Publications by authors named "Daniel Keszthelyi"

82 Publications

Age-Related Decrease in Abdominal Pain and Associated Structural- and Functional Mechanisms: An Exploratory Study in Healthy Individuals and Irritable Bowel Syndrome Patients.

Front Pharmacol 2021 16;12:806002. Epub 2021 Dec 16.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, Netherlands.

The world population is ageing, resulting in increased prevalence of age-related comorbidities and healthcare costs. Limited data are available on intestinal health in elderly populations. Structural and functional changes, including altered visceroperception, may lead to altered bowel habits and abdominal symptoms in healthy individuals and irritable bowel syndrome (IBS) patients. Our aim was to explore age-related changes in gastrointestinal symptoms and underlying mechanisms. In total, 780 subjects (IBS patients = 463, healthy subjects = 317) from two separate studies were included. Subjects were divided into different age groups ranging from young adult to elderly. Demographics and gastrointestinal symptom scores were collected from all participants using validated questionnaires. A subset of 233 IBS patients and 103 controls underwent a rectal barostat procedure to assess visceral hypersensitivity. Sigmoid biopsies were obtained from 10 healthy young adults and 10 healthy elderly. Expression of the visceral pain-associated receptors transient receptor potential (TRP) Ankyrin 1 (TRPA1) and Vanilloid 1 (TRPV1) genes were investigated by quantitative RT-PCR and immunofluorescence. Both elderly IBS and healthy individuals showed significantly lower scores for abdominal pain ( < 0.001) and indigestion ( < 0.05) as compared to respective young adults. Visceral hypersensitivity was less common in elderly than young IBS patients ( < 0.001). Relative TRPA1 gene transcription, as well as TRPA1 and TRPV1 immunoreactivity were significantly lower in healthy elderly versus healthy young adults ( < 0.05). Our findings show an age-related decrease in abdominal pain perception. This may in part be related to decreased TRPA1 and/or TRPV1 receptor expression. Further studies are needed to reveal precise underlying mechanisms and the associations with intestinal health.
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http://dx.doi.org/10.3389/fphar.2021.806002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8716827PMC
December 2021

Raising interest for neurogastroenterology: Bottom-up from the undergraduate medical curriculum?

United European Gastroenterol J 2021 Dec 28. Epub 2021 Dec 28.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands.

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http://dx.doi.org/10.1002/ueg2.12192DOI Listing
December 2021

Digital Instruments for Reporting of Gastrointestinal Symptoms in Clinical Trials: Comparison of End-of-Day Diaries Versus the Experience Sampling Method.

JMIR Form Res 2021 Nov 24;5(11):e31678. Epub 2021 Nov 24.

Division of Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands.

Background: Questionnaires are necessary tools for assessing symptoms of disorders of the brain-gut interaction in clinical trials. We previously reported on the excellent adherence to a smartphone app used as symptom diary in a randomized clinical trial on irritable bowel syndrome (IBS). Other sampling methods, such as the experience sampling method (ESM), are better equipped to measure symptom variability over time and provide useful information regarding possible symptom triggers, and they are free of ecological and recall bias. The high frequency of measurements, however, could limit the feasibility of ESM in clinical trials.

Objective: This study aimed to compare the adherence rates of a smartphone-based end-of-day diary and ESM for symptom assessment in IBS and functional dyspepsia (FD).

Methods: Data from 4 separate studies were included. Patients with IBS participated in a randomized controlled trial, which involved a smartphone end-of-day diary for a 2+8-week (pretreatment + treatment) period, and an observational study in which patients completed ESM assessments using a smartphone app for 1 week. Patients with FD participated in a randomized controlled trial, which involved a smartphone end-of-day diary for a 2+12-week (pretreatment + treatment) period, and an observational study in which patients completed ESM assessments using a smartphone app for 1 week. Adherence rates were compared between these 2 symptom sampling methods.

Results: In total, 25 patients with IBS and 15 patients with FD were included. Overall adherence rates for the end-of-day diaries were significantly higher than those for ESM (IBS: 92.7% vs 69.8%, FD: 90.1% vs 61.4%, respectively).

Conclusions: This study demonstrates excellent adherence rates for smartphone app-based end-of-day diaries as used in 2 separate clinical trials. Overall adherence rates for ESM were significantly lower, rendering it more suitable for intermittent sampling periods rather than continuous sampling during longer clinical trials.
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http://dx.doi.org/10.2196/31678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8663435PMC
November 2021

Patient preferences of healthcare delivery in irritable bowel syndrome: a focus group study.

BMC Gastroenterol 2021 Nov 23;21(1):438. Epub 2021 Nov 23.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Center +, PO Box 5800, 6202 AZ, Maastricht, The Netherlands.

Background: Irritable bowel syndrome (IBS) is a highly prevalent disorder with significant negative impact on quality of life of patients that results in high healthcare use and costs. Improving healthcare outcomes for IBS patients is warranted, however the exact needs of IBS patients with regard to therapy and control of symptoms are unknown.

Methods: Focus group interviews, using a two-stage model, were performed with twenty-three IBS patients meeting Rome III criteria and one mother of a patient, from four different regions from the Netherlands.

Results: Twenty-four participants were included of whom majority were female (n = 21), mean age was 43 years, and mean duration of IBS was 18 years. Five categories of patients' perspectives were identified: clear communication, a multidisciplinary treatment team, centers of expertise, focus on scientific research and information about IBS that is widely available for patients.

Conclusions: Based on these findings we highlight the need for IBS care givers to take these key items into account in IBS care. These elements aid clinicians, but mostly patients, in coping and management of symptoms and subsequent healthcare outcomes, reducing overall healthcare use and costs.
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http://dx.doi.org/10.1186/s12876-021-02030-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8609738PMC
November 2021

Evidence for engagement of the nucleus of the solitary tract in processing intestinal chemonociceptive input irrespective of conscious pain response in healthy humans.

Pain 2021 Nov 15. Epub 2021 Nov 15.

Department of Internal Medicine, Division of Gastroenterology-Hepatology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, the Netherlands 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. Cognitive and Affective Neuroscience Lab, Department of Psychological and Brain Sciences, Dartmouth College, Hanover, NH, USA. Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. School for Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands. Spinoza Center for Neuroimaging, Royal Netherlands Academy of Arts and Sciences (KNAW), Amsterdam, The Netherlands Department of Cognitive Neuroscience, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, the Netherlands. University of Sydney, Faculty of Medicine and Health, Pain Management Research Institute, Sydney, NSW, Australia Wingate Institute of Neurogastroenterology, Centre for Digestive Diseases, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK Translational Pain Research Unit, Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. Department of Medical Psychology and Medical Sociology, Ruhr University Bochum, Bochum, Germany.

Abstract: Neuroimaging studies have revealed important pathomechanisms related to disorders of brain-gut interactions, such as irritable bowel syndrome and functional dyspepsia. More detailed investigations aimed at neural processing in the brainstem, including the key relay station of the nucleus of the solitary tract (NTS), have hitherto been hampered by technical shortcomings. To ascertain these processes in more detail, we used multi-echo multiband 7T functional magnetic resonance imaging (fMRI) and a novel translational experimental model based on a nutrient-derived intestinal chemonociceptive stimulus. In a randomized cross-over fashion, subjects received duodenal infusion of capsaicin (the pungent principal in red peppers) and placebo (saline). During infusion, fMRI data and concomitant symptom ratings were acquired. Of 26 healthy female volunteers included, 18 were included in the final analysis. Significantly increased brain activation over time during capsaicin infusion, as compared to placebo, was observed in brain regions implicated in pain processing, in particular the NTS. Brain activation in the thalamus, cingulate cortex and insula were more pronounced in subjects who reported abdominal pain (visual analogue scale > 10mm), as compared to subjects who experienced no pain. On the contrary, activations at the level of the NTS were independent of subjective pain ratings. The current experimental paradigm therefore allowed us to demonstrate activation of the principal relay station for visceral afferents in the brainstem, the NTS, which was engaged irrespective of the conscious pain response. These findings contribute to understanding the fundamental mechanism necessary for developing novel therapies aimed at correcting disturbances in visceral afferent pain processing.
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http://dx.doi.org/10.1097/j.pain.0000000000002538DOI Listing
November 2021

How to raise the interest for neurogastroenterology among young gastroenterologists?

United European Gastroenterol J 2021 Dec 1;9(10):1193-1196. Epub 2021 Nov 1.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands.

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http://dx.doi.org/10.1002/ueg2.12174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8672086PMC
December 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

The estimation of a preference-based single index for the IBS-QoL by mapping to the EQ-5D-5L in patients with irritable bowel syndrome.

Qual Life Res 2021 Sep 21. Epub 2021 Sep 21.

Department of Clinical Epidemiology and Medical Technology Assessment, CAPHRI Care and Public Health Research Institute, Maastricht University Medical Center, Maastricht, The Netherlands.

Purpose: The Irritable Bowel Syndrome Quality of Life (IBS-QoL) questionnaire is a commonly used and validated IBS-specific QoL instrument. However, this questionnaire is in contrast to the EQ-5D-5L, not preference-based and as such does not allow calculation of QALYs. The objective of this study was to describe the convergent- and known-group validity of both questionnaires and to develop a mapping algorithm from EQ-5D-5L which enable IBS-QoL scores to be transformed into utility scores for use in economic evaluations.

Methods: We used data from two multicenter randomized clinical trials, which represented the estimation and external validation dataset. The convergent validity was investigated by examining correlations between the EQ-5D-5L and IBS-QoL and the known-group validity by calculating effect sizes. Ordinary least squares (OLS), censored least absolute deviations (CLAD), and mixture models were used in this mapping approach.

Results: 283 IBS patients were included (n = 189 vs. n = 84). Mean IBS-QoL score was 71.13 (SD 15.66) and mean EQ-5D-5L utility score was 0.73 (SD 0.19). The overall sensitivity of the IBS-QoL and EQ-5D-5L to discriminate between patient and disease characteristics was similar. CLAD model 4, containing the total IBS-QoL score and squared IBS-SSS (IBS severity scoring system), was chosen as the most appropriate model to transform IBS-QoL scores into EQ-5D-5L utility scores.

Conclusion: This study reports the development of an algorithm where the condition-specific questionnaire IBS-QoL can be used to calculate utility values for use in economic evaluations. Including a clinical measure, IBS-SSS, in the model improved the performance of the algorithm.
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http://dx.doi.org/10.1007/s11136-021-02995-yDOI Listing
September 2021

The interplay between stress and fullness in patients with functional dyspepsia and healthy controls: an exploratory experience sampling method study.

Psychosom Med 2021 Sep 14. Epub 2021 Sep 14.

Division of Gastroenterology-Hepatology, Department of Internal Medicine, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Centre+, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands Food Innovation and Health, Centre for Healthy Eating and Food Innovation, Maastricht University, 5911 AA Venlo, The Netherlands Department of Psychiatry and Psychology, Maastricht University Medical Centre, Maastricht, The Netherlands.

Objective: Fullness is a cardinal symptom in functional dyspepsia (FD). The use of real-time symptom assessment might provide more insight in factors, such as daily stress, that can influence fullness. Therefore, this study aimed to use the Experience Sampling Method (ESM, a real-time, repeated measurement method making use of repeated questionnaires available at random moments for a limited amount of time) to assess the association between stress and fullness in patients with FD and healthy controls (HC).

Methods: Thirty-five patients with FD (25 female, mean age 44.7 years) and 34 HC (24 female, mean age 44.1 years) completed ESM (a maximum of 10 random moments per day) for seven consecutive days. Stress and fullness were rated on an 11-point Numeric Rating Scale. Data between patients with FD and HC were statistically compared using a student samples t-test and linear mixed-effects models with repeated measures (level 1) nested within participants (level 2).

Results: Average fullness scores were 2.23 (SE 0.37) points higher in patients with FD compared with HC (p < 0.001). Average stress scores were 1.37 (SE 0.30) points higher in patients with FD compared with HC (p = 0.002).In FD, fullness scores increased with 0.14 for every 1-point increase in concurrent stress scores (p = 0.010). Fullness scores at t = 0 increased with 0.12 for every 1-point increase in stress scores at t = -1 (p = 0.019). T = 0 stress scores were not associated with change in t = -1 fullness scores. No associations between concurrent symptom scores were found for HC.

Conclusions: Concurrent and preceding stress scores are positively associated with fullness scores in patients with FD, but not in HC. These findings indicate that increased levels of stress may precede feelings of fullness in patients with FD.
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http://dx.doi.org/10.1097/PSY.0000000000001012DOI Listing
September 2021

A trial-based economic evaluation of peppermint oil for the treatment of irritable bowel syndrome.

United European Gastroenterol J 2021 Nov 1;9(9):997-1006. Epub 2021 Sep 1.

Division of Gastroenterology-Hepatology, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands.

Background: Irritable Bowel Syndrome (IBS) is a prevalent, chronic gastrointestinal disorder that imposes a substantial socioeconomic burden. Peppermint oil is a frequently used treatment for IBS, but evidence about cost-effectiveness is lacking.

Objective: We aimed to assess cost-effectiveness of small-intestinal release peppermint oil versus placebo in IBS patients.

Methods: In a multicenter randomized placebo-controlled trial, cost-effectiveness was evaluated from a societal perspective. The incremental cost-effectiveness ratios (ICERs) were expressed as (1) incremental costs per Quality Adjusted Life Years (QALY), and (2) incremental costs per successfully treated patient, that is per abdominal pain responder (according to FDA definitions), both after an eight-week treatment period with placebo versus peppermint oil. Cost-utility and uncertainty were estimated using non-parametric bootstrapping. Sensitivity analyses were performed.

Results: The analysis comprised 126 patients (N = 64 placebo, N = 62 small-intestinal release peppermint oil). Peppermint oil was a dominant treatment compared to placebo in 46% of bootstrap replications. Peppermint oil was also more effective but at higher cost in 31% of replications. The net-benefit acceptability curve showed that peppermint oil has a 56% probability of being cost-effective at a conservative willingness-to-pay threshold of €10.000/QALY. Peppermint oil was also a dominant treatment per additional successfully treated patient according to FDA definitions, that is in 51% of replications. In this case, the acceptability curve showed an 89% probability of being cost-effective.

Conclusions: In patients with IBS, small-intestinal release peppermint oil appears to be a cost-effective treatment although there is uncertainty surrounding the ICER. When using abdominal pain responder as outcome measure for the ICER, peppermint oil has a high probability of being cost-effective. The use of peppermint oil, which is a low-cost treatment, can be justified by the modest QALY gains and slightly higher proportion of abdominal pain responders. More research and long-term data are necessary to confirm the cost-effectiveness of peppermint oil. NCT02716285.
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http://dx.doi.org/10.1002/ueg2.12134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8598953PMC
November 2021

A Review of Irritable Bowel Syndrome.

JAMA 2021 07;326(2):189

Laboratory for Brain-Gut Axis Studies, KU Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1001/jama.2021.6755DOI Listing
July 2021

Irritable Bowel Syndrome and Functional Dyspepsia: Different Ends of the Same Spectrum of Intestinal Barrier Dysfunction?

Am J Gastroenterol 2021 07;116(7):1556

Division of Gastroenterology-Hepatology, Department of Internal Medicine, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Center+, Maastricht, the Netherlands.

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http://dx.doi.org/10.14309/ajg.0000000000001174DOI Listing
July 2021

A putative anti-inflammatory role for TRPM8 in irritable bowel syndrome-An exploratory study.

Neurogastroenterol Motil 2021 09 19;33(9):e14170. Epub 2021 Jun 19.

Division of Gastroenterology & Hepatology, Department of Internal Medicine, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands.

Background: Chronic and recurring pain is a characteristic symptom in irritable bowel syndrome (IBS). Altered signaling between immune cells and sensory neurons within the gut may promote generation of pain symptoms. As transient receptor potential melastatin 8 (TRPM8) agonists, such as L-menthol in peppermint oil, have shown to attenuate IBS pain symptoms, we began investigating potential molecular mechanisms.

Methods: Colonic biopsy tissues were collected from patients with IBS and controls, in two separate cohorts. Immunohistochemistry was performed to identify TRPM8 localization. Quantitative PCR was performed to measure mucosal mRNA levels of TRPM8. In addition, functional experiments with the TRPM8 agonist icilin were performed ex vivo to examine cytokine release from biopsies. Daily diaries were collected to ascertain pain symptoms.

Results: In biopsy tissue from IBS patients, we showed that TRPM8 immunoreactivity is colocalized with immune cells predominantly of the dendritic cell lineage, in close approximation to nerve endings, and TRPM8 protein and mRNA expression was increased in IBS patients compared to controls (p < 0.001). TRPM8 mRNA expression showed a significant positive association with abdominal pain scores (p = 0.015). Treatment of IBS patient biopsies with icilin reduced release of inflammatory cytokines IL-1β, IL-6, and TNF-α (p < 0.05).

Conclusions And Inferences: These data indicate TRPM8 may have important anti-inflammatory properties and by this virtue can impact neuro-immune disease mechanisms in IBS.
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http://dx.doi.org/10.1111/nmo.14170DOI Listing
September 2021

Wheat ATIs: Characteristics and Role in Human Disease.

Front Nutr 2021 28;8:667370. Epub 2021 May 28.

Laboratory of Food Chemistry, Wageningen University and Research, Wageningen, Netherlands.

Amylase/trypsin-inhibitors (ATIs) comprise about 2-4% of the total wheat grain proteins and may contribute to natural defense against pests and pathogens. However, they are currently among the most widely studied wheat components because of their proposed role in adverse reactions to wheat consumption in humans. ATIs have long been known to contribute to IgE-mediated allergy (notably Bakers' asthma), but interest has increased since 2012 when they were shown to be able to trigger the innate immune system, with attention focused on their role in coeliac disease which affects about 1% of the population and, more recently, in non-coeliac wheat sensitivity which may affect up to 10% of the population. This has led to studies of their structure, inhibitory properties, genetics, control of expression, behavior during processing, effects on human adverse reactions to wheat and, most recently, strategies to modify their expression in the plant using gene editing. We therefore present an integrated account of this range of research, identifying inconsistencies, and gaps in our knowledge and identifying future research needs.   This paper is the outcome of an invited international ATI expert meeting held in Amsterdam, February 3-5 2020.
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http://dx.doi.org/10.3389/fnut.2021.667370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192694PMC
May 2021

Review on the Regional Effects of Gastrointestinal Luminal Stimulation on Appetite and Energy Intake: (Pre)clinical Observations.

Nutrients 2021 May 11;13(5). Epub 2021 May 11.

Division of Gastroenterology-Hepatology, Maastricht University Medical Center, 6229 HX Maastricht, The Netherlands.

Macronutrients in the gastrointestinal (GI) lumen are able to activate "intestinal brakes", feedback mechanisms on proximal GI motility and secretion including appetite and energy intake. In this review, we provide a detailed overview of the current evidence with respect to four questions: (1) are regional differences (duodenum, jejunum, ileum) present in the intestinal luminal nutrient modulation of appetite and energy intake? (2) is this "intestinal brake" effect macronutrient specific? (3) is this "intestinal brake" effect maintained during repetitive activation? (4) can the "intestinal brake" effect be activated via non-caloric tastants? Recent evidence indicates that: (1) regional differences exist in the intestinal modulation of appetite and energy intake with a proximal to distal gradient for inhibition of energy intake: ileum and jejunum > duodenum at low but not at high caloric infusion rates. (2) the "intestinal brake" effect on appetite and energy appears not to be macronutrient specific. At equi-caloric amounts, the inhibition on energy intake and appetite is in the same range for fat, protein and carbohydrate. (3) data on repetitive ileal brake activation are scarce because of the need for prolonged intestinal intubation. During repetitive activation of the ileal brake for up to 4 days, no adaptation was observed but overall the inhibitory effect on energy intake was small. (4) the concept of influencing energy intake by intra-intestinal delivery of non-caloric tastants is intriguing. Among tastants, the bitter compounds appear to be more effective in influencing energy intake. Energy intake decreases modestly after post-oral delivery of bitter tastants or a combination of tastants (bitter, sweet and umami). Intestinal brake activation provides an interesting concept for preventive and therapeutic approaches in weight management strategies.
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http://dx.doi.org/10.3390/nu13051601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151500PMC
May 2021

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

United European Gastroenterol J 2021 04;9(3):307-331

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/10.1002/ueg2.12061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259261PMC
April 2021

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

Neurogastroenterol Motil 2021 12 3;33(12):e14161. Epub 2021 May 3.

Division of Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, The Netherlands.

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 (r  = 0.735 and r  = 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.
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http://dx.doi.org/10.1111/nmo.14161DOI Listing
December 2021

Psychometric evaluation of an experience sampling method-based patient-reported outcome measure in functional dyspepsia.

Neurogastroenterol Motil 2021 09 2;33(9):e14136. Epub 2021 May 2.

Division of Gastroenterology-Hepatology, Department of Internal Medicine, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Centre+, Maastricht, The Netherlands.

Background: Due to important biases, conventional end-of-day and end-of-week assessment methods of gastrointestinal symptoms in functional dyspepsia (FD) are considered suboptimal. Real-time symptom assessment based on the experience sampling method (ESM) could be a more accurate measurement method. This study aimed to evaluate validity and reliability of an ESM-based patient-reported outcome measure (PROM) for symptom assessment in FD.

Methods: Thirty-five patients with FD (25 female, mean age 44.7 years) completed the ESM-based PROM (a maximum of 10 random moments per day) and an end-of-day symptom diary for 7 consecutive days. On day 7, end-of-week questionnaires were completed including the Nepean Dyspepsia Index (NDI) and Patient Assessment of Gastrointestinal Symptom Severity Index (PAGI-SYM).

Key Results: Experience sampling method and corresponding end-of-day scores for gastrointestinal symptoms were significantly associated (ICCs range 0.770-0.917). However, end-of-day scores were significantly higher (Δ0.329-1.031) than mean ESM scores (p < 0.05). Comparing ESM with NDI and PAGI-SYM scores, correlations were weaker (Pearson's r range 0.467-0.846). Cronbach's α coefficient was good for upper gastrointestinal symptoms (α = 0.842). First half-week and second half-week scores showed very good consistency (ICCs range 0.913-0.975).

Conclusion And Inferences: Good validity and reliability of a novel ESM-based PROM for assessing gastrointestinal symptoms in FD patients was demonstrated. Moreover, this novel PROM allows to evaluate individual symptom patterns and can evaluate interactions between symptoms and environmental/contextual factors. ESM has the potential to increase patients' disease insight, provide tools for self-management, and improve shared decision making. Hence, this novel tool may aid in the transition toward personalized health care for FD patients.
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http://dx.doi.org/10.1111/nmo.14136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8519073PMC
September 2021

Effect of Obesity on the Expression of Nutrient Receptors and Satiety Hormones in the Human Colon.

Nutrients 2021 Apr 13;13(4). Epub 2021 Apr 13.

Centre for Neuroscience, Surgery and Trauma, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London E1 2AT, UK.

Background: Receptors located on enteroendocrine cells (EECs) of the colon can detect nutrients in the lumen. These receptors regulate appetite through a variety of mechanisms, including hormonal and neuronal signals. We assessed the effect of obesity on the expression of these G-protein coupled receptors (GPCRs) and hormones at both mRNA and protein level.

Methods: qPCR and immunohistochemistry were used to examine colonic tissue from cohorts of patients from the Netherlands (proximal and sigmoid tissue) and the United Kingdom (tissue from across the colon) and patients were grouped by body mass index (BMI) value (BMI < 25 and BMI ≥ 25).

Results: The mRNA expression of the hormones/signaling molecules serotonin, glucagon, peptide YY (PYY), CCK and somatostatin were not significantly different between BMI groups. GPR40 mRNA expression was significantly increased in sigmoid colon samples in the BMI ≥ 25 group, but not proximal colon. GPR41, GPR109a, GPR43, GPR120, GPRC6A, and CaSR mRNA expression were unaltered between low and high BMI. At the protein level, serotonin and PYY containing cell numbers were similar in high and low BMI groups. Enterochromaffin cells (EC) showed high degree of co-expression with amino acid sensing receptor, CaSR while co-expression with PYY containing L-cells was limited, regardless of BMI.

Conclusions: While expression of medium/long chain fatty acid receptor GPR40 was increased in the sigmoid colon of the high BMI group, expression of other nutrient sensing GPCRs, and expression profiles of EECs involved in peripheral mechanisms of appetite regulation were unchanged. Collectively, these data suggest that in human colonic tissue, EEC and nutrient-sensing receptor expression profiles are not affected despite changes to BMI.
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http://dx.doi.org/10.3390/nu13041271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070384PMC
April 2021

Web-Based Educational Intervention for Patients With Uninvestigated Dyspepsia Referred for Upper Gastrointestinal Tract Endoscopy: A Randomized Clinical Trial.

JAMA Intern Med 2021 06;181(6):825-833

Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Nijmegen, the Netherlands.

Importance: Diagnostic yield of upper gastrointestinal (GI) tract endoscopy for uninvestigated dyspepsia is low, and its clinical implications are limited. There is an unmet need for better strategies to reduce the volume of upper GI tract endoscopic procedures for dyspepsia.

Objective: To study the effectiveness of a web-based educational intervention as a tool to reduce upper GI tract endoscopy in uninvestigated dyspepsia.

Design, Setting, And Participants: This open-label, multicenter, randomized clinical trial enrolled participants between November 1, 2017, and March 31, 2019, with follow-up 52 weeks after randomization, at 4 teaching hospitals in the Netherlands. Participants included patients with uninvestigated dyspeptic symptoms who were referred for upper GI tract endoscopy by their general health care clinician without prior consultation of a gastroenterologist. A total of 119 patients, aged 18 to 69 years, were included. Patients were excluded if any of the following red flag symptoms were present: (indirect) signs of upper GI tract hemorrhage (hematemesis, melena, hematochezia, or anemia), unintentional weight loss of 5% or higher of normal body weight during a period of 6 to 12 months, persistent vomiting, dysphagia, or jaundice.

Interventions: Patients were randomly assigned (1:1) to education (intervention) or upper GI tract endoscopy (control). Education consisted of a self-managed web-based educational intervention, containing information on gastric function, dyspepsia, and upper GI tract endoscopy.

Main Outcomes And Measures: Difference in the proportion of upper GI tract endoscopy procedures between those who received access to the web-based educational intervention and those who did not at 12 weeks and 52 weeks after randomization, analyzed in the intention-to-treat population. Secondary outcomes included quality of life (Nepean Dyspepsia Index) and symptom severity (Patient Assessment of Gastrointestinal Disorders Symptom Severity Index) measured at baseline and 12 weeks.

Results: Of 119 patients included (median age, 48 years [interquartile range, 37-56 years]; 48 men [40%]), 62 were randomized to web-based education (intervention) and 57 to upper GI tract endoscopy (control). Significantly fewer patients compared with controls underwent upper GI tract endoscopy after using the web-based educational intervention: 24 (39%) vs 47 (82%) (relative risk, 0.46; 95% CI, 0.33-0.64; P < .001). Symptom severity and quality of life improved equivalently in both groups. One additional patient in the intervention group required upper GI tract endoscopy during follow-up.

Conclusions And Relevance: Findings of this study indicate that web-based patient education is an effective tool to decrease the need for upper GI tract endoscopy in uninvestigated dyspepsia.

Trial Registration: ClinicalTrials.gov Identifier: NCT03205319.
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http://dx.doi.org/10.1001/jamainternmed.2021.1408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077042PMC
June 2021

The enteric nervous system in gastrointestinal disease etiology.

Cell Mol Life Sci 2021 May 26;78(10):4713-4733. Epub 2021 Mar 26.

Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.

A highly conserved but convoluted network of neurons and glial cells, the enteric nervous system (ENS), is positioned along the wall of the gut to coordinate digestive processes and gastrointestinal homeostasis. Because ENS components are in charge of the autonomous regulation of gut function, it is inevitable that their dysfunction is central to the pathophysiology and symptom generation of gastrointestinal disease. While for neurodevelopmental disorders such as Hirschsprung, ENS pathogenesis appears to be clear-cut, the role for impaired ENS activity in the etiology of other gastrointestinal disorders is less established and is often deemed secondary to other insults like intestinal inflammation. However, mounting experimental evidence in recent years indicates that gastrointestinal homeostasis hinges on multifaceted connections between the ENS, and other cellular networks such as the intestinal epithelium, the immune system, and the intestinal microbiome. Derangement of these interactions could underlie gastrointestinal disease onset and elicit variable degrees of abnormal gut function, pinpointing, perhaps unexpectedly, the ENS as a diligent participant in idiopathic but also in inflammatory and cancerous diseases of the gut. In this review, we discuss the latest evidence on the role of the ENS in the pathogenesis of enteric neuropathies, disorders of gut-brain interaction, inflammatory bowel diseases, and colorectal cancer.
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http://dx.doi.org/10.1007/s00018-021-03812-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195951PMC
May 2021

The placebo response rate in pharmacological trials in patients with irritable bowel syndrome: a systematic review and meta-analysis.

Lancet Gastroenterol Hepatol 2021 06 23;6(6):459-473. Epub 2021 Mar 23.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, Netherlands.

Background: Clinical trials in irritable bowel syndrome are associated with high placebo response rates. We aimed to identify the magnitude of the placebo response and the contributing factors to this occurrence.

Methods: We did a systematic review and meta-analysis with a search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials between April 1, 1959, and April 30, 2020. We included all randomised controlled trials that compared an active pharmacotherapeutic agent with placebo and had a dichotomous outcome of response to therapy (in terms of global improvement or improvement in abdominal pain) in adults (aged ≥18 years) with irritable bowel syndrome. Exclusion criteria were trials reporting on treatment satisfaction as a dichotomous outcome of response to therapy or clinician-reported outcomes and a treatment duration of less than 4 weeks. Our main outcome was identification of the magnitude of the pooled placebo response rate for the following endpoints: global improvement, abdominal pain, and US Food and Drug Administration (FDA) endpoints. We extracted information from published reports and pooled proportions through meta-analysis with random effects. The study was registered with PROSPERO, CRD42020170908.

Findings: Of the 6863 publications identified, 70 articles describing 73 randomised controlled trials were included in our analysis. The pooled placebo response rate was 27·3% (95% CI 24·3-30·9) using the global improvement endpoint, 34·4% (31·2-37·8) using the abdominal pain endpoint, and 17·9% (15·2-21·0) using the composite FDA endpoint responder definition, all with substantial heterogeneity between the trials. Studies published before 2006, and those done in Europe, with a parallel design, a run-in period of 2 weeks or less, a dose schedule of three times a day or more, or a smaller sample size of the control group were significantly associated with an increased pooled placebo response rate.

Interpretation: More than a quarter of patients with irritable bowel syndrome had a placebo response in terms of global improvement, with multiple associated moderators. We recommend future trials apply a run-in period of at least 2 weeks and dose once or twice a day to minimise the placebo response rate.

Funding: None.
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http://dx.doi.org/10.1016/S2468-1253(21)00023-6DOI Listing
June 2021

Impact of gastrointestinal tract variability on oral drug absorption and pharmacokinetics: An UNGAP review.

Eur J Pharm Sci 2021 Jul 20;162:105812. Epub 2021 Mar 20.

Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium; Chairperson of the UNGAP network, COST CA 16205. Electronic address:

The absorption of oral drugs is frequently plagued by significant variability with potentially serious therapeutic consequences. The source of variability can be traced back to interindividual variability in physiology, differences in special populations (age- and disease-dependent), drug and formulation properties, or food-drug interactions. Clinical evidence for the impact of some of these factors on drug pharmacokinetic variability is mounting: e.g. gastric pH and emptying time, small intestinal fluid properties, differences in pediatrics and the elderly, and surgical changes in gastrointestinal anatomy. However, the link of colonic factors variability (transit time, fluid composition, microbiome), sex differences (male vs. female) and gut-related diseases (chronic constipation, anorexia and cachexia) to drug absorption variability has not been firmly established yet. At the same time, a way to decrease oral drug pharmacokinetic variability is provided by the pharmaceutical industry: clinical evidence suggests that formulation approaches employed during drug development can decrease the variability in oral exposure. This review outlines the main drivers of oral drug exposure variability and potential approaches to overcome them, while highlighting existing knowledge gaps and guiding future studies in this area.
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http://dx.doi.org/10.1016/j.ejps.2021.105812DOI Listing
July 2021

Satiation or satiety? More than mere semantics.

Lancet 2021 03;397(10279):1060-1061

Division of Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University Medical Center, 6202 AZ Maastricht, Netherlands.

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http://dx.doi.org/10.1016/S0140-6736(21)00245-2DOI Listing
March 2021

Gut-Brain Interactions in Patients with Inflammatory Bowel Disease and the Role of Hypnotherapy in Managing Symptoms.

J Crohns Colitis 2021 Oct;15(10):1780-1781

Department of Internal Medicine, Division of Gastroenterology-Hepatology, Maastricht University Medical Center, Maastricht, the Netherlands.

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http://dx.doi.org/10.1093/ecco-jcc/jjab053DOI Listing
October 2021

Correction: Smart Data Collection for the Assessment of Treatment Effects in Irritable Bowel Syndrome: Observational Study.

JMIR Mhealth Uhealth 2021 Feb 18;9(2):e27998. Epub 2021 Feb 18.

Division Gastroenterology-Hepatology, Department of Internal Medicine, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, Netherlands.

[This corrects the article DOI: 10.2196/19696.].
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http://dx.doi.org/10.2196/27998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932838PMC
February 2021

Effects of gastrointestinal delivery of non-caloric tastants on energy intake: a systematic review and meta-analysis.

Eur J Nutr 2021 Sep 8;60(6):2923-2947. Epub 2021 Feb 8.

Division of Gastroenterology-Hepatology, Department of Internal Medicine, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Center+, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands.

Purpose: Taste receptors are expressed throughout the gastrointestinal tract. The activation of post-oral taste receptors using tastants could provide a non-invasive treatment option in combating the obesity epidemic. The aim of this review was to examine the effect of post-oral delivery of non-caloric tastants on eating behavior reflected by primary outcome energy intake and secondary outcomes GI symptoms and perceptions and potential underlying mechanisms. This review was conducted according to the PRISMA guidelines for systematic reviews.

Methods: A systematic literature search of the Cochrane, PubMed, Embase, and Medline databases was performed. This systematic review and meta-analysis was registered in the PROSPERO database on 26 February 2020 (ID: CRD42020171182). Two researchers independently screened 11,912 articles and extracted information from 19 articles. If at least two studies investigated the effect of the same taste compound on primary outcome energy intake, a meta-analysis was performed to determine pooled effect sizes.

Results: Nineteen papers including healthy volunteers were included. In the 19 papers analyzed, effects of various tastants were investigated in healthy volunteers. Most extensively investigated were bitter tastants. The meta-analysis of effects of bitter tastants showed a significant reduction in energy intake of 54.62 kcal (95% CI - 78.54 to - 30.69, p = 0.0014).

Conclusions: Bitter stimuli are most potent to influence eating behavior. Energy intake decreased after post-oral delivery of bitter tastants. This highlights the potential of a preventive role of bitter tastants in battling the obesity epidemic.
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http://dx.doi.org/10.1007/s00394-021-02485-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354866PMC
September 2021

The development of a faecal incontinence core outcome set: an international Delphi study protocol.

Int J Colorectal Dis 2021 Mar 2;36(3):617-622. Epub 2021 Feb 2.

Department of Surgery and Colorectal Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands.

Purpose: Faecal incontinence (FI) is estimated to affect around 7.7% of people. There is a lack of uniformity in outcome definitions, measurement and reporting in FI studies. Until now, there is no general consensus on which outcomes should be assessed and reported in FI research. This complicates comparison between studies and evidence synthesis, potentially leading to recommendations not evidence-based enough to guide physicians in selecting an FI therapy. A solution for this lack of uniformity in reporting of outcomes is the development of a Core Outcome Set (COS) for FI. This paper describes the protocol for the development of a European COS for FI.

Methods: Patient interviews and a systematic review of the literature will be performed to identify patient-, physician- and researcher-oriented outcomes. The outcomes will be categorised using the COMET taxonomy and put forward to a group of patients, physicians (i.e. colorectal surgeons, gastroenterologists and general practitioners) and researchers in a Delphi consensus exercise. This exercise will consist of up to three web-based rounds in which participants will prioritise and condense the list of outcomes, which is expected to result in consensus. A consensus meeting with participants from all stakeholder groups will take place to reach a final agreement on the COS.

Discussion: This study protocol describes the development of a European COS to improve reliability and consistency of outcome reporting in FI studies, thereby improving evidence synthesis and patient care.

Trial Registration: This project has been registered in the COMET database on the 1st of April 2020, available at http://www.comet-initiative.org/Studies/Details/1554 . The systematic review has been registered on the PROSPERO database on the 31st of August 2020, available at https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=202020&VersionID=1381336 .
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http://dx.doi.org/10.1007/s00384-021-03865-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895769PMC
March 2021

Gastric peroral endoscopic pyloromyotomy for decompensated gastroparesis: comprehensive motility analysis in relation to treatment outcomes.

Endosc Int Open 2021 Feb 25;9(2):E137-E144. Epub 2021 Jan 25.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands.

There are no reliable data to predict which patients with gastroparesis (GP) would benefit the most from gastric peroral endoscopic pyloromyotomy (G-POEM). The aim of the present study was to assess whether antro-duodenal motility patterns and pyloric distensibility can predict the outcome of G-POEM in patients with decompensated GP. In an open-label study, patients with GP and refractory symptoms were eligible for treatment with G-POEM if treatment attempts according to a standardized stepwise protocol had failed. Baseline assessment included Gastroparesis Cardinal Symptom Index (GCSI), C13-octanoic gastric emptying breath test and high-resolution antro-duodenal manometry. Pyloric distensibility using EndoFlip measurements was assessed at baseline and 3 months after the procedure. Explorative analyses were performed on potential predictors of response using logistic regression analyses. Twenty-four patients with decompensated GP underwent G-POEM. At baseline, 78.3 % and 61.9 % of patients showed antral hypomotility and neuropathic motor patterns, respectively. The technical success rate was 100 % (24/24). Mean GCSI improved significantly at 3, 6, and 12 months after G-POEM (  = 0.01). Median distensibility index (DI) improved significantly as compared with baseline (7.5 [6.9;11.7] vs. 5.3[3.1;8.1],  = 0.004). A significant correlation was found between clinical response at 6 months and pyloric DI improvement (  = 0.003). No potential predictors of clinical response after G-POEM could be identified in an explorative analysis. G-POEM improved pyloric distensibility patterns in patients with decompensated GP. Clinical response at 6 months after G-POEM was associated with pyloric distensibility improvement. However, no potential predictors of response could be identified from either antro-duodenal motility patterns or pyloric distensibility.
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http://dx.doi.org/10.1055/a-1311-0859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834704PMC
February 2021

Large-scale association analyses identify host factors influencing human gut microbiome composition.

Nat Genet 2021 02 18;53(2):156-165. Epub 2021 Jan 18.

Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 × 10) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10 < P < 5 × 10) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.
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http://dx.doi.org/10.1038/s41588-020-00763-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8515199PMC
February 2021
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