Psychological Processes, Not Physiological Parameters, Are Most Important Contributors to Symptom Severity in Patients With Refractory Heartburn/Regurgitation Symptoms.

BACKGROUND & AIMS: Physiological and psychological factors have been found to influence esophageal symptom reporting. We aimed to evaluate which of these factors are associated with 3 reflux symptom severity outcomes (ie, Total Reflux, Heartburn, and Sleep Disturbance) through a traditional statistical and a complementary machine-learning approach. METHODS: Consecutive adult patients with refractory heartburn/regurgitation symptoms underwent standard 24-hour pH-impedance monitoring and completed questionnaires assessing past and current gastrointestinal and psychological health. In the traditional statistical approach, hierarchical general linear models assessed relationships of psychological and physiological variables (eg, total number of reflux episodes) with reflux severity scores. Mediation analyses further assessed pathways between relevant variables. In the machine-learning approach, all psychological and physiological variables were entered into 11 different models and cross-validated model performance was compared among the different models to select the best model. RESULTS: Three hundred ninety-three participants (mean [SD] age, 48.5 [14.1] years; 60% were female) were included. General psychological functioning emerged as an important variable in the traditional statistical approach, as it was significantly associated with all 3 outcomes and mediated the relationship between childhood trauma and both Total Reflux and Heartburn Severity. In the machine-learning analyses, general psychological variables (eg, depressive symptoms) were most important for Total Reflux and Sleep Disturbance outcomes, and symptom-specific variables, like visceral anxiety, were more influential for Heartburn Severity. Physiological variables were not significant contributors to reflux symptom severity outcomes in our sample across reflux classifications and statistical methodology. CONCLUSIONS: Psychological processes, both general and symptom-specific, should be considered as another important factor within the multifactorial processes that impact reflux symptom severity reporting across the reflux spectrum.

Poor Subjective Sleep Quality Predicts Symptoms in Irritable Bowel Syndrome Using the Experience Sampling Method.

INTRODUCTION: Sleep quality may affect symptom experience in irritable bowel syndrome (IBS). Our aim was to investigate the relationship between sleep quality and gastrointestinal (GI) symptoms using actigraphy and the experience sampling method. METHODS: Patients with IBS were recruited from a tertiary Neurogastroenterology clinic and the community. GI symptoms and mood were recorded on a smartphone application, 10 times per day, over 7 consecutive days. Subjective sleep quality was recorded every morning to reflect the night before. Objective measures of sleep quality were estimated from wrist-worn actigraphy. Cross-lagged structural equation models were built to assess the directionality of sleep-symptom relationships over time. RESULTS: Eighty patients with IBS completed the study (mean age: 37 years [range 20-68], 89% female, 78% community). Approximately 66% had a Pittsburgh Sleep Quality Index score ≥ 8, indicating a clinically significant sleep disturbance. Approximately 82% (95% CI: 72-90) screened positive for a sleep disorder, most commonly insomnia. In cross-lagged analysis, poor subjective sleep quality predicted next-day abdominal pain (0.036 < P < 0.040) and lower GI symptoms (0.030 < P < 0.032), but not vice versa. No significant relationship with GI symptoms was found for any objective sleep measure using actigraphy. DISCUSSION: Poor subjective sleep quality was associated with higher next-day lower GI symptom levels, but not vice versa. Objective sleep measures did not predict next-day abdominal symptoms, potentially supporting the conclusion that it is the perception of sleep quality that is most influential. This study may be used to guide future research into the effect of sleep interventions on GI symptoms.

The circulating and central endocannabinoid system in obesity and weight loss.

Major advances have been made in obesity treatment, focusing on restoring disturbances along the gut-brain axis. The endocannabinoid system (ECS) is a neuromodulatory signaling system, present along the entire gut-brain axis, that plays a critical role in central and peripheral regulation of food intake and body weight. Evidence on the impact of weight loss on the ECS is, however, more limited. Therefore, we set out to review the existing literature for changes in central and circulating endocannabinoid levels after bariatric surgery and other weight loss strategies in humans. The PubMed, Embase and Web of Science databases were searched for relevant articles. Fifty-six human studies were identified. Most studies measuring circulating 2-arachidonoylglycerol (2-AG) found no difference between normal weight and obesity, or no correlation with BMI. In contrast, studies measuring circulating arachidonoylethanolamine (AEA) found an increase or positive correlation with BMI. Two studies found a negative correlation between BMI and cannabinoid receptor type 1 (CB1) receptor availability in the brain. Only one study investigated the effect of pharmacological weight management on circulating endocannabinoid concentrations and found no effect on AEA concentrations. So far, six studies investigated potential changes in circulating endocannabinoids after bariatric surgery and reported conflicting results. Available evidence does not univocally support that circulating endocannabinoids are upregulated in individuals with obesity, which may be explained by variability across studies in several potential confounding factors (e.g. age and sex) as well as heterogeneity within the obesity population (e.g. BMI only vs. intra-abdominal adiposity). While several studies investigated the effect of lifestyle interventions on the circulating ECS, more studies are warranted that focus on pharmacologically and surgically induced weight loss. In addition, we identified several research needs which should be fulfilled to better understand the role of the ECS in obesity and its treatments.

Coffee, Alcohol, and Artificial Sweeteners Have Temporal Associations with Gastrointestinal Symptoms.

BACKGROUND: Various dietary strategies for managing irritable bowel syndrome (IBS) target mechanisms such as brain-gut interactions, osmotic actions, microbial gas production, and local immune activity. These pathophysiological mechanisms are diverse, making it unclear which foods trigger IBS symptoms for a substantial proportion of patients. AIM: To identify associations between foods and gastrointestinal symptoms. METHODS: From the mySymptoms smartphone app, we collected anonymized diaries of food intake and symptoms (abdominal pain, diarrhea, bloating, and gas). We selected diaries that were at least 3 weeks long. The diaries were analyzed for food-symptom associations using a proprietary algorithm. As the participants were anonymous, we conducted an app-wide user survey to identify IBS diagnoses according to Rome IV criteria. RESULTS: A total of 9,710 food symptom diaries that met the quality criteria were collected. Of the survey respondents, 70% had IBS according to Rome IV criteria. Generally, strong associations existed for caffeinated coffee (diarrhea, 1-2 h postprandial), alcoholic beverages (multiple symptoms, 4-72 h postprandial), and artificial sweeteners (multiple symptoms, 24-72 h postprandial). Histamine-rich food intake was associated with abdominal pain and diarrhea. Some associations are in line with existing literature, whilst the absence of an enriched FODMAP-symptom association contrasts with current knowledge. CONCLUSIONS: Coffee, alcohol, and artificial sweeteners were associated with GI symptoms in this large IBS-predominant sample. Symptom onset is often within 2 h postprandial, but some foods were associated with a delayed response, possibly an important consideration in implementing dietary recommendations. Clinical trials must test the causality of the demonstrated food-symptom associations.

Neural responses to oral administration of erythritol vs. sucrose and sucralose explain differences in subjective liking ratings.

INTRODUCTION: High sugar intake is associated with many chronic diseases. However, non-caloric sweeteners (NCSs) might fail to successfully replace sucrose due to the mismatch between their rewarding sweet taste and lack of caloric content. The natural NCS erythritol has been proposed as a sugar substitute due to its satiating properties despite being non-caloric. We aimed to compare brain responses to erythritol vs. sucrose and the artificial NCS sucralose in a priori taste, homeostatic, and reward brain regions of interest (ROIs). METHODS: We performed a within-subject, single-blind, counterbalanced fMRI study in 30 healthy men (mean ± SEM age:24.3 ± 0.8 years, BMI:22.3 ± 0.3 kg/m2). Before scanning, we individually matched the concentrations of both NCSs to the perceived sweetness intensity of a 10% sucrose solution. During scanning, participants received 1 mL sips of the individually titrated equisweet solutions of sucrose, erythritol, and sucralose, as well as water. After each sip, they rated subjective sweetness liking. RESULTS: Liking ratings were significantly higher for sucrose and sucralose vs. erythritol (both pHolm = 0.0037); water ratings were neutral. General Linear Model (GLM) analyses of brain blood oxygen level-depended (BOLD) responses at qFDR<0.05 showed no differences between any of the sweeteners in a priori ROIs, but distinct differences were found between the individual sweeteners and water. These results were confirmed by Bayesian GLM and machine learning-based models. However, several brain response patterns mediating the differences in liking ratings between the sweeteners were found in whole-brain multivariate mediation analyses. Both subjective and neural responses showed large inter-subject variability. CONCLUSION: We found lower liking ratings in response to oral administration of erythritol vs. sucrose and sucralose, but no differences in neural responses between any of the sweeteners in a priori ROIs. However, differences in liking ratings between erythritol vs. sucrose or sucralose are mediated by multiple whole-brain response patterns.

Psychological symptoms do not discriminate between reflux phenotypes along the organic-functional refractory GERD spectrum.

OBJECTIVE: Historically, psychological processes are associated with disorders at the functional end of the gastro-oesophageal reflux disease (GERD) spectrum. However, recent research suggests that psychological symptoms are relevant across the entire GERD spectrum. We aim to investigate whether psychological symptoms are associated with reflux phenotype (True GERD, Borderline GERD, reflux hypersensitivity, functional heartburn) along the GERD spectrum in a cohort of refractory reflux patients. DESIGN: Consecutive adult patients with refractory reflux symptoms underwent standard 24-hour pH-impedance monitoring and completed questionnaires assessing demographic, clinical and psychological information. Bayesian one-way analysis of variance assessed whether psychological variables differed across reflux phenotypes. Next, we applied multinomial and ordinal logistic regressions with clinical, demographic and psychological variables set as independent variables and reflux phenotype as the outcome variable. The complementary machine-learning approach entered all demographic, clinical and psychological variables into models, with reflux phenotype set nominally and ordinally. Cross-validated model performance was used to select the best model. RESULTS: 393 participants (mean (SD) age=48.5 (14.1); 60% female) were included. The Bayesian analyses found no difference in psychological variables across reflux phenotypes. Similarly, age, gender and proton pump inhibitor use were the only significant variables in the multinomial logistic regression and body mass index was significant in both regressions. Machine-learning analyses revealed poorly performing models with high misclassification rates (67-68%) in both models. CONCLUSION: Psychological symptoms do not differ between nor predict reflux phenotype membership in refractory reflux patients. Findings suggest that psychological symptoms are relevant across the spectrum of GERD, rather than specific to functional oesophageal disorders.

The Brain Activation-Based Sexual Image Classifier (BASIC): A Sensitive and Specific fMRI Activity Pattern for Sexual Image Processing.

Previous studies suggest there is a complex relationship between sexual and general affective stimulus processing, which varies across individuals and situations. We examined whether sexual and general affective processing can be distinguished at the brain level. In addition, we explored to what degree possible distinctions are generalizable across individuals and different types of sexual stimuli, and whether they are limited to the engagement of lower-level processes, such as the detection of visual features. Data on sexual images, nonsexual positive and negative images, and neutral images from Wehrum et al. (2013) (N = 100) were reanalyzed using multivariate support vector machine models to create the brain activation-based sexual image classifier (BASIC) model. This model was tested for sensitivity, specificity, and generalizability in cross-validation (N = 100) and an independent test cohort (N = 18; Kragel et al. 2019). The BASIC model showed highly accurate performance (94-100%) in classifying sexual versus neutral or nonsexual affective images in both datasets with forced choice tests. Virtual lesions and tests of individual large-scale networks (e.g., visual or attention networks) show that individual networks are neither necessary nor sufficient to classify sexual versus nonsexual stimulus processing. Thus, responses to sexual images are distributed across brain systems.

Illness Identity in Inflammatory Bowel Disease.

BACKGROUND: We examined the degree to which adults with inflammatory bowel disease (IBD) integrated their illness into their identity and linked illness identity to important patient-reported outcomes. METHODS: A total of 109 adults with IBD, aged 18 to 60 (Mage = 35.93; 77% women) completed questionnaires on the four illness identity dimensions (rejection, acceptance, engulfment, and enrichment), medication adherence, depressive symptoms, life satisfaction, health status, and health-related quality of life (HRQoL). The illness identity scores of adults with IBD were compared to existing data from adults with congenital heart disease (CHD), refractory epilepsy (RE), and multisystemic connective tissue disorders (MSDs) using multivariate analyses of covariance. In adults with IBD, associations between illness identity and patient-reported outcomes were examined through hierarchical regression analyses, controlling for sex, age, illness duration, diagnosis, self-reported flares, and co-existing illnesses. RESULTS: Adults with IBD scored higher on rejection and engulfment and lower on acceptance than adults with CHD, lower on rejection but higher on engulfment than adults with RE, and higher on engulfment and enrichment but lower on rejection than adults with MSDs. Higher engulfment scores were related to more depressive symptoms, lower life satisfaction, and a poorer health status and HRQoL. In contrast, higher enrichment scores were related to more life satisfaction and a better HRQoL. Rejection and acceptance were not uniquely related to any of the outcomes. CONCLUSIONS: Adults with IBD showed relatively high levels of engulfment. Substantial associations were observed between illness identity and patient-reported outcomes, with engulfment being the strongest, most consistent predictor.

End-Tidal CO2 in Patients with Panic Disorder, Stress-Related or Functional Syndromes, Versus Healthy Controls.

A dysregulated autonomic stress physiology is hypothesized to play an important role in the etiology and perpetuation of somatic symptoms that cannot be (fully) explained by an organic disease. The aim of this study was to focus on the role of the respiratory system. We examined end-tidal CO2 concentration (PetCO2) in healthy controls (n = 30), patients with panic disorder (n = 36), and patients with stress-related (overstrain; n = 35, burnout; n = 44) or functional syndromes [fibromyalgia (FM) and/or chronic fatigue syndrome (CFS); n = 36]. Participants went through a rest period and a respiratory challenge with recovery, whilst PetCO2 was continuously monitored by a capnograph. Taken together, our results suggest: (1) an overactive respiratory system to be a possible transdiagnostic underlying factor of overstrain, burnout, and panic disorder, and (2) the presence of a less active respiratory fight-flight response in the more chronic and severe functional syndromes (FM/CFS).

Personal identity, somatic symptoms, and symptom-related thoughts, feelings, and behaviors in adolescence: Examining between- and within-person associations and the role of depressive symptoms.

Recent literature highlights the complex relationship between personal identity and body-related pathology, yet there is a lack of integrative longitudinal research on the relationship between identity and somatic symptoms. The present study investigated the longitudinal associations between identity functioning and (psychological characteristics of) somatic symptoms, and examined the role of depressive symptoms in this relationship. A total of 599 community adolescents (Time 1: 41.3% female; Mage = 14.93, SD = 1.77, range = 12-18 years) participated in three annual assessments. Using cross-lagged panel models, a bidirectional relationship between identity and (psychological characteristics of) somatic symptoms, mediated by depressive symptoms, emerged at the between-person level; whereas only a unidirectional relationship from psychological characteristics of somatic symptoms to identity functioning, mediated by depressive symptoms, emerged at the within-person level. Identity and depressive symptoms were bidirectionally related at both levels. The present study suggests that adolescent identity development is closely related to somatic and emotional distress.

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

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

Cross-paradigm integration shows a common neural basis for aversive and appetitive conditioning.

Sharing imaging data and comparing them across different psychological tasks is becoming increasingly possible as the open science movement advances. Such cross-paradigm integration has the potential to identify commonalities in findings that neighboring areas of study thought to be paradigm-specific. However, even the integration of research from closely related paradigms, such as aversive and appetitive classical conditioning is rare - even though qualitative comparisons already hint at how similar the 'fear network' and 'reward network' may be. We aimed to validate these theories by taking a multivariate approach to assess commonalities across paradigms empirically. Specifically, we quantified the similarity of an aversive conditioning pattern derived from meta-analysis to appetitive conditioning fMRI data. We tested pattern expression in three independent appetitive conditioning studies with 29, 76 and 38 participants each. During fMRI scanning, participants in each cohorts performed an appetitive conditioning task in which a CS+ was repeatedly rewarded with money and a CS- was never rewarded. The aversive pattern was highly similar to appetitive CS+ > CS- contrast maps across samples and variations of the appetitive conditioning paradigms. Moreover, the pattern distinguished the CS+ from the CS- with above-chance accuracy in every sample. These findings provide robust empirical evidence for an underlying neural system common to appetitive and aversive learning. We believe that this approach provides a way to empirically integrate the steadily growing body of fMRI findings across paradigms.

Proton Pump Inhibitors Reduce Duodenal Eosinophilia, Mast Cells, and Permeability in Patients With Functional Dyspepsia.

BACKGROUND & AIMS: Despite the growing recognition of duodenal alterations in the pathophysiology of functional dyspepsia (FD), the effect and mechanism of proton pump inhibitors (PPIs) or first-line therapy remain unclear. We studied duodenal and systemic alterations in relation to PPI therapy in patients with FD and healthy volunteers (HVs). METHODS: We performed a prospective interventional study assessing symptoms (Patient Assessment of Gastrointestinal Symptom Severity Index), duodenal alterations, and systemic factors in patients with FD ("FD-starters") and HVs before and after PPI therapy (pantoprazole 40 mg once daily for 4 weeks). Duodenal mucosal eosinophils, mast cells and permeability were quantified. Luminal pH and bile salts were determined in duodenal aspirates. Procedures were also performed in PPI-refractory patients with FD ("FD-stoppers") before and 8 weeks after PPI withdrawal. Between- and within-group changes from baseline and associations with duodenal or systemic factors were analyzed using linear mixed models. RESULTS: The study was completed by 30 HV, 27 FD-starters, and 18 FD-stoppers. Symptoms and duodenal eosinophils, mast cells (all, P < .0001), and paracellular passage (P = .02) were significantly higher in FD-starters vs HVs and reduced with PPI therapy. Symptoms and duodenal immune cells also decreased in FD-stoppers off PPIs. In contrast, immune cells and permeability increased in HVs on PPIs. Dyspeptic symptoms correlated with eosinophils before and during PPI therapy, and increased eosinophils and permeability in HVs on PPIs were associated with changes in bile salts. CONCLUSIONS: We provide the first prospective evidence for eosinophil-reducing effects as a therapeutic mechanism of PPIs in FD, with differential effects in HVs pointing to a role of luminal changes. ClinicalTrials.gov, Number: NCT03545243.

Global prevalence and burden of meal-related abdominal pain.

BACKGROUND: Patients with disorders of gut-brain interaction (DGBI) report meal intake to be associated with symptoms. DGBI patients with meal-related symptoms may have more severe symptoms overall and worse health outcomes, but this subgroup has not been well characterized. We aimed to describe the global prevalence of meal-related abdominal pain and characterize this subgroup. METHODS: The data analyzed originated from the Internet survey component of the population-based Rome Foundation Global Epidemiology Study, completed in 26 countries (n = 54,127). Adult subjects were asked whether they had abdominal pain and how often this was meal-related. Respondents were categorized into "no," "occasional," and "frequent" meal-related abdominal pain groups based on 0%, 10-40%, and ≥50% of the pain episodes being meal-related, respectively. DGBI diagnoses, frequency of other GI symptoms, psychological distress, non-GI somatic symptoms, quality of life, and healthcare utilization were compared between groups. Mixed linear and ordinal regression was used to assess independent associations between psychological distress, non-GI somatic symptoms, quality of life, other GI symptoms, and meal-related abdominal pain. RESULTS: Overall, 51.9% of the respondents reported abdominal pain in the last 3 months, and 11.0% belonged to the group with frequent meal-related abdominal pain, which included more females and younger subjects. DGBI diagnoses were more common in subjects with frequent meal-related abdominal pain, and the frequency of several GI symptoms was associated with having more frequent meal-related abdominal pain. Having meal-related abdominal pain more frequently was also associated with more severe psychological distress, non-GI somatic symptoms, and a poorer quality of life. The group with frequent meal-related abdominal pain also more often consulted a doctor for bowel problems compared to the other groups of meal-related abdominal pain. CONCLUSION: Reporting frequent meal-related abdominal pain is common across the globe and associated with other GI and non-GI somatic symptoms, psychological distress, healthcare utilization, and a poorer quality of life. Individuals who frequently experience meal-related abdominal pain also more frequently fulfill the diagnostic criteria for DGBI. Assessing meal-related symptoms in all DGBI patients could be of major importance to improve and individualize symptom management.

Relationship Between Abuse History and Gastrointestinal and Extraintestinal Symptom Severity in Irritable Bowel Syndrome.

OBJECTIVE: This study aimed to investigate the associations between the different abuse types, and gastrointestinal (GI) and extraintestinal symptom severity in irritable bowel syndrome (IBS), and possible mediators of these relationships. METHODS: We assessed sexual and physical abuse in childhood and adulthood with the Drossman and Leserman abuse questionnaire, whereas GI and extraintestinal symptoms were assessed with the Gastrointestinal Symptom Rating Scale and the Symptom Check List-90 Revised. General linear models with bootstrapping tested the mediating role of depressive symptoms, anxiety symptoms, and GI-specific anxiety and rectal pain threshold. A path model analysis testing all relationships simultaneously was also performed. RESULTS: Among our 186 patients with IBS, an overall history of abuse (i.e., at least one type) was found in 37%. The effects of child and adult sexual abuse on GI symptom severity were fully mediated by GI-specific anxiety and rectal pain threshold (F = 21.540, R2 = 0.43, and F = 22.330, R2 = 0.44, respectively; p < .001 for both). The effect of adult sexual abuse and child physical abuse on extraintestinal symptom severity was fully mediated by GI-specific anxiety, depressive symptoms, and rectal pain threshold, whereas the effect of child sexual abuse was partially mediated (F = 14.992, R2 = 0.28; F = 15.065, R2 = 0.30; and F = 18.037, R2 = 0.32, respectively; p < .001 for all). When analyzed in a single path model, child sexual abuse and adult physical abuse only had a direct effect on extraintestinal symptom severity, whereas child physical abuse had an indirect effect through depressive symptoms. CONCLUSIONS: Abuse is associated with increased GI and extraintestinal symptom severity in IBS. These associations are mediated by levels of GI-specific anxiety, depressive symptoms, and rectal sensitivity.

The Role of D-allulose and Erythritol on the Activity of the Gut Sweet Taste Receptor and Gastrointestinal Satiation Hormone Release in Humans: A Randomized, Controlled Trial.

BACKGROUND: Glucose induces the release of gastrointestinal (GI) satiation hormones, such as glucagon-like peptide 1 (GLP-1) and peptide tyrosine tyrosine (PYY), in part via the activation of the gut sweet taste receptor (T1R2/T1R3). OBJECTIVES: The primary objective was to investigate the importance of T1R2/T1R3 for the release of cholecystokinin (CCK), GLP-1, and PYY in response to D-allulose and erythritol by assessing the effect of the T1R2/T1R3 antagonist lactisole on these responses and as secondary objectives to study the effect of the T1R2/T1R3 blockade on gastric emptying, appetite-related sensations, and GI symptoms. METHODS: In this randomized, controlled, double-blind, crossover study, 18 participants (5 men) with a mean ± SD BMI (in kg/m2) of 21.9 ± 1.7 and aged 24 ± 4 y received an intragastric administration of 25 g D-allulose, 50 g erythritol, or tap water, with or without 450 parts per million (ppm) lactisole, respectively, in 6 different sessions. 13C-sodium acetate was added to all solutions to determine gastric emptying. At fixed time intervals, blood and breath samples were collected, and appetite-related sensations and GI symptoms were assessed. Data were analyzed with linear mixed-model analysis. RESULTS: D-allulose and erythritol induced a significant release of CCK, GLP-1, and PYY compared with tap water (all PHolm < 0.0001, dz >1). Lactisole did not affect the D-allulose- and erythritol-induced release of CCK, GLP-1, and PYY (all PHolm > 0.1). Erythritol significantly delayed gastric emptying, increased fullness, and decreased prospective food consumption compared with tap water (PHolm = 0.0002, dz = -1.05; PHolm = 0.0190, dz = 0.69; and PHolm = 0.0442, dz = -0.62, respectively). CONCLUSIONS: D-allulose and erythritol stimulate the secretion of GI satiation hormones in humans. Lactisole had no effect on CCK, GLP-1, and PYY release, indicating that D-allulose- and erythritol-induced GI satiation hormone release is not mediated via T1R2/T1R3 in the gut.

The neurobiological reward system and binge eating: A critical systematic review of neuroimaging studies.

OBJECTIVE: Changes in reward processing are hypothesized to play a role in the onset and maintenance of binge eating (BE). However, despite an increasing number of studies investigating the neurobiological reward system in individuals who binge eat, no comprehensive systematic review exists on this topic. Therefore, this review has the following objectives: (1) identify structural and functional changes in the brain reward system, either during rest or while performing a task; and (2) formulate directions for future research. METHODS: A search was conducted of articles published until March 31, 2022. Neuroimaging studies were eligible if they wanted to study the reward system and included a group of individuals who binge eat together with a comparator group. Their results were summarized in a narrative synthesis. RESULTS: A total of 58 articles were included. At rest, individuals who binge eat displayed a lower striatal dopamine release, a change in the volume of the striatum, frontal cortex, and insula, as well as a lower frontostriatal connectivity. While performing a task, there was a higher activity of the brain reward system when anticipating or receiving food, more model-free reinforcement learning, and more habitual behavior. Most studies only included one patient group, used general reward-related measures, and did not evaluate the impact of comorbidities, illness duration, race, or sex. DISCUSSION: Confirming previous hypotheses, this review finds structural and functional changes in the neurobiological reward system in BE. Future studies should compare disorders, use measures that are specific to BE, and investigate the impact of confounding factors. PUBLIC SIGNIFICANCE STATEMENT: This systematic review finds that individuals who binge eat display structural and functional changes in the brain reward system. These changes could be related to a higher sensitivity to food, relying more on previous experiences when making decisions, and more habitual behavior. Future studies should use a task that is specific to binge eating, look across different patient groups, and investigate the impact of comorbidities, illness duration, race, and sex.

OBJETIVO: Se plantea la hipótesis de que los cambios en el procesamiento de la recompensa desempeñan un papel en el inicio y mantenimiento de los atracones (BE). Sin embargo, a pesar de un número creciente de estudios que investigan el sistema de recompensa neurobiológica en individuos que comen en atracones, no existe una revisión sistemática exhaustiva sobre este tema. Por lo tanto, esta revisión tiene los siguientes objetivos: (1) identificar cambios estructurales y funcionales en el sistema de recompensa cerebral, ya sea en reposo o mientras se realiza una tarea; (2) formular direcciones para futuras investigaciones. MÉTODOS: Se realizó una búsqueda de artículos publicados hasta el 31 de marzo de 2022. Los estudios de neuroimagen eran elegibles si querían estudiar el sistema de recompensa e incluían a un grupo de individuos que comían en atracón junto con un grupo de comparación. Sus resultados se resumieron en una síntesis narrativa. RESULTADOS: Se incluyeron un total de 58 artículos. En reposo, los individuos que comen en atracón mostraron una menor liberación de dopamina estriatal, un cambio en el volumen del cuerpo estriado, la corteza frontal y la ínsula, así como una menor conectividad frontostriatal. Al realizar una tarea, hubo una mayor actividad del sistema de recompensa cerebral al anticipar o recibir alimentos, más aprendizaje de refuerzo sin modelos y un comportamiento más habitual. La mayoría de los estudios sólo incluyeron un grupo de pacientes, utilizaron medidas generales relacionadas con la recompensa y no evaluaron el impacto de las comorbilidades, la duración de la enfermedad, la raza o el sexo. DISCUSIÓN: Confirmando hipótesis anteriores, esta revisión encuentra cambios estructurales y funcionales del sistema de recompensa neurobiológica en BE. Los estudios futuros deben comparar los trastornos, utilizar medidas que sean específicas para el comer en atracones e investigar el impacto de los factores de confusión.

Intragastric fructose administration interacts with emotional state in homeostatic and hedonic brain regions.

Background: Interoceptive properties of food may influence emotional state and its neural basis, as shown for fatty acids but remains unstudied for carbohydrates.Objectives: To study the effects of fructose and its interaction with sad emotion on brain activity in homeostatic and hedonic regions and investigate whether gut hormone responses can explain effects.Design: In 15 healthy subjects, brain activity for 40min after intragastric infusion of fructose (25g) or water was recorded using a cross-over pharmacological magnetic resonance imaging (phMRI) paradigm. Sad or neutral emotional states were induced by classical music and emotional facial expressions. Emotional state was assessed using the Self-Assessment Manikin. Blood samples were taken to assess gut hormone levels. Brain responses to fructose versus placebo, sad versus neutral emotion, and their interaction were analyzed over time in a single mask of a priori defined regions of interest at a voxel-level threshold of pFWEcorrected <0.05. Effects on emotion and hormones were tested using linear mixed models.Results: No main effects of fructose, emotion, or fructose-by-emotion interaction on emotional ratings were observed. Main effects of fructose, emotion and aninteraction effect were found on brain activity (medulla, midbrain, hypothalamus, basal ganglia, anterior insula, orbitofrontal cortex, anterior cingulate cortex and amygdala). An increase in circulating GLP-1 after fructose in neutral emotion was abolished during sad emotion (fructose-by-emotion-by-time, p=0.041). Ghrelin levels were higher in sad emotion (time-by-emotion, p=0.037).Conclusions: Emotional state interacts with brain and endocrine responses to intragastric infusion of 25 g of fructose, however such an effect was not found at behavioral level.Trial registration: ClinicalTrials.gov identifier: NCT02946983.

Erythritol and xylitol differentially impact brain networks involved in appetite regulation in healthy volunteers.

BACKGROUND: There is a growing consensus that sugar consumption should be reduced and the naturally occurring, low-calorie sweeteners xylitol and erythritol are gaining popularity as substitutes, but their effect on brain circuitry regulating appetite is unknown. AIM: The study's objective was to examine the effects of the two sweeteners on cerebral blood flow (rCBF) and resting functional connectivity in brain networks involved in appetite regulation, and test whether these effects are related to gut hormone release. METHODS: The study was performed as a randomized, double-blind, placebo-controlled, cross-over trial. Twenty volunteers received intragastric (ig) loads of 50g xylitol, 75g erythritol, 75g glucose dissolved in 300mL tap water or 300mL tap water. Resting perfusion and blood oxygenation level-dependent data were acquired to assess rCBF and functional connectivity. Blood samples were collected for determination of CCK, PYY, insulin and glucose. RESULTS: We found: (i) xylitol, but not erythritol, increased rCBF in the hypothalamus, whereas glucose had the opposite effect; (ii) graph analysis of resting functional connectivity revealed a complex pattern of similarities and differences in brain network properties following xylitol, erythritol, and glucose; (iii) erythritol and xylitol induced a rise in CCK and PYY, (iv) erythritol had no and xylitol only minimal effects on glucose and insulin. CONCLUSION: Xylitol and erythritol have a unique combination of properties: no calories, virtually no effect on glucose and insulin while promoting the release of gut hormones, and impacting appetite-regulating neurocircuitry consisting of both similarities and differences with glucose.

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

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: 1) the site of administration: intragastrically (IG) or intraduodenally (ID), 2) the bitter tastant itself, quinine hydrochloride (QHCl) or denatonium benzoate (DB), and 3) 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.NEW & NOTEWORTHY 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."