DOMINO trial post hoc analysis: evaluation of the diet effects on symptoms in IBS subtypes.

Background: Irritable bowel syndrome (IBS) is a disorder of gut-brain interaction characterized by recurrent abdominal pain related to defecation and/or associated to a change in bowel habits. According to the stool type, four different IBS subtypes can be recognized, constipation predominant (IBS-C), diarrhea predominant (IBS-D), mixed (IBS-M), and undefined (IBS-U). Patients report that their IBS symptoms are exacerbated by food. Thus, it is important to find a nutritional approach that could be effective in reducing IBS symptoms. Objective: The present work is a post hoc analysis of the previously published DOMINO trial. It aimed to evaluate the effects of a self-instructed FODMAP-lowering diet smartphone application on symptoms and psychosocial aspects in primary care IBS stratifying the results for each IBS subtypes. Design: Post hoc analysis. Methods: Two hundred twenty-two primary care IBS patients followed a FODMAP-lowering diet for 8 weeks with the support of a smartphone application. Two follow-up visits were scheduled after 16 and 24 weeks. IBS-Symptoms Severity Score (IBS-SSS), quality of life (QoL), and adherence and dietary satisfaction were evaluated. Results: After 8 weeks, IBS-SSS improved in all IBS subtypes (p < 0.0001). Physician Health Questiionnaire (PHQ-15) improved only in IBS-D (p = 0.0006), whereas QoL improved both in IBS-D (p = 0.01) and IBS-M (p = 0.005). Conclusion: This post hoc analysis showed that the app is useful in all IBS subtypes; thus, it could be used as an effective tool by both general practitioners and patients to manage symptoms in primary care. Trial registration: Ethical Commission University Hospital of Leuven reference number: S59482. Clinicaltrial.gov reference number: NCT04270487.

What is already known about this subject? The low FODMAP (fermentable oligo-, di-, and monosaccharides and polyols) diet has shown efficacy for controlling IBS (irritable bowel syndrome) symptoms in small controlled trials in tertiary care patients. As this approach requires several visits with an experienced dietitian, it seems less suitable for primary care. What are the new findings? The benefit of the FODMAP lowering app was already present at 4 weeks and persisted during follow-up until 24 weeks. How might it impact on clinical practice in the foreseeable future? Given its superiority to standard first-line pharmacotherapy, and its ease of use, a FODMAP lowering app has the potential to become the preferred first-line treatment for primary care IBS.

A neuronal circuit driven by GLP-1 in the olfactory bulb regulates insulin secretion.

Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and holds significant pharmacological potential. Nevertheless, the regulation of energy homeostasis by centrally-produced GLP-1 remains partially understood. Preproglucagon cells, known to release GLP-1, are found in the olfactory bulb (OB). We show that activating GLP-1 receptors (GLP-1R) in the OB stimulates insulin secretion in response to oral glucose in lean and diet-induced obese male mice. This is associated with reduced noradrenaline content in the pancreas and blocked by an α2-adrenergic receptor agonist, implicating functional involvement of the sympathetic nervous system (SNS). Inhibiting GABAA receptors in the paraventricular nucleus of the hypothalamus (PVN), the control centre of the SNS, abolishes the enhancing effect on insulin secretion induced by OB GLP-1R. Therefore, OB GLP-1-dependent regulation of insulin secretion relies on a relay within the PVN. This study provides evidence that OB GLP-1 signalling engages a top-down neural mechanism to control insulin secretion via the SNS.

PHYSIOLOGICAL AND PSYCHOLOGICAL FACTORS CONTRIBUTE TO REAL-TIME ESOPHAGEAL SYMPTOM REPORTING IN REFRACTORY REFLUX PATIENTS.

BACKGROUND: Real-time symptom reporting during ambulatory reflux monitoring plays a key role in the evaluation of esophageal symptoms, although the underlying processes are poorly understood. We aim to identify the psychological and physiological factors associated with real-time reflux symptom reporting and symptom-reflux association parameters. METHODS: Adult patients with refractory reflux symptoms completed psychosocial questionnaires and standard 24-hour pH-impedance monitoring. A Hurdle-Poisson model evaluated the association between psychological and physiological (proton-pump inhibitor (PPI) use, total number of reflux episodes) variables on real-time symptom frequency, assessed via a button press within two minutes of experiencing a symptom. Logistic regression assessed the variables associated with symptom-association probability (SAP) and symptom index (SI) classification (positive/negative). Complementary machine learning analyses with 8-fold cross-validation further identified variables associated with symptom frequency and sought to optimize SAP classification performance. FINDINGS: Both psychological (pain-related anxiety, depressive symptoms, trait anxiety) and physiological (total number of reflux episodes, off PPI during testing) variables were associated with symptom frequency. The total number of reflux episodes and being studied off PPI were significantly associated with a higher likelihood of being classified as SAP or SI positive. The best-performing model in the machine-learning analysis demonstrated a poor job of correctly classifying patients as SAP positive/negative (misclassification rate=41.4%). INTERPRETATION: Real-time reflux symptom reporting is a multifactorial process, with both psychological and physiological processes contributing to different aspects of the reflux disease experience. Findings build on questionnaire-based research to underscore the importance of including psychological processes in our understanding of esophageal symptom reporting.

The combination of L-menthol and caraway oil does not affect gastric function but increases hunger in healthy subjects.

BACKGROUND: The heterogeneous character of functional gastrointestinal disorders, recently renamed into disorders of gut-brain interaction, makes finding effective treatment options challenging. Compared to synthetic drugs, phytotherapy can have broader pharmacological effects and is often better tolerated. This study aimed to investigate the effect of peppermint oil and caraway oil (POCO) on gastric function and symptom levels in 32 healthy subjects in a single-blinded, placebo-controlled, randomized, parallel design. METHODS: Gastric emptying rate was assessed using a 13C-breath test. Intragastric pressure was measured using high-resolution manometry in fasted state and during intragastric infusion of a nutrient drink (350 mL or until full satiation). GI symptoms were rated on a 100 mm VAS. Data were analyzed using linear mixed models. KEY RESULTS: POCO had no effect on intragastric pressure in fasted or fed state (p > 0.08 for all). No significant differences in gastric emptying rate were observed (p = 0.54). In the fasted state, a stronger increase in hunger and decrease in satiety were observed following POCO (p = 0.016 and p = 0.008, respectively). No differences in hunger and satiety were observed in the fed state (p > 0.31 for all). POCO induced less epigastric burning, bloating, and fullness (p < 0.05 for all). CONCLUSIONS: Acute POCO administration did not affect gastric function in healthy subjects, but increased fasted hunger ratings. The effects of POCO on gastric function and hunger sensations in patients with disorders of gut-brain interaction, and the contribution to symptom improvement, needs to be elucidated in future studies.

Pain is a cardinal symptom cutting across Rome IV anatomical categories in disorders of gut-brain interaction: A network-based approach.

INTRODUCTION: Disorders of gut-brain interaction (DGBI) are symptom-based disorders categorized by anatomic location but have high overlap and heterogeneity. Viewing DGBI symptoms on a spectrum (i.e. dimensionally) rather than categorically may better inform interventions to accommodate complex clinical presentations. We aimed to evaluate symptom networks to identify how DGBI symptoms interact. METHODS: We used the Rome IV Diagnostic Questionnaire continuously/ordinally scored items collected from the Rome Foundation Global Epidemiology Study. We excluded participants who reported ≥1 organic/structural gastrointestinal disorder(s). We sought to (1) identify core symptoms in the DGBI symptom networks, (2) identify bridge pathways between Rome IV diagnostic categories (esophageal, bowel, gastroduodenal, anorectal), and (3) explore how symptoms group together into communities. RESULTS: Of 54,127 adults, 20,229 met criteria for at least one DGBI (age mean = 42.2 ± 15.5; 57% female). General abdominal pain and epigastric pain were the core symptoms in the DGBI symptom network (i.e., had the strongest connections to other symptoms). Pain symptoms emerged as bridge pathways across existing DGBI diagnostic anatomic location (i.e., abdominal pain connected to chest pain, epigastric pain, rectal pain). Without a priori category definitions, exploratory network community analysis showed that symptoms grouped together into "pain," "gastroduodenal," and "constipation," rather than into groups by anatomic location. CONCLUSION: Our findings suggest pain symptoms are central and serve as a key connection to other symptoms, crosscutting anatomic location. Future longitudinal research is needed to test symptom network relations longitudinally and investigate whether targeting pain symptoms (rather than anatomic- or disorder-specific symptoms) has clinical impact.

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.

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.

No harmful effect of propranolol administered prior to fear memory extinction in rats and humans.

Exposure therapy is an evidence-based treatment option for anxiety-related disorders. Many patients also take medication that could, in principle, affect exposure therapy efficacy. Clinical and laboratory evidence indeed suggests that benzodiazepines may have detrimental effects. Large clinical trials with propranolol, a common beta-blocker, are currently lacking, but several preclinical studies do indicate impaired establishment of safety memories. Here, we investigated the effects of propranolol given prior to extinction training in 9 rat studies (N = 215) and one human study (N = 72). A Bayesian meta-analysis of our rat studies provided strong evidence against propranolol-induced extinction memory impairment during a drug-free test, and the human study found no significant difference with placebo. Two of the rat studies actually suggested a small beneficial effect of propranolol. Lastly, two rat studies with a benzodiazepine (midazolam) group provided some evidence for a harmful effect on extinction memory, i.e., impaired extinction retention. In conclusion, our midazolam findings are in line with prior literature (i.e., an extinction retention impairment), but this is not the case for the 10 studies with propranolol. Our data thus support caution regarding the use of benzodiazepines during exposure therapy, but argue against a harmful effect of propranolol on extinction learning.

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.

The Leuven Prolonged Acute Stress Test (L-PAST): A novel paradigm to induce a subjective and glucocorticoid stress response for at least ninety minutes.

Laboratory stress tests typically administer stress acutely, ranging from 3 to 15 minutes. However, everyday stressors usually last longer than ten minutes (e.g., examination stressors, work stressors, and social stressors. Moreover, in some studies, it may be relevant to induce stress for a longer period to affect certain psychological or physiological parameters. To this end, we developed a novel stress test that intends to induce psychosocial stress for 90 minutes. The Leuven Prolonged Acute Stress Test (L-PAST) combines physical (hand immersion in cold water), cognitive (mental arithmetic), and psychosocial (social evaluation and feelings of failure) stress elements of two well-known laboratory stress tests, the Maastricht Acute Stress Test (MAST) and the Montreal Imaging Stress Test (MIST). Fifty healthy women were subjected to both the L-PAST and a sham (control) test in a randomized and counterbalanced manner. The stress response was determined by salivary cortisol measurements and assessment of subjective stress ratings at regular time points during the time preceding the stress period (5 min), the stress period (90 min), and the recovery period (35 min). Cognitive reactivity to failure and subjective pain levels were also assessed at various time points. The childhood trauma questionnaire (CTQ) and the perceived stress scale (PSS) were administered prior to the testing phase. As expected, linear mixed models revealed that the stress response was significantly higher during the L-PAST as indicated by a significant time point by condition interaction effect for both the cortisol response (F(10,450)=12.21, p < 0.0001, ηp2=0.11) and the subjective stress response (F(13,637)=13.98, p < 0.0001, ηp2 = 0.12). Moreover, there was a significant time point by condition interaction effect for cognitive reactivity to failure (F(13,637) = 7.97, p < 0.0001, ηp2 = 0.07) and subjective pain (F(13,637) = 38.52, p < 0.0001, ηp2 = 0.27), indicating that the levels were higher during the L-PAST at most stress induction time points. Lastly, higher CTQ scores were associated with higher subjective pain levels during the L-PAST (F(1,44)=6.05, p = 0.02). Collectively, our results confirm the efficacy of the L-PAST in inducing a prolonged subjective as well as cortisol stress response.

Do we perceive sensations inside and outside of our body differently? Perceptual, emotional, and behavioral differences between visceral and somatic sensation, discomfort, and pain.

BACKGROUND: Experimental research evaluating differences between the visceral and somatic stimulation is limited to pain and typically uses different induction methods for visceral and somatic stimulation (e.g., rectal balloon distention vs. tactile hand stimulation). Our study aimed to compare differences in response time, intensity, unpleasantness, and threat between identical electrical visceral and somatic stimulations at both painful and non-painful perceptual thresholds. METHODS: Electrical stimulation was applied to the wrist and distal esophagus in 20 healthy participants. A double pseudorandom staircase determined perceptual thresholds of Sensation, Discomfort, and Pain for the somatic and visceral stimulations, separately. Stimulus reaction time (ms, via button press), and intensity, unpleasantness, and threat ratings were recorded after each stimulus. General linear mixed models compared differences in the four outcomes by stimulation type, threshold, and the stimulation type-by-threshold interaction. Sigmoidal maximum effect models evaluated differences in outcomes across all delivered stimulation intensities. KEY RESULTS: Overall, visceral stimulations were perceived as more intense, threatening, and unpleasant compared to somatic stimulations, but participants responded faster to somatic stimulations. There was no significant interaction effect, but planned contrasts demonstrated differences at individual thresholds. Across all delivered intensities, higher intensity stimulations were needed to reach the half-maximum effect of self-reported intensity, unpleasantness, and threat ratings in the visceral domain. CONCLUSIONS AND INFERENCES: Differences exist between modalities for both non-painful and painful sensations. These findings may have implications for translating paradigms and behavioral treatments from the somatic domain to the visceral domain, though future research in larger clinical samples is needed.

Predictors of symptom trajectory in newly diagnosed ulcerative colitis: a 3-year follow-up cohort study.

BACKGROUND AND AIMS: Psychological symptoms are associated with poorer ulcerative colitis (UC)-related outcomes. However, the majority of research is cross-sectional. We aimed to identify subgroups based on the longitudinal evolution of GI symptom levels and health-related quality of life (HRQoL), and to disentangle the directionality of effects between GI symptom levels and psychological distress. METHODS: Self-reported GI symptom severity, HRQoL, inflammatory biomarkers and psychological distress were assessed in 98 newly diagnosed UC patients at disease onset and yearly for 3 consecutive years. Latent class growth analysis was used to determine subgroups based on longitudinal trajectories of symptom severity and HRQoL, and baseline predictors of trajectory group membership were determined. Cross-lagged structural equation models were used to disentangle temporal relationships between psychological functioning and symptom severity. RESULTS: Patients with higher initial psychological distress had increased probability of maintaining higher levels of diarrhea and abdominal pain. Conversely, patients with lower initial levels of diarrhea and abdominal pain had higher chances of maintaining lower levels of psychological distress. Higher levels of C-reactive protein at baseline predicted greater improvements in mental health after anti-inflammatory treatment. Reductions in diarrhea and abdominal pain preceded reductions in psychological symptoms over time. CONCLUSIONS: Baseline psychological distress is predictive of increased GI symptom severity and reduced mental HRQoL over time, suggesting early assessment of psychological symptoms may identify patients who may have worse disease trajectories. Abdominal pain predicted increased psychological distress, but not the other way around. Intervening on abdominal pain may help prevent or reduce future psychological distress.

Colonic butyrate administration modulates fear memory but not the acute stress response in men: A randomized, triple-blind, placebo-controlled trial.

Short-chain fatty acids (SCFAs) are produced in the colon following bacterial fermentation of dietary fiber and are important microbiota-gut-brain messengers. However, their mechanistic role in modulating psychobiological processes that underlie the development of stress- and anxiety-related disorders is scarcely studied in humans. We have previously shown that colonic administration of a SCFA mixture (acetate, propionate, butyrate) lowers the cortisol response to stress in healthy participants, but does not impact fear conditioning and extinction. To disentangle the effects of the three main SCFAs, we examined whether butyrate alone would similarly modulate these psychobiological responses in a randomized, triple-blind, placebo-controlled intervention study in 71 healthy male participants (Mage = 25.2, MBMI = 22.7 [n = 35 butyrate group, n = 36 placebo group]). Colon-delivery capsules with pH-dependent coating were used to administer 5.28 g of butyrate or placebo daily for one week. Butyrate administration significantly increased serum butyrate concentrations without modulating serum acetate or propionate, nor fecal SCFAs. Butyrate administration also significantly modulated fear memory at the subjective but not physiological levels. Contrary to expectations, no changes in subjective nor neuroendocrine responses to acute stress were evident between the treatment groups from pre- to post-intervention. We conclude that colonic butyrate administration alone is not sufficient to modulate psychobiological stress responses, unlike administration of a SCFA mixture. The influence of colonic and systemic butyrate on fear memory and the persistence of fear extinction should be further systematically investigated in future studies.

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.

Psychosocial stress-induced intestinal permeability in healthy humans: What is the evidence?

An impaired intestinal barrier function can be detrimental to the host as it may allow the translocation of luminal antigens and toxins into the subepithelial tissue and bloodstream. In turn, this may cause local and systemic immune responses and lead to the development of pathologies. In vitro and animal studies strongly suggest that psychosocial stress is one of the factors that can increase intestinal permeability via mast-cell dependent mechanisms. Remarkably, studies have not been able to yield unequivocal evidence that such relation between stress and intestinal permeability also exists in (healthy) humans. In the current Review, we discuss the mechanisms that are involved in stress-induced intestinal permeability changes and postulate factors that influence these alterations and that may explain the translational difficulties from in vitro and animal to human studies. As human research differs highly from animal research in the extent to which stress can be applied and intestinal permeability can be measured, it remains difficult to draw conclusions about the presence of a relation between stress and intestinal permeability in (healthy) humans. Future studies should bear in mind these difficulties, and more research into in vivo methods to assess intestinal permeability are warranted.

The role of short-chain fatty acids (SCFAs) in regulating stress responses, eating behavior, and nutritional state in anorexia nervosa: protocol for a randomized controlled trial.

OBJECTIVE: This protocol proposes investigating the effects of short-chain fatty acids (SCFAs)-namely acetate, propionate, and butyrate-as mediators of microbiota-gut-brain interactions on the acute stress response, eating behavior, and nutritional state in malnourished patients with anorexia nervosa (AN). SCFAs are produced by bacterial fermentation of dietary fiber in the gut and have recently been proposed as crucial mediators of the gut microbiota's effects on the host. Emerging evidence suggests that SCFAs impact human psychobiology through endocrine, neural, and immune pathways and may regulate stress responses and eating behavior. METHOD: We will conduct a randomized, triple-blind, placebo-controlled trial in 92 patients with AN. Patients will receive either a placebo or a mixture of SCFAs (acetate propionate, butyrate) using pH-dependent colon-delivery capsules for six weeks. This clinical trial is an add-on to the standard inpatient psychotherapeutic program focusing on nutritional rehabilitation. HYPOTHESES: We hypothesize that colonic SCFAs delivery will modulate neuroendocrine, cardiovascular, and subjective responses to an acute laboratory psychosocial stress task. As secondary outcome measures, we will assess alterations in restrictive eating behavior and nutritional status, as reflected by changes in body mass index. Additionally, we will explore changes in microbiota composition, gastrointestinal symptoms, eating disorder psychopathology, and related comorbidities. DISCUSSION: The findings of this study would enhance our understanding of how gut microbiota-affiliated metabolites, particularly SCFAs, impact the stress response and eating behavior of individuals with AN. It has the potential to provide essential insights into the complex interplay between the gut, stress system, and eating behavior and facilitate new therapeutic targets for stress-related psychiatric disorders. This protocol is prospectively registered with ClinicalTrials.gov, with trial registration number NCT06064201.

Brief cognitive-behavioral treatment for avoidant/restrictive food intake disorder in the context of functional dyspepsia: Study protocol for a feasibility randomized controlled trial.

BACKGROUND: Avoidant/restrictive food intake disorder (ARFID) symptoms are common (up to 40%) among adults with functional dyspepsia (FD), a disorder of gut-brain interaction characterized by early satiation, post-prandial fullness, epigastric pain, and/or epigastric burning. Using an 8-session exposure-based cognitive-behavioral treatment (CBT) for adults with FD + ARFID compared to usual care (UC) alone, we aim to: (1) determine feasibility, (2) evaluate change in clinical outcomes in, and (3) explore possible mechanisms of action. METHODS: We will randomize adults with FD who meet criteria for ARFID with ≥5% weight loss (N = 50) in a 1:1 ratio to CBT (with continued UC) or to UC alone. A priori primary benchmarks will be: ≥75% eligible participants enroll; ≥75% participants complete assessments; ≥70% participants attend 6/8 sessions; ≥70% of sessions have all content delivered; ≥70% participants rate Client Satisfaction Questionnaire scores above scale midpoint. We will also examine the size of changes in FD symptom severity and related quality of life within and between groups, and explore possible mechanisms of action. CONCLUSIONS: Findings from this trial will inform next steps with treatment development or evaluation-either for further refinement or for next-step efficacy testing with a fully-powered clinical trial.

Brain mediators of negative affect-induced physical symptom reporting in patients with functional somatic syndromes.

Functional somatic syndromes (FSS) include fibromyalgia, irritable bowel syndrome (IBS), and others. In FSS patients, merely viewing negative affective pictures can elicit increased physical symptoms. Our aim was to investigate the neural mechanisms underlying such negative affect-induced physical symptoms in FSS patients. Thirty patients with fibromyalgia and/or IBS and 30 healthy controls (all women) watched neutral, positive and negative affective picture blocks during functional MRI scanning and rated negative affect and physical symptoms after every block. We compared brain-wide activation during negative versus neutral picture viewing in FSS patients versus controls using robust general linear model analysis. Further, we compared neurologic pain signature (NPS), stimulus intensity-independent pain signature (SIIPS) and picture-induced negative emotion signature (PINES) responses to the negative versus neutral affect contrast and investigated whether they mediated between-group differences in affective picture-induced physical symptom reporting. More physical symptoms were reported after viewing negative compared to neutral pictures, and this effect was larger in patients than controls (p = 0.025). Accordingly, patients showed stronger activation in somatosensory regions during negative versus neutral picture viewing. NPS, but not SIIPS nor PINES, responses were higher in patients than controls during negative versus neutral pictures (p = 0.026). These differential NPS responses partially mediated between-group differences in physical symptoms. In conclusion, picture-induced negative affect elicits physical symptoms in FSS patients as a result of activation of somatosensory and nociceptive brain patterns, supporting the idea that affect-driven alterations in processing of somatic signals is a critical mechanism underlying FSS.

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.