life decreased with increasing number of DGBI regions (P < .0001). In a logistic mixed model, non-GI symptoms (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.08-1.10), being very vs not concerned (OR, 2.55; 95% CI, 2.27-2.90), being very vs not embarrassed about bowel function (OR, 1.20; 95% CI, 1.08-1.33), and mean number of doctor visits (OR, 1.23; 95% CI, 1.115-1.32) were most strongly associated with number of DGBI regions.

Conclusions: DGBI in multiple anatomic GI regions is associated with increased psychological comorbidity, health care utilization, and IBS severity. Physician awareness of overlap could improve quality of care, prevent unnecessary interventions, and yield more positive health outcomes.
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http://dx.doi.org/10.1016/j.cgh.2021.05.042DOI Listing
May 2021

The endocrine effects of bitter tastant administration in the gastrointestinal system: intragastric versus intraduodenal administration.

Am J Physiol Endocrinol Metab 2021 07 24;321(1):E1-E10. Epub 2021 May 24.

Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium.

Bitter tastants are recently introduced as potential hunger-suppressive compounds, the so-called "Bitter pill." However, the literature about bitter administration lacks consistency in methods and findings. We want to test whether hunger ratings and hormone plasma levels are affected by: ) the site of administration: intragastrically (IG) or intraduodenally (ID), ) the bitter tastant itself, quinine hydrochloride (QHCl) or denatonium benzoate (DB), and ) the timing of infusion. Therefore, 14 healthy, female volunteers participated in a randomized, placebo-controlled six-visit crossover study. After an overnight fast, DB (1 µmol/kg), QHCl (10 µmol/kg), or placebo were given IG or ID via a nasogastric feeding tube. Blood samples were taken 10 min before administration and every 10 min after administration for a period of 2 h. Hunger was rated at the same time points on a visual analogue scale. ID bitter administration did not affect hunger sensations, motilin, or acyl-ghrelin release compared with its placebo infusion. IG QHCl infusion tended to suppress hunger increase, especially between 50 and 70 min after infusion, simultaneously with reduced motilin values. Here, acyl-ghrelin was not affected. IG DB did not affect hunger or motilin, however acyl-ghrelin levels were reduced 50-70 minutes after infusion. Plasma values of glucagon-like peptide 1 and cholecystokinin were too low to be properly detected or to have any physiological relevance. In conclusion, bitter tastants should be infused into the stomach to reduce hunger sensations and orexigenic gut peptides. QHCl has the best potential to reduce hunger sensations, and it should be infused 60 min before food intake. Bitter tastants are a potential new weight-loss treatment. This is a noninvasive, easy approach, which should be received with considerable enthusiasm by the public. However, literature about bitter administration lacks consistency in methods and findings. We summarize how the compound should be given based on: the site of administration, the best bitter compound to use, and at what timing in respect to the meal. This paper is therefore a fundamental step to continue research toward the further development of the "bitter pill."
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http://dx.doi.org/10.1152/ajpendo.00636.2020DOI Listing
July 2021

Establishing Minimal Clinically Important Differences in Quality of Life Measures in Opioid-Induced Constipation.

Clin Gastroenterol Hepatol 2021 Aug 5. Epub 2021 Aug 5.

Upstate Clinical Research Associates, Williamsville, New York.

Background & Aims: Opioids have a role in chronic pain management. However, opioid-induced constipation may cause patients to skip or reduce opioid doses, leading to inadequate pain relief and negatively impacting quality of life. We sought to establish a minimal clinically important difference to understand whether changes in quality of life scores are of value to patients.

Methods: Integrated data from the double-blind, controlled, phase 3 COMPOSE-1 and COMPOSE-2 trials of naldemedine in chronic noncancer pain and opioid-induced constipation were used to determine minimal clinically important differences using Patient Assessment of Constipation Symptoms (PAC-SYM) and Patient Assessment of Constipation Quality of Life (PAC-QOL) questionnaires. Patients completed the questionnaires (5-point Likert scale; predose, Weeks 2, 4, and 12), kept a daily log of Bowel Movement and Constipation Assessment, and rated satisfaction at end of study. Minimal clinically important differences were computed using an anchor-based method with 6 anchors: 5 from the Bowel Movement and Constipation Assessment and 1 from patient satisfaction. Threshold values for each anchor were set to define responders versus nonresponders based on score definitions. Clinically meaningful cutoff values for changes in PAC-SYM and PAC-QOL scores were determined using receiver operating characteristic curves.

Results: Data from 1095 patients (549, naldemedine; 546, placebo) were analyzed. The area under the curve for the receiver operating characteristic curves (ranges, 0.719 to 0.798 for PAC-SYM and 0.734 to 0.833 for PAC-QOL) indicated that both instruments can discriminate responders and nonresponders for each anchor. PAC-SYM cutoff values ranged from -1.04 to -0.83; PAC-QOL cutoff values ranged from -0.93 to -0.82.

Conclusions: Based on data derived from the anchor method, reductions in PAC-SYM and PAC-QOL scores of >1.0 in patients with chronic noncancer pain and opioid-induced constipation are clinically meaningful. ClinicalTrials.gov Registration: NCT01965158; NCT01993940.
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http://dx.doi.org/10.1016/j.cgh.2021.05.004DOI Listing
August 2021

Nutrient Drinking Test as Biomarker in Functional Dyspepsia.

Am J Gastroenterol 2021 07;116(7):1387-1395

Translational Research Center for Gastrointestinal Diseases (TARGID), Department of Chronic diseases and Metabolism, University of Leuven, Leuven, Belgium.

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.
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http://dx.doi.org/10.14309/ajg.0000000000001242DOI Listing
July 2021
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