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Background: This study compared the effects of ondansetron and placebo in patients with diabetes mellitus and symptoms of dyspepsia (diabetic gastroenteropathy [DGE])., Methods: We performed a randomized, double-blinded, placebo-controlled study of ondansetron tablets (8 mg) three times daily for 4 weeks in DGE patients. Symptoms were assessed with the Gastroparesis Cardinal Symptom Index daily diaries. Gastric emptying (GE) of solids (scintigraphy) and duodenal lipid infusions (300 kcal over 2 h) were each assessed twice, with placebo and ondansetron. Drug effects on GE, symptoms during the GE study and during lipid infusion, and daily symptoms were analyzed., Key Results: Of 41 patients, 37 completed both GE studies and one completed 1; 31 completed both lipid infusions and four only placebo; and all 35 randomized patients completed 4 weeks of treatment. Compared to placebo, ondansetron reduced the severity of fullness (p = 0.02) and belching (p = 0.049) during lipid infusion but did not affect GE T 1/2 . Both ondansetron and placebo improved daily symptoms versus the baseline period (p < 0.05), but the differences were not significant. In the analysis of covariance of daily symptoms during the treatment period, the interaction term between treatment and the acute effect of ondansetron on symptoms during lipid challenge was significant (p = .024)., Conclusions & Inferences: Ondansetron significantly reduced fullness during enteral lipid infusion in patients with DGE. Overall, ondansetron did not improve daily symptoms versus placebo. But patients in whom ondansetron improved symptoms during enteral lipid challenge were perhaps more likely to experience symptom relief during daily treatment., (© 2024 John Wiley & Sons Ltd.)

Amomum tsaoko (AT) is commonly used in clinical practice to treat abdominal distension and pain. It is also a seasoning for cooking, with the functions of appetizing, invigorating the spleen, and being digestive-promoting. Amomum tsaoko (AT) has three adulterants, Amomum paratsaoko (AP), Amomum koenigii (AK), and Alpinia katsumadai Hayata, because of the confusion in historical classics regarding recorded sources as well as the near geographic distribution and fruit morphological similarities. In this study, we established a functional dyspepsia (FD) rat model and then treated it with the corresponding medicinal solutions AT, AP, AK, and AKH. The gastric emptying rate, intestinal propulsion rate, serum biochemical indicators, histopathological changes, and fecal metabolism were measured. The efficacy and mechanism of AT, AP, AK, and AKH in the treatment of FD were compared. Fecal metabolomics revealed that 20 potential biomarkers were involved in seven significant metabolic pathways in FD rats. These pathways include ubiquinone and other terpenoid-quinone biosynthesis, glycerophospholipid metabolism, tyrosine metabolism, primary bile acid biosynthesis, purine metabolism, folate biosynthesis, and amino sugar and nucleotide sugar metabolism. AP regulates 6 metabolic pathways, 5 metabolic pathways affected by AT, 4 metabolic pathways affected by AK, and 2 metabolic pathways affected by AKH.The above results suggest that the different effects of AT, AP, AK, and AKH on FD rats may be due to their different regulatory effects on the metabolome., Competing Interests: Declaration of Competing Interest We declare that the manuscript has been approved by all the authors who have no conflict of interest at submission. It has not been previously published in any journal., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: To evaluate gastric emptying (GE) and the glycaemic response to a 75-g oral glucose load in newly diagnosed, treatment-naïve Han Chinese with type 2 diabetes (T2D) before insulin pump therapy, after 4 weeks of insulin pump therapy, and 12-15 months after insulin pump therapy., Materials and Methods: Twenty participants with T2D (baseline glycated haemoglobin [± SD] 10.7% [± 1.2%] 93 [± 10] mmol/mol) ingested a 75-g glucose drink containing 150 mg 13 C-acetate, to determine the gastric half-emptying time, and underwent assessment of plasma glucose and serum insulin, C-peptide and glucagon-like peptide-1 (GLP-1) over 180 min before and after 4 weeks of insulin pump therapy (discontinued for 48 h before re-assessment). Data were compared to those in 19 healthy participants matched for sex and age. After 12-15 months, GE was re-measured in 14 of the T2D participants., Results: At baseline, participants with T2D exhibited substantially augmented fasting and post-glucose glycaemia, diminished insulin secretion, and more rapid GE (p < 0.05 each), but comparable GLP-1, compared to healthy participants. Following insulin pump therapy, insulin secretion increased, GLP-1 secretion was attenuated, fasting and post-glucose glycaemia were lower, and GE was slowed (p < 0.05 each). The slowing of GE in T2D participants was sustained over 12-15 months of follow-up., Conclusions: In newly diagnosed Han Chinese with T2D, GE is often accelerated despite poor glycaemic control and is slowed by short-term insulin pump therapy. The effect on GE is maintained for at least 12 months., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Purpose: The traditional Chinese herbal medicine Suaeda salsa (L.) Pall (S. salsa) with a digesting food effect was taken as the research object, and its chemical composition and action mechanism were explored., Methods: The chemical constituents of S. salsa were isolated and purified by column chromatography, and their structures were characterized by nuclear magnetic resonance. The food accumulation model in mice was established, and the changes of the aqueous extract of S. salsa in gastric emptying and intestinal propulsion rate, colonic tissue lesions, serum brain-gut peptide hormone, colonic tissue protein expression, and gut microbiota structure were compared., Results: Ten compounds were isolated from S. salsa named as naringenin (1), hesperetin (2), baicalein (3), luteolin (4), isorhamnetin (5), taxifolin (6), isorhamnetin-3-O-β-D-glucoside (7), luteolin-3'-D-glucuronide (8), luteolin-7-O-β-D-glucuronide (9), and quercetin-3-O-β-D-glucuronide (10), respectively. The aqueous extract of S. salsa can improve the pathological changes of the mice colon and intestinal peristalsis by increasing the rate of gastric emptying and intestinal propulsion. By adjusting the levels of 5-HT, CCK, NT, SS, VIP, GT-17, CHE, MTL, and ghrelin, it can upregulate the levels of c-kit, SCF, and GHRL protein, and restore the imbalanced structure of gut microbiota, further achieve the purpose of treating the syndrome of indigestion. The effect is better with the increase of dose., Conclusion: S. salsa has a certain therapeutic effect on mice with the syndrome of indigestion. From the perspective of "brain-gut-gut microbiota", the mechanism of digestion and accumulation of S. salsa was discussed for the first time, which provided an experimental basis for further exploring the material basis of S. salsa., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Gastric emptying of a glucose drink was measured in people with type 2 diabetes given lixisenatide (20 μg/day or placebo) for 8 weeks. Intragastric retention at 240 min (2 (0-11)% vs 48 (3-97)%; P < 0.0001) was much greater with lixisenatide than placebo. Accordingly, lixisenatide may delay liquid gastric emptying markedly., Competing Interests: Declaration of competing interest This manuscript represents a secondary analysis of our published randomised clinical trial (RCT) evaluating the effect of chronic (8 week) treatment with the short-acting glucagon-like peptide-1 (GLP-1) receptor agonist, lixisenatide on gastric emptying, using the gold standard technique, scintigraphy, and glucose metabolism in people with type 2 diabetes (Rayner et al. Diabetes Care 2020;43:1813–1821). An erratum of the original paper was subsequently published (Rayner et al. Diabetes Care 2021;44:297) correcting some minor errors unrelated to this submission., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are effective in diabetes and obesity, reducing hyperglycemia by increasing insulin release and delaying gastric emptying. However, they can cause gastroparesis, raising concerns about aspiration during procedures. Recent guidelines advise discontinuing GLP-1 RA before surgery to reduce the risk of pulmonary aspiration., Aim: To evaluate the effect of GLP-1 RAs on gastric residual contents during endoscopic procedures., Methods: A retrospective chart review at BronxCare Health System, New York, from January 2019 to October 2023, assessed gastric residue and aspiration in GLP-1 RA patients undergoing endoscopic procedures. Two groups were compared based on dietary status before the procedure. Data included demographics, symptoms of gastroparesis, opiate use, hemoglobin A1c, GLP-1 agonist indication, endoscopic details, and aspiration occurrence. IBM SPSS was used for analysis, calculating means, standard deviations, and applying Pearson's chi-square and t-tests for associations, with P < 0.05 as being significant., Results: During the study, 306 patients were included, with 41.2% on a clear liquid/low residue diet and 58.8% on a regular diet before endoscopy. Most patients (63.1%) were male, with a mean age of 60 ± 12 years. The majority (85.6%) were on GLP-1 RAs for diabetes, and 10.1% reported digestive symptoms before endoscopy. Among those on a clear liquid diet, 1.5% had residual food at endoscopy compared to 10% on a regular diet, which was statistically significant ( P = 0.03). Out of 31 patients with digestive symptoms, 13% had residual food, all from the regular diet group ( P = 0.130). No complications were reported during or after the procedures., Conclusion: The study reflects a significant rise in GLP-1 RA use for diabetes and obesity. A 24-hour liquid diet seems safe for endoscopic procedures without aspiration. Patients with upper gastrointestinal symptoms might have a higher residual food risk, though not statistically significant. Further research is needed to assess risks based on diabetes duration, gastroparesis, and GLP-1 RA dosing, aiming to minimize interruptions in therapy during procedures., Competing Interests: Conflict-of-interest statement: We have no financial relationships to disclose., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

The emptying rate of specific nutrients in enteral formulas is poorly understood, despite the importance of controlling the emptying rate in tube-fed patients. Because of their viscosity, thickened formulas are widely used to avoid gastric reflux and reduce the burden on caregivers. This study examined how thickeners in enteral formulas affected the gastric emptying rates of proteins and carbohydrates. A semi-dynamic gastric model was used to prepare and digest test enteral formulas that contained either no thickeners or agar (0.2%). The amounts of protein and carbohydrates in each emptied aliquot were determined, and the emptying rate was calculated. We found that agar accelerated protein emptying, and an exploratory experiment with agar (0.5%) suggested the possibility of concentration dependence. Additionally, experiments using gellan gum (0.08%), guar gum (0.2%), or carrageenan (0.08%, 0.2%) suggested that protein emptying could vary depending on the thickener type and that carrageenan might slow it. These results could help with the appropriate selection of thickeners added to liquid foods based on the patient's metabolic profile to manage nutrition, not only for tube-fed patients but also for those with oropharyngeal dysphagia or diabetes.

The misuse of anabolic androgenic steroid associated or not with physical workouts disrupts gastrointestinal (GI) function homeostasis. Our goal was to investigate the effects of nandrolone decanoate (ND) and moderate swimming on the GI transit of solid meals, GI motor contractility, and intestinal histology in rats. Male Wistar rats were allocated to four groups that received intramuscular injections of ND (5.0 mg/kg) or vehicle (60.0 µL) and were submitted or not to swimming sessions (60 min, 5% body weight overload) for 4 weeks. Gastric emptying, intestinal transit, in vitro GI contractility, intestinal morphometry, and duodenal mucosal mast cells were evaluated in all experimental groups. ND treatment accelerated gastric emptying, slowed small intestine transit time, enhanced gastric carbachol-mediated reactivity, decreased crypt depth and villus height, reduced mucosal thickness, and increased the circular and longitudinal muscle layer thickness of the duodenum in sedentary rats. Moderate exercise accelerated intestinal transit time and reduced submucosa thickness. In vehicle-treated animals, a strong negative correlation was found between intestinal transit and mucosal mast cells, which was reversed by ND treatment. Combining ND treatment and swimming accelerated gastric emptying, increased duodenal cholinergic reactivity, inhibited the sodium nitroprusside relaxing response, increased the number of duodenal mast cells, decreased villus height, and increased the thickness of all muscle layers. ND changed the morphological and functional properties of the GI tract over time, with intense dysmotility, especially in sedentary animals, but moderate exercise seemed to have played a compensatory role in these harmful effects in the gut.

Purpose: Glucagon-like receptor agonists (GLP1-RAs) have raised peri-procedural concerns due to their potential to delay gastric emptying. The American Association of Anesthesiologists has advised pausing a single dose before elective endoscopy. However, a subsequent directive from multiple gastroenterology societies underscored the need for further assessment to substantiate this practice. We aimed to evaluate the frequency of serious adverse events and retained gastric products during endoscopic sleeve gastroplasty (ESG) with uninterrupted GLP1-RA use., Materials and Methods: We conducted a retrospective evaluation of all patients undergoing ESG while on GLP1-RAs at three centers from August 2022 to February 2024. Per standard protocol, all patients had refrained from solid foods for at least 24 h and maintained nil per os for 12 h preceding their ESG. Records were reviewed for patient characteristics and medication type and doses. Primary outcomes included serious adverse events and retained gastric products based on patient records, procedure reports, and procedural videos., Results: Fifty-seven consecutive adults (89.5% women, mean age of 44 ± 9 years, mean BMI of 40.1 ± 8.1 kg/m 2 , 35.1% with T2DM, and 26.3% with pre-T2DM) underwent ESG without stopping GLP1-RAs, which included semaglutide (45.6%), liraglutide (19.3%), dulaglutide (22.8%), and tirzepatide (12.3%). During intubation, endoscopy, and recovery, there were no instances of retained gastric solids, pulmonary aspiration, gastroesophageal regurgitation, or hypoxia., Conclusion: A ≥ 24-h pre-endoscopy liquid-only diet with ≥ 12-h pre-endoscopy fast may negate the need for GLP1-RA interruption for routine upper endoscopy in adults with native gastric anatomy., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Scientists were chasing an incretin hormone, and when GLP-1 was finally discovered, we found that it had a pronounced satiety effect, slowed down gastric emptying, and actually reduced postprandial insulin response. These mechanisms are the basis for the highly efficacious GLP-1 analogues that today offer safe and effective treatment in millions of people living with obesity. Moreover, the combined GLP-1 mechanisms of weight loss and delayed carbohydrate absorption may also be the key drivers of remission of type 2 diabetes and reduced cardiovascular events found by GLP-1 analogues., (© 2024. The Author(s).)

Background: Glucagon-like peptide-1 receptor agonists are used increasingly in the management of patients living with type 2 diabetes mellitus and obesity. In patients using glucagon-like peptide-1 receptor agonists, a key concern in the peri-operative period is the increased risk of pulmonary aspiration due to delayed gastric emptying. This review provides an overview of the pharmacodynamic and pharmacokinetic properties of glucagon-like peptide-1 receptor agonists and the risk of delayed gastric emptying and aspiration., Methods: We conducted searches of MEDLINE and EMBASE databases of articles published before January 2024 using the keywords and medical subject headings: incretins; glucagon-like peptide-1; GLP-1; glucagon-like peptide-1 receptor agonists; GLP-1 RA; peri-operative period; perioperative; peri-operative; stomach emptying; gastric emptying; pulmonary aspiration; aspiration; food regurgitation; and regurgitation. The evidence was analysed, synthesised and reported narratively., Results: A total of 1213 articles were located after duplicates were removed. Two authors screened the titles and abstracts to identify those studies which assessed specifically the risk of delayed gastric emptying and pulmonary aspiration or regurgitation in the peri-operative period. We searched manually the reference lists of relevant studies to identify any additional case reports. Ten studies were identified. Available evidence was limited to case reports, case series and observational work., Conclusions: There is insufficient evidence to put forward definitive guidance regarding the ideal cessation period for glucagon-like peptide-1 receptor agonists before elective surgery. Precautionary practice is required until more evidence becomes available. We suggest an individualised, evidence-based approach. In patients living with type 2 diabetes mellitus, there is concern that prolonged cessation before surgery will have a detrimental effect on peri-operative glycaemic control and discussion with an endocrinologist is advised. For patients taking glucagon-like peptide-1 receptor agonists for weight management, these drugs should be withheld for at least three half-lives before an elective surgical procedure., (© 2024 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists.)

Competing Interests: Declaration of competing interest JS is a consultant for Intuitive Surgical and Enterra Medical. None of these relationships influenced the current study. The other authors declare no competing interests.

Mountain caviar is a fruit of Kochia scoparia that contains momordin Ic as a major saponin constituent. Its extract (MCE) has been shown to suppress blood glucose elevations in the human oral glucose tolerance test (OGTT) as well as increases in blood glucose in OGTT, gastric emptying (GE), and glucose incorporation in the small intestine in rats. However, the effects of MCE and momordin Ic on glucose absorption in mice and these action mechanisms have not been examined for more than 2 decades. Therefore, we herein investigated the effects of MCE, its saponin fraction, and momordin Ic on blood glucose elevations in mice. Mouse blood glucose elevation tests were performed on carbohydrate-loaded mice. The mountain caviar saponin fraction significantly delayed blood glucose elevations in glucose-, sucrose-, and soluble starch-loaded mice. In glucose-loaded mice, the saponin fraction, MCE, and momordin Ic significantly suppressed rapid glucose elevations after glucose loading, but not sucrose loading. A mouse GE study was performed by loading with glucose and phenolphthalein solution. Momordin Ic and MCE strongly suppressed mouse GE. Intestinal glucose absorption was evaluated by the incorporation of 2-deoxyglucose (2-DG) into Caco-2 cell layers and mouse duodenum wall vesicles. The results obtained showed that momordin Ic inhibited the incorporation of 2-DG into Caco-2 cells and mouse duodenum vesicles. Collectively, these results suggest that MCE, particularly the principal saponin, momordin Ic, preferably suppressed glucose-induced blood glucose elevations and delayed carbohydrate-induced glucose elevations in mice. The underlying mechanism was found to involve the suppression of GE and intestinal glucose absorption., (© 2024. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)

Purpose of Review: To summarize the mechanism of action, clinical outcomes, and perioperative implications of glucagon-like peptide-1 receptor agonists (GLP-1-RAs). Specifically, this review focuses on the available literature surrounding complications (primarily, bronchoaspiration) and current recommendations, as well as knowledge gaps and future research directions on the perioperative management of GLP-1-RAs., Recent Findings: GLP-1-RAs are known to delay gastric emptying. Accordingly, recent case reports and retrospective observational studies, while anecdotal, suggest that the perioperative use of GLP-1-RAs may increase the risk of bronchoaspiration despite fasting intervals that comply with (and often exceed) current guidelines. As a result, guidelines and safety bulletins have been published by several Anesthesiology Societies., Summary: While rapidly emerging evidence suggests that perioperative GLP-1-RAs use is associated with delayed gastric emptying and increased risk of bronchoaspiration (particularly in patients undergoing general anesthesia and/or deep sedation), high-quality studies are needed to provide definitive answers with respect to the safety and duration of preoperative drug cessation, and optimal fasting intervals according to the specific GLP-1-RA agent, the dose/duration of administration, and patient-specific factors. Meanwhile, clinicians must be aware of the potential risks associated with the perioperative use of GLP-1-RAs and follow the recommendations put forth by their respective Anesthesiology Societies., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Divergent recommendations for periprocedural management of glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1 RA) medications rely on limited evidence. We performed a systematic review and meta-analysis to provide quantitative measures of gastric emptying relevant to mechanisms of weight loss and to periprocedural management of GLP-1 RA. We hypothesized that the magnitude of gastric emptying delay would be low and of limited clinical significance to procedural sedation risks., Methods: A protocolized search identified studies on GLP-1 RA that quantified gastric emptying measures. Pooled estimates using random effects were presented as a weighted mean difference with 95% confidence intervals (CIs). Univariate meta-regression was performed to assess the influence of GLP-1 RA type, short-acting vs long-acting mechanism of action, and duration of treatment on gastric emptying., Results: Fifteen studies met the inclusion criteria. Five studies (n = 247) utilized gastric emptying scintigraphy. Mean T 1/2 was 138.4 minutes (95% CI 74.5-202.3) for GLP-1 RA vs 95.0 minutes (95% CI 54.9-135.0) for placebo, with a pooled mean difference of 36.0 minutes (95% CI 17.0-55.0, P < 0.01, I2 = 79.4%). Ten studies (n = 411) utilized the acetaminophen absorption test, with no significant delay in gastric emptying measured by T max , area under the curve (AUC) 4hr , and AUC 5hr with GLP-1 RA ( P > 0.05). On meta-regression, the type of GLP-1 RA, mechanism of action, and treatment duration did not impact gastric emptying ( P > 0.05)., Discussion: While a gastric emptying delay of ∼36 minutes is quantifiable on GLP-1 RA medications, it is of limited magnitude relative to standard periprocedural fasting periods. There were no substantial differences in gastric emptying on modalities reflective of liquid emptying (acetaminophen absorption test), particularly at time points relevant to periprocedural care., (Copyright © 2024 by The American College of Gastroenterology.)

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) prescribed for weight loss and type 2 diabetes mellitus (T2DM) can delay gastric emptying, but risk factors and impact on procedure outcomes remain unclear., Methods: We compared frequency of gastric residue on upper endoscopy in patients on a GLP-1RA and propensity score-matched controls in this retrospective case-control study of consecutive patients undergoing endoscopic procedures over a 3.5-year period. GLP-1RAs were not held before endoscopy. The gastric residue presence was assessed by reviewing endoscopy reports and images. Predictors and consequences of gastric residue with GLP-1RA were determined., Results: In 306 GLP-1RA users compared with matched controls, rates of gastric residue were significantly higher with GLP-1RA use (14% vs 4%, P < 0.01), especially in patients with T2DM (14% vs 4%, P < 0.01), with insulin dependence (17% vs 5%, P < 0.01) and T2DM complications (15% vs 2%, P < 0.01). Lower gastric residue rates were noted after prolonged fasting and clear liquids for concurrent colonoscopy (2% vs 11%, P < 0.01) and in patients with afternoon procedures (4% vs 11%, P < 0.01). While 22% with gastric residue required intubation and 25% had early procedure termination, no procedural complications or aspiration were recorded., Discussion: GLP-1RA use is associated with increased gastric residue on upper endoscopy, particularly in patients with T2DM, surpassing the impact of opiates alone. Risk is highest in the presence of T2DM complications while prolonged fasting and a clear-liquid diet are protective. This increased risk of gastric residue does not appear to translate to an increased risk of procedural complications., (Copyright © 2024 by The American College of Gastroenterology.)

Autism spectrum disorder (ASD) has increased in incidence over the past several decades, and is associated with a range of co-morbidities including gastrointestinal (GI) dysfunctions including gastroesophageal reflux, abdominal pain, bloating, constipation and/or diarrhea. Several animal models have been used that replicate several aspects of ASD but no single model has been able to replicate the entire disease pathophysiology. In humans, prenatal exposure to valproic acid (VPA) has been identified as a significant risk factor and rodent models have shown that in utero VPA exposure leads to behavioral deficits in offspring. The present study aimed to investigate whether in utero exposure to VPA induces GI dysfunction in rats. Timed pregnant Sprague-Dawley rats were injected with a single dose of VPA at embryonic day 12.5. Both male and female offspring subsequently underwent behavioral studies and assessment of GI function in adulthood. In utero VPA treatment induced social deficits in both male and female offspring, decreasing sociability and social novelty. Histological examination showed that VPA treated offspring had decreased thickness of GI muscle and mucosa, while immunohistochemical studies showed a decrease in myenteric neuron number in the fundus. Functional studies showed that both male and female VPA offspring had a delay in gastric emptying compared to vehicle treated offspring. Results of the current study suggest that the rat VPA model of behavioral deficits may be a convenient model by which both mechanistic and functional insights into GI dysfunction may be studied., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Metabolic syndrome (MetS), which can be induced or exacerbated by the current class of antipsychotic drugs, is highly prevalent in patients with schizophrenia and presents significant challenges to lifetime disease management. Supported by initial clinical results, trace amine-associated receptor 1 (TAAR1) agonists have emerged as potential novel treatments for schizophrenia. Notably, non-clinical studies have also shown weight-lowering and glucoregulatory effects of TAAR1 agonists, including the investigational agent ulotaront. However, the translatability of these findings to humans has not been adequately assessed. Given that delayed gastric emptying (GE) was identified as a potential mechanism contributing to the metabolic benefits of TAAR1 agonists in rodents, the aim of this study was to evaluate the effect of ulotaront on GE in patients with schizophrenia and concurrent MetS with prediabetes., Methods: Patients with schizophrenia were randomized to receive a single oral dose of ulotaront (150 mg) and their previous antipsychotic (PA) in an open-label, crossover, two-sequence design (NCT05402111). Eligible participants fulfilled at least three of five MetS criteria and had prediabetes defined by elevated glycated haemoglobin (5.7-6.4%) and/or fasting homeostatic model assessment of insulin resistance (i.e. ≥2.22). Following an overnight fast and 4 h post-dose, participants ingested a 99m Tc-sulphur colloid radiolabelled egg meal (320 kcal, 30% fat). GE was measured by scintigraphy over 4 h. Endpoints included GE of solids half-time (T 1/2 ) and percentage gastric retention at 1, 2 and 4 h., Results: Thirty-one adults were randomized and 27 completed the study. Ulotaront significantly delayed GE of solids [median GE T 1/2 ulotaront at 139 min (119, 182) vs. the participant's PA of 124 min (109, 132), p = .006]. A significant increase in gastric retention was seen in the ulotaront versus the PA group at 1 h (80% vs. 75%, p = .015), 2 h (61% vs. 50%, p = .023) and 4 h (17% vs. 7%, p = .002) post-meal., Conclusion: Ulotaront delayed the GE of solids in patients with schizophrenia and concurrent MetS with prediabetes. Additional studies are needed to assess whether treatment with TAAR1 agonists is associated with weight loss and glucoregulatory improvement., (© 2024 Sumitomo Pharma America and The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Gastroparesis is a condition that affects the motility of the gastrointestinal (GI) tract, causing a delay in the emptying process and leading to nausea, vomiting, bloating, and upper abdominal pain. Motility treatment along with symptom management can be done using antiemetics or prokinetics. This study highlights the diagnostic and therapeutic challenges of gastroparesis and suggests a potential link between facial trauma and symptom remission, indicating the need for further investigation., Case Presentation: A 46-year-old Hispanic man with hypertension, type 2 diabetes (T2D), and hyperlipidemia on amlodipine 10 mg, lisinopril 5 mg, empagliflozin 25 mg, and insulin glargine presented with a diabetic foot ulcer with probable osteomyelitis. During hospitalization, the patient developed severe nausea and vomiting. The gastroenterology team advised continuing antiemetic medicine and trying very small sips of clear liquids. However, the patient didn't improve. Therefore, the gastroenterology team was contacted again. They advised having stomach emptying tests to rule out gastroparesis as the source of emesis. In addition, they recommended continuing metoclopramide, and starting erythromycin due to inadequate improvement. Studies found a 748-min stomach emptying time. Normal is 45-90 min. An uneventful upper GI scope was done. Severe gastroparesis was verified, and the gastroenterology team advised a percutaneous jejunostomy or gastric pacemaker for gastroparesis. Unfortunately, the patient suffered a mechanical fall resulting in facial trauma. After the fall, the patient's nausea eased, and emesis stopped. He passed an oral liquids trial after discontinuation of erythromycin and metoclopramide., Conclusion: This case exemplifies the difficulties in diagnosing and treating gastroparesis. An interesting correlation between parasympathetic surges and recovery in gastroparesis may be suggested by the surprising remission of symptoms following face injuries., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Variability of the gastrointestinal tract is rarely reflected in in vitro test protocols but often turns out to be crucial for the oral dosage form performance. In this study, we present a generation method of dissolution profiles accounting for the variability of fasted gastric conditions. The workflow featured 20 biopredictive tests within the physiological variability. The experimental array was constructed with the use of the design of experiments, based on three parameters: gastric pH and timings of the intragastric stress event and gastric emptying. Then, the resulting dissolution profiles served as a training data set for the dissolution process modeling with the machine learning algorithms. This allowed us to generate individual dissolution profiles under a customizable gastric pH and motility patterns. For the first time ever, we used the method to successfully elucidate dissolution properties of two dosage forms: pellet-filled capsules and bare pellets of the marketed dabigatran etexilate product Pradaxa. We showed that the dissolution of capsules was triggered by mechanical stresses and thus was characterized by higher variability and a longer dissolution onset than observed for pellets. Hence, we proved the applicability of the method for the in vitro and in silico characterization of immediate-release dosage forms and, potentially, for the improvement of in vitro - in vivo extrapolation.

Patients undergoing chemotherapy with cisplatin commonly present gastrointestinal effects such as constipation and gastric emptying (GE) delay. Both the purinergic system and physical exercise modulate the gastrointestinal (GI) tract. In the current study, we investigated the role of ATP, physical exercise, and P2X7 receptor blocking on GE delay induced by cisplatin in rats. Male rats were divided into the following groups: control (C), cisplatin (Cis), exercise (Ex), Brilliant Blue G (BBG), ATP, Cis+Ex, Cis+ATP, Cis+BBG, Cis+Ex+BBG, Cis+Ex+BBG+ATP, and Cis+ATP+BBG. GE delay was induced by treatment with 1 mg/kg cisplatin (1 time/week for 5 weeks, ip). The moderate physical exercise was swimming (1 h/day, 5 days/week for 5 weeks). At the end of the treatment or exercise and 30 min before the GE assessment, some groups received BBG (50 mg/kg, sc) or ATP (2 mg/kg, sc). Then, GE was assessed after a 10-min postprandial period. Chronic use of Cis decreased GE delay (P<0.05) compared to the control group. Both exercise and ATP prevented (P<0.05) GE delay compared to Cis. The pretreatment with BBG significantly inhibited (P<0.05) the effect of exercise and ATP. On the other hand, the association between exercise and ATP reversed (P<0.05) the effect of the BBG and prevented GE delay. Therefore, we suggest that both exercise and treatment with ATP activate P2X7 receptors and prevent GE delay induced by cisplatin in rats.

Background: The Calcium-sensing receptor (CaSR) participates in the regulation of gastrointestinal (GI) motility under normal conditions and might be involved in the regulation of GI dysmotility in patients with Parkinson's disease (PD)., Methods: CaSR antagonist-NPS-2143 was applied in in vivo and ex vivo experiments to study the effect and underlying mechanisms of CaSR inhibition on GI dysmotility in the MPTP-induced PD mouse model., Findings: Oral intake of NPS-2143 promoted GI motility in PD mice as shown by the increased gastric emptying rate and shortened whole gut transit time together with improved weight and water content in the feces of PD mice, and the lack of influence on normal mice. Meanwhile, the number of cholinergic neurons, the proportion of serotonergic neurons, as well as the levels of acetylcholine and serotonin increased, but the numbers of nitrergic and tyrosine hydroxylase immunoreactive neurons, and the levels of nitric oxide synthase and dopamine decreased in the myenteric plexus in the gastric antrum and colon of PD mice in response to NPS-2143 treatment. Furthermore, the numbers of c-fos positive neurons in the nucleus tractus solitarius (NTS) and cholinergic neurons in the dorsal motor nucleus of the vagus (DMV) increased in NPS-2143 treated PD mice, suggesting the involvement of both the enteric (ENS) and central (CNS) nervous systems. However, ex vivo results showed that NPS-2143 directly inhibited the contractility of antral and colonic strips in PD mice via a non-ENS mediated mechanism. Further studies revealed that NPS-2143 directly inhibited the voltage gated Ca 2+ channels, which might, at least in part, explain its direct inhibitory effects on the GI muscle strips., Interpretation: CaSR inhibition by its antagonist ameliorated GI dysmotility in PD mice via coordinated neuronal regulation by both ENS and CNS in vivo, although the direct effects of CaSR inhibition on GI muscle strips were suppressive., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest in this research., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Biopsychosocial factors are associated with disorders of gut-brain interaction (DGBI) and exacerbate gastrointestinal symptoms. The mechanisms underlying pathophysiological alterations of stress remain unclear. Corticotropin-releasing hormone (CRH) is a central regulator of the hormonal stress response and has diverse impact on different organ systems. The aim of the present study was to investigate the effects of peripheral CRH infusion on meal-related gastrointestinal symptoms, gastric electrical activity, and gastric sensorimotor function in healthy volunteers (HVs). In a randomized, double-blinded, placebo-controlled, crossover study, we evaluated the effects of CRH on gastric motility and sensitivity. HVs were randomized to receive either peripheral-administered CRH (100 µg bolus + 1 µg/kg/h) or placebo (saline), followed by at least a 7-day washout period and assignment to the opposite treatment. Tests encompassed saliva samples, gastric-emptying (GE) testing, body surface gastric mapping (BSGM, Gastric Alimetry; Alimetry) to assess gastric myoelectrical activity with real-time symptom profiling, and a gastric barostat study to assess gastric sensitivity to distention and accommodation. Twenty HVs [13 women, mean age 29.2 ± 5.3 yr, body mass index (BMI) 23.3 ± 3.8 kg/m 2 ] completed GE tests, of which 18 also underwent BSGM measurements during the GE tests. The GE half-time decreased significantly after CRH exposure (65.2 ± 17.4 vs. 78.8 ± 24.5 min, P = 0.02) with significantly increased gastric amplitude [49.7 (34.7-55.6) vs. 31.7 (25.7-51.0) µV, P < 0.01], saliva cortisol levels, and postprandial symptom severity. Eleven HVs also underwent gastric barostat studies on a separate day. However, the thresholds for discomfort during isobaric distensions, gastric compliance, and accommodation did not differ between CRH and placebo. NEW & NOTEWORTHY In healthy volunteers, peripheral corticotropin-releasing hormone (CRH) infusion accelerates gastric-emptying rate and increases postprandial gastric response, accompanied by a rise in symptoms, but does not alter gastric sensitivity or meal-induced accommodation. These findings underscore a significant link between stress and dyspeptic symptoms, with CRH playing a pivotal role in mediating these effects.

Introduction: Gastric peroral endoscopic myotomy (G-POEM) is a promising technique for treating refractory gastroparesis. We present the first double-blind randomized study comparing the clinical efficacy of G-POEM versus pyloric botulinum toxin injection (BTI)., Methods: This randomized study, conducted in two expert centers, enrolled patients with refractory gastroparesis, medically managed for >6 months and confirmed by gastric emptying scintigraphy (GES), into two groups, G-POEM versus BTI, with follow-up of 1 year. The primary end point was the 3-month clinical efficacy, defined as a >1-point decrease in the mean Gastroparesis Cardinal Symptom Index (GCSI) score. Secondary end points were: 1-year efficacy, GES evolution, adverse events, and quality of life., Results: 40 patients (22 women; mean age 48.1 [SD 17.4]), with mean symptom duration of 5.8 (SD 5.7) years, were randomized. Etiologies included idiopathic (n=18), diabetes (n=11), postoperative (n=6), and mixed (n=4). G-POEM showed a higher 3-month clinical success than BTI (65% vs. 40%, respectively; P =0.10), along with non-significantly higher 1-year clinical success (60% vs. 40%, respectively) on intention-to-treat analysis. The GCSI decreased in both groups at 3 months and 1 year. Only three minor adverse events occurred in the G-POEM group. The GES improvement rate was 72% in the G-POEM group versus 50% in the BTI group (non-significant)., Conclusion: G-POEM seems to have a higher clinically relevant success rate than BTI, but this was not statistically demonstrated. This study confirms the interest in treatments targeting the pylorus, either mechanically or chemically, for managing refractory gastroparesis., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Introduction: Gastroparesis is a chronic disorder characterized by decreased gastric emptying and presents with nausea, vomiting, and abdominal pain which impacts patients' quality of life greatly. The treatment modalities available for gastroparesis have been expanding over the past 2 decades. Currently, there are multiple options available for gastroparesis, albeit with only one FDA-approved medication until June 2021., Areas Covered: We review the different treatments available for gastroparesis and discuss the recently FDA-approved intranasal formulation of metoclopramide. This nasal spray guarantees metoclopramide absorption within 15 min of application bypassing first pass metabolism in the liver and overcoming the limitations of the oral formulation not passing into the small intestine for absorption because of a gastroparetic stomach or a patient unable to take the oral metoclopramide because of nausea and vomiting., Expert Opinion: We now find ourselves in an oasis after spending many years in a 'desert' regarding pharmacologic therapies available for gastroparesis. The expansion of the research involving dopamine receptor antagonists and delving into alternative mechanisms of alleviating gastroparesis symptoms has been crucial in the landscape of gastroparesis. This is especially true as our knowledge of gastroparesis has proven that simply improving gastric emptying does not necessarily translate to clinical improvement.

Postprandial regulation of the gastric emptying (GE) rate plays an important role in food intake. Although oral sweetening with glucose may accelerate GE, the effects of different sweetness intensities of glucose (10% and 20%, w/v) and other energy sweeteners (e.g. fructose and sucrose) remain uncertain. The purpose of this study was to determine the effects of different glucose concentrations (Experiment 1) and different sugars with the same sweet taste intensity (Experiment 2) on postprandial GE. In both experiments, after ingesting a 200 kcal carbohydrate solution containing 50 g of maltodextrin, participants repeatedly sipped, but did not swallow, one of three (water, 10% and 20%, w/v glucose) or four (water and equally sweet 20%, w/v glucose, 12%, w/v fructose, and 14%, w/v sucrose) solutions for 1 min every 5 min over a 30 min period. GE was evaluated by measuring the temporal change in the cross-sectional area of the gastric antrum using ultrasound. In Experiment 1, oral stimulation with 20% (w/v) glucose resulted in greater GE than the control stimulus (i.e. water), but the effect of stimulation with 10% (w/v) glucose on GE was not different from that of the control stimulus. In Experiment 2, stimulation with 20% (w/v) glucose or 12% (w/v) fructose resulted in greater GE than the control stimulus. However, the effect of stimulation with 14% (w/v) sucrose on GE did not differ from that of the control stimulus. Consequently, oral stimulation with glucose or fructose solutions of moderate to high sweetness following a meal facilitates postprandial GE., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Ethnopharmacological Relevance: The combination of Coptis chinensis (RC) and Dolomiaea souliei (VR) has long been used as a classic herb pair for the treatment of gastrointestinal diseases, but the underlying mechanisms remain unknown., Materials and Methods: In this study, the rationality of evidence-based RC and VR combination was explored from the perspective of metabolism, gut microbiota and gastrointestinal function., Results: After 5 weeks treatment, VR extracts (700 mg/kg) and RC alkaloids (800 mg/kg) showed no toxic effect on mice. However, RC administration significantly decreased the body weight of mice. Gastric emptying, gastrointestinal motility function and the absorption of FITC dextran were retarded in the mice of RC group, taking RC along with low dose VR (RC-VRL) and high dose VR (RC-VRH) reversed the impaired gastrointestinal function caused by RC. RC administration significantly increased villus height/crypt depth value. Notably, VR administration increased the number of crypts in mice ileum and reduced villus height/crypt depth value in VR and RC combination group. RC treatment significantly increased the expression of occludin compared to NC group; RC-VRL treatment reversed this tendency. While, VR administration increased ZO1 expression by 99.4% compared to NC mice. As for gut microbiota, RC gavage decreased the gut microbiota diversity, but gut microbiota in VR group was similar to NC group, and VR and RC combination increased gut microbiota diversity. RC administration obviously increased the proportion of Akkermansia muciniphila, Bacteroides thetaiotaomicron, Parabacteroides distasonis, and Escherichia coli, compared to NC mice. VR treatment increased the richness of Bacteroides thetaiotaomicron, Parabacteroides distasonis. RC-VRL and RC-VRH treatment dose-dependently increased the richness of Rikenellaceae RC9, Lactobacillus, and decreased the abundance of Psychrobacter, Bacteroides and Ruminococcus in mice. Serum metabolomic analysis revealed that RC gavage significantly down regulated 76 metabolites and up regulated 31 metabolites. VR treatment significantly down regulated 30 metabolites and up regulated 12 metabolites. Weight loss caused by RC may attribute to the elevated methylxanthine level in mice. The potential adverse effects caused by high dose RC intake may partially alleviate by high serum contents of adenosine, inosine and urolithin A resulted from VR coadministration., Conclusion: VR may alleviate RC caused "fluid retention" via normalizing gastrointestinal function, gut microbiota and modulating the perturbed metabolism., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Lactate serves as an alternative energy fuel but is also an important signaling metabolite. We aimed to investigate whether oral lactate administration affects appetite-regulating hormones, slows gastric emptying rate, and dampens appetite., Methods: Ten healthy male volunteers were investigated on two separate occasions: 1) following oral ingestion of D/L-Na-lactate and 2) following oral ingestion of isotonic iso-voluminous NaCl and intravenous iso-lactemic D/L-Na-lactate infusions. Appetite was evaluated by questionnaires and ad libitum meal tests were performed at the end of each study day. Gastric emptying rate was evaluated using the acetaminophen test., Results: Plasma concentrations of growth differential factor 15 (GDF15, primary outcome) increased following oral and iv administration of lactate (p < 0.001) with no detectable difference between interventions (p = 0.15). Oral lactate administration lowered plasma concentrations of acylated ghrelin (p = 0.02) and elevated glucagon like peptide-1 (GLP-1, p = 0.045), insulin (p < 0.001), and glucagon (p < 0.001) compared with iv administration. Oral lactate administration slowed gastric emptying (p < 0.001), increased the feeling of being "full" (p = 0.008) and lowered the "anticipated future food intake" (p = 0.007) compared with iv administration. Food intake during the ad libitum meal test did not differ between the two study days., Conclusion: Oral lactate administration has a direct effect on the upper gastrointestinal tract, affecting gut hormone secretion, motility and appetite sensations which cannot be mediated through lactate in the systemic circulation alone. These data suggest that compounds rich in lactate may be useful in the treatment of metabolic disease., Clinical Trial Registry Number: NCT0429981, https://clinicaltrials.gov/ct2/show/NCT04299815., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: We investigated the changes in blood glucose fluctuation, gastric emptying, and vascular endothelial function by switching from an exenatide twice-daily formulation (BID) to a once-weekly formulation (QW) since the evaluation of postprandial glucose excursion and glycemic variability (GV) by continuous glucose monitoring (CGM) after switching was lacking., Methods: Twenty-nine patients with type 2 diabetes treated with exenatide BID were included in this study and switched to exenatide QW for 24 weeks. GV assessed by CGM, gastric emptying (by 13  C-acetate breath test) and vascular endothelial function (by reactive hyperemia - peripheral arterial tonometry) were evaluated at baseline and 24 weeks after switching., Results: HbA1c decreased significantly from the baseline to week 24, while postprandial glucose levels after breakfast and dinner significantly increased (both P <0.05). However, the increases in GV indices were modest and not statistically significant at week 24. Vascular endothelial function was also not significantly changed after switching (P >0.05). Gastric emptying was significantly accelerated at week 24 (T max 83.4 ± 12.1 min vs. 58.2 ± 16.4 min) (P <0.001) and correlated with increased postprandial glucose levels after breakfast and dinner (both P <0.05)., Conclusions: Despite the increase in postprandial glucose associated with accelerated gastric emptying after switching from exenatide BID to QW, change in GV was modest and no significant deterioration in vascular endothelial function was observed after switching. These results support the superiority of treatment with exenatide QW over exenatide BID in clinical practice; however, attention should be paid to the monitoring and management of postprandial glucose levels when selecting exenatide QW., Trial Registration: Clinical trial registry number; UMIN000016390 and jRCTs031180320 . Approval date of Registry and the Registration: December 12, 2014., (© 2022. The Author(s).)

Aims/introduction: Differences in the glucose-lowering mechanisms of glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been noted. Clarifying these differences could facilitate the choice of optimal drugs for individuals with type 2 diabetes and requires investigation in a clinical setting., Materials and Methods: A single-arm, prospective, observational study was conducted to evaluate the effects of various GLP-1RAs on postprandial glucose excursion, secretions of insulin and glucagon as well as on the gastric emptying rate. Participants were subjected to meal tolerance tests before and 2 weeks and 12 weeks after GLP-1RA initiation. Effects on postprandial secretions of glucose-dependent insulinotropic polypeptide (GIP) and apolipoprotein B48 were also investigated., Results: Eighteen subjects with type 2 diabetes received one of three GLP-1RAs, i.e., lixisenatide, n = 7; liraglutide, n = 6; or dulaglutide, n = 5. While 12-week administration of all of the GLP-1RAs significantly reduced HbA1c, only lixisenatide and liraglutide, but not dulaglutide, significantly reduced body weight. Postprandial glucose elevation was improved by all of the GLP-1RAs. Postprandial insulin levels were suppressed by lixisenatide, while insulin levels were enhanced by liraglutide. Postprandial glucagon levels were suppressed by lixisenatide. The gastric emptying rate was significantly delayed by lixisenatide, while liraglutide and dulaglutide had limited effects on gastric emptying. GIP secretion was suppressed by lixisenatide and liraglutide. Apolipoprotein B48 secretion was suppressed by all of the GLP-1RAs., Conclusions: All of the GLP-1RAs were found to improve HbA1c in a 12-week prospective observational study in Japanese individuals with type 2 diabetes. However, differences in the mechanisms of the glucose-lowering effects and body weight reduction were observed., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Gastroparesis is a motility disorder that causes severe gastric symptoms and delayed gastric emptying, where the majority of sufferers are females (80%), with 29% of sufferers also diagnosed with Type-1 or Type-2 diabetes. Current clinical recommendations involve stringent dietary restriction and includes the avoidance and minimization of dietary fibre. Dietary fibre lowers the glycaemic index of food, reduces inflammation and provides laxation. Lack of dietary fibre in the diet can affect long-term gastrointestinal health. Our previously published rheological study demonstrated that "low-viscosity" soluble fibres could be a potentially tolerable source of fibre for the gastroparetic population. A randomised controlled crossover pilot clinical study was designed to compare Partially-hydrolysed guar gum or PHGG (test fibre 1), gum Arabic (test fibre 2), psyllium husk (positive control) and water (negative control) in mild-to-moderate symptomatic gastroparesis patients (requiring no enteral tube feeding). The principal aim of the study was to determine the short-term physiological effects and tolerability of the test fibres. In n = 10 female participants, post-prandial blood glucose, gastroparesis symptoms, and breath test measurements were recorded. Normalized clinical data revealed that test fibres PHGG and gum Arabic were able to regulate blood glucose comparable to psyllium husk, while causing far fewer symptoms, equivalent to negative control. The test fibres did not greatly delay mouth-to-caecum transit, though more data is needed. The study data looks promising, and a longer-term study investigating these test fibres is being planned.

Ethnopharmacological Relevance: Nowadays, gastrointestinal motility disorders (GMD) have reduced the quality of people's daily life worldwide, but there is still a lack of effective western medicine treatment. Fructus aurantii (FA), a representative regulating-qi herbal medicine, has been widely used to treat GMD in China for thousands of years, but it is not clear that which specific components contribute to the efficacy., Aim of the Study: The efficacy differences of various fractions of FA on normal mice and GMD rats were compared, so as to find out the main effective fraction of FA, and to screen the main regulating-qi components based on spectrum-effect relationship and multivariate statistical analysis., Materials and Methods: The fingerprints of different fractions of FA were established and main compounds were identified with UHPLC-Q-TOF/MS technique. The promoting gastrointestinal motility activities of FA were evaluated by defecation test, gastric emptying and intestinal propulsion test in mice, and further investigated according to the biochemical analysis of 5-HT, SP, MLT, GAS and VIP in GMD rats' plasma. One-way ANOVA was used to find out the difference of efficacy. The active components were screened through spectrum-effect relationship with PCA-X, Pearson bivariate correlation analysis and OPLS analysis., Conclusions: Ethyl acetate fraction is the main active fraction, and nine compounds are the major regulating-qi components. The developed spectrum-effect analysis can be used for the screening of bioactive components in natural products with high accuracy and reliability., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Pancreatic polypeptide (PP) is known to affect food intake. In this exploratory study, we set out to investigate its supraphysiological effect on food tolerance, gastric accommodation, and emptying. In 12 healthy volunteers, 0, 3, or 10 pmol*kg -1 *min -1 PP was administered intravenously (PP0, PP3 or PP10). Thirty minutes thereafter, nutrient drink infusion (60 ml*min -1 ) through a nasogastric feeding tube was started until maximum satiation. Gastric accommodation was assessed by measuring the intragastric pressure (IGP; nasogastric manometry). In a separate test, the effect of PP0 or PP10 on gastric emptying was tested in 10 healthy volunteers and assessed using the 13 C breath test. Results are presented as mean ± SEM, and p < 0.05 was considered significant. For the IGP test, PP increased ingested nutrient volume: 886 ± 93, 1059 ± 124, and 1025 ± 125 ml for PP0, PP3, and PP10, respectively (p = 0.048). In all groups, Nadir IGP values were reached upon food intake (transformed values: 1.5 ± 0.2, 1.7 ± 0.3, and 1.6 ± 0.3 mmHg for PP0, PP3, and PP10, respectively; NS) to return to baseline thereafter. For the gastric emptying study, volunteers ingested a similar nutrient volume: 802 ± 119 and 1089 ± 128 ml (p = 0.016), and gastric half-emptying time was 281 ± 52 and 249 ± 37 min for PP0 and PP10, respectively (NS). No significant correlation between tolerated nutrient volume and IGP drop (R² < 0.01; p = 0.88 for PP0 vs. PP3 and R² =0.07; p = 0.40 for PP0 vs. PP10, respectively) or gastric half-emptying time (R² = 0.12; p = 0.32) was found. A supraphysiological PP dose enhances food tolerance; however, this effect is not mediated through gastric motility. CLINICAL TRIAL REGISTRY NUMBER: NCT03854708 is obtained from clinicaltrials.gov., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

In 2008, the first evidence of a new hormone called neuronostatin was published. The hormone was discovered using a bioinformatic method and found to originate from the same preprohormone as somatostatin. This small peptide hormone of 13 amino acids and a C-terminal amidation was soon found to exert pleiotropic physiological effects. In animal studies, neuronostatin has been shown to reduce food intake and delay gastric emptying and gastrointestinal transit. Furthermore, neuronostatin has been shown to affect glucose metabolism by increasing glucagon secretion during situations when glucose concentrations are low. Additionally, neuronostatin has been shown to affect neural tissue and cardiomyocytes by suppressing cardiac contractility. The effects of neuronostatin have not yet been delineated in humans, but if the effects found in animal studies translate to humans it could position neuronostatin as a promising target in the treatment of obesity, hypertension and diabetes. In this review, we describe the discovery of neuronostatin and the current understanding of its physiological role and potential therapeutic applicability.

Background: Emulsion droplet triacylglycerol (TAG) crystallinity and colloidal stability can alter the postprandial metabolism, although evidence of their interactive effects is limited., Objectives: This acute meal crossover study investigated the influences of droplet TAG crystallinity at 37°C and colloidal gastric stability on gastric emptying (GE), acute lipemia, and satiety., Methods: We gave 15 healthy adult males (mean ± SD age, 24.9 y ± 4.5 y; BMI, 26.0 kg/m2 ± 2.0 kg/m2; fasting TAG, 0.9 mmol/L  ± 0.3 mmol/L) 250 mL of four 20% palm stearin or palm olein emulsions with similar particle size distributions and containing partially crystalline droplets that remained stable (SS) or destabilized (SU) or containing liquid droplets that remained stable (LS) or destabilized (LU) when exposed to simulated gastric conditions. Baseline and 6-h postprandial ultrasound gastric antrum measurements, satiety visual analogue scales (VAS), and blood samples for analyses of plasma TAG, peptide YY (PYY), glucagon-like peptide-1 (GLP-1), ghrelin, leptin, glucose-dependent insulinotropic polypeptide, insulin, and glucose were collected. Changes from baseline and incremental area under the curve (iAUC) values were analyzed by repeated-measures ANOVA., Results: TAG responses did not differ significantly. The gastric antrum area decreased faster (P ≤ 0.01) after treatment with the acid-unstable emulsions (SU and LU), and satiety VAS ratings and plasma endpoints differed between treatments. After LS treatment, participants had 65% and 59% lower 3-h iAUC values for hunger (P = 0.021) and desire to eat (P = 0.031), respectively, compared to after SU treatment. LS treatment resulted in higher 6-h iAUC values for ghrelin (141%; P = 0.023) and PYY (150%; P = 0.043) compared to SU treatment, and LS treatment also resulted in higher GLP-1 values compared to SU (38%; P = 0.016) and LU (76%; P = 0.001) treatment., Conclusion: Emulsion acid colloidal stability, independent of TAG physical state, delayed GE, and satiety was enhanced after consuming acid stable emulsions containing TAG in the liquid state. The study was registered at clinicaltrials.gov as NCT03990246., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Introduction: The gastric residual volume (GRV) monitoring in patients with mechanical ventilation (MV) is a common and important challenge. The purpose of this study was to compare the effect of neostigmine and metoclopramide on GRV among MV patients in the intensive care unit (ICU)., Methods: In a double-blind randomized clinical trial, a total of 200 mechanically ventilated ICU patients with GRV > 120 ml (6 hours after the last gavage) were randomly assigned into two groups (A and B) with 100 patients in each group. Patients in groups A and B received intravenous infusion of neostigmine at a dose of 2.5 mg/100 ml normal saline and metoclopramide at a dose of 10 mg/100 ml normal saline, within 30 minutes, respectively. GRV was evaluated 5 times for each patient, once before the intervention and 4 times (at 3, 6, 9, and 12 hours) after the intervention. In addition, demographic characteristics including age and gender, as well as severity illness based on the sequential organ failure assessment score (SOFA), were initially recorded for all patients., Results: After adjusting of demographic and clinical characteristics (age, gender, and SOFA score), the generalized estimating equation (GEE) model revealed that neostigmine treatment increased odds of GRV improvement compared to the metoclopramide group (OR = 2.45, 95% CI: 1.60-3.76, P < 0.001). However, there is a statistically significant time trend (within-subject differences or time effect) regardless of treatment groups ( P < 0.001)., Conclusion: According to the results, although neostigmine treatment significantly improved GRV in more patients in less time, within 12 hours of treatment, all patients in both groups had complete recovery. Considering that there was no significant difference between the two groups in terms of side effects, it seems that both drugs are effective in improving the GRV of ICU patients., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this article., (Copyright © 2021 Alireza Rahat-Dahmardeh et al.)

Background: There is no established view of how gastric acid suppression affects the time for gastric emptying. Vonoprazan fumarate shows potent and durable gastric acid inhibitory effects, but its effects on gastric emptying have not been studied widely. We investigated the effects of vonoprazan fumarate on gastric emptying and measured serum gastrin and plasma ghrelin levels in healthy adults., Methods: Ten participants were administered 10 mg vonoprazan fumarate daily for 14 days, then 20 mg vonoprazan fumarate daily for 14 days. The gastric emptying breath test was performed and serum gastrin levels were measured at baseline and after each medication administration period. The protocol was then repeated, with the gastric emptying breath test and serum gastrin and plasma desacyl-ghrelin levels measured at baseline and the end of the medication trial., Results: Mean serum gastrin levels increased in a dose-dependent manner [baseline: 104.7 ± 50.4, after 10 mg protocol: 328 ± 123.8, after 20 mg protocol: 555 ± 378.8 (pg/mL, mean ± standard deviation), p = 0.0008]. There was a significant difference between the gastric emptying breath test Tmax at baseline and just after the 20 mg protocol (baseline: 45.5 ± 15.3, after 20 mg protocol: 60.5 ± 19.6 min, p = 0.0418). Plasma desacyl-ghrelin levels increased significantly just after the 20 mg protocol compared to those at baseline [baseline: 222.3 ± 106.4, after 20 mg protocol: 366.2 ± 178.6 (fmol/mL), p = 0.0008]., Conclusions: In healthy adults, 14 days of vonoprazan fumarate administration at 20 mg/day delayed gastric emptying., Trial Registration: This clinical trial was registered in the University hospital Medical Information Network Clinical Trial Registry (Trial No. UMIN000039199 and UMIN000042969)., (© 2021. Japanese Society of Gastroenterology.)

YH12852, a novel, highly selective 5-hydroxytryptamine 4 (5-HT 4 ) receptor agonist, is currently under development to treat patients with functional constipation. In this study, we aimed to develop a pharmacokinetic (PK)-pharmacodynamic (PD) model that adequately described the time courses of the plasma concentrations of YH12852 and its prokinetic effect as assessed by the Gastric Emptying Breath Test (GEBT) and to predict the prokinetic effect of YH12852 at higher doses through PD simulation. We used the plasma concentrations of YH12852 from patients with functional constipation and healthy subjects and the GEBT results from healthy subjects obtained from a phase I/IIa trial. The PK-PD modeling and covariate analysis were performed using NONMEM software. The prokinetic effect of YH12852 was described using a semimechanistic multicompartment PD model and an empirical model by Ghoos et al. A two-compartment model with first-order absorption adequately described the observed concentration-time profiles of YH12852. The semimechanistic multicompartment PD model and the revised Ghoos model with two slope parameters adequately described the observed kPCD t (the percent dose of 13 C excreted in the exhaled air at minute t after completing the test meal, multiplied by 1000) values. YH12852 accelerated gastric emptying even at low doses of 0.05-0.1 mg, and its prokinetic effect was greater in subjects suffering from more severe functional constipation. The PD simulation experiments revealed that the change from baseline in the half time for gastric emptying induced by YH12852 increased in a dose-dependent manner at 0.05-5 mg although the results at doses >0.1 mg were extrapolated. We also showed that the empirical Ghoos model is a special case of the general semimechanistic multicompartment PD model for gastric emptying., (© 2021 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Background: Xiaoyaosan (XYS), a classic traditional Chinese medicine (TCM) prescription that contained eight Chinese herbs, has been used for treating depression for thousands of years. Yet, the underlying mechanisms are still unclear, which need to be investigated from various perspectives. Disassembling a prescription is one of the effective approaches to study the effects and the mechanisms of TCM prescriptions. By disassembling the prescription, we can find effective combinations of individual herbs to simplify the scale of a given prescription. Accordingly, herein, XYS was disassembled into Shugan and Jianpi groups., Purpose: This study aimed to explore the anti-depressive effects of XYS and its disassembled groups on the digestive system functions and the cecal microbiota of rats., Methods: XYS was divided into two efficacy groups, i.e., the Shugan (SG) and the Jianpi (JP) groups. A depression model was applied by using the chronic unpredictable mild stress (CUMS) method. Various classic behavioral tests were performed to assess the anti-depressive effects of the XYS, the SG, and the JP. Afterward, the effects of the three groups on the digestive system functions and the cecum microbiota of depression rats were evaluated. On top of this, correlation analyses between behavioral and digestive system function indexes and cecum microbiota were conducted., Results: The XYS, the SG, and the JP had significant callback effects on depressive behaviors and gastrointestinal dysfunctions of CUMS rats. The compositions of the gut bacterial community were variable among the five groups. The community composition of the SG was the most similar to that of NC, followed by the XYS and the JP. At phylum, family, and genus levels, 31 potential microbial biomarkers associated with CUMS were identified. Twenty biomarkers were significantly reversed by the SG while 16 and 11 biomarkers were reversed by the XYS and the JP, respectively. The results of degrees of regulatory effects showed that the SG had the highest efficacy index (EI) than the XYS and the JP., Conclusion: Regarding the regulation of cecal microbiota of depression rats, the SG treatment was better than XYS and JP. Therefore, SG could be used individually for the clinical treatment of depression, especially in patients with gastrointestinal and gut microbiota disorders., (Copyright © 2021. Published by Elsevier GmbH.)

This study aims to explore the effect of chronic central neuropeptide-S (NPS) treatment on gastrointestinal dysmotility and the changes of cholinergic neurons in the dorsal motor nucleus of the vagus (DMV) of a Parkinson's disease (PD) rat model. The PD model was induced through a unilateral medial forebrain bundle (MFB) administration of the 6-hydroxydopamine (6-OHDA). Locomotor activity (LMA), solid gastric emptying (GE), and gastrointestinal transit (GIT) were measured 7 days after the surgery. NPS was daily administered (1 nmol, icv, 7 days). In substantia nigra (SN), dorsal motor nucleus of the vagus (DMV), and gastric whole-mount samples, changes in tyrosine hydroxylase (TH), choline acetyltransferase (ChAT), neuronal nitric oxide synthase (nNOS), glial fibrillary acidic protein (GFAP), NPS receptor (NPSR), and alpha-synuclein (Ser129) were examined by immunohistochemistry. Cuprolinic blue staining was used to evaluate the number of neuronal cells in myenteric ganglia. The GIT rate, the total number of myenteric neurons, and the expressions of ChAT, nNOS, TH, and GFAP in the myenteric plexus were not changed in rats that received the 6-OHDA. Chronic NPS treatment reversed 6-OHDA-induced impairment of the motor performance, and GE, while preventing the loss of dopaminergic and cholinergic neurons in SN and DMV, respectively. NPS attenuated 6-OHDA-induced α-syn (Ser129) pathology both in SN and DMV. Additionally, expression of NPSR protein was detected in gastro-projecting cells in DMV. Taken together, centrally applied NPS seems to prevent 6-OHDA-induced gastric dysmotility through a neuroprotective action on central vagal circuitry., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Immune checkpoint inhibitors (ICI) have improved outcomes in patients with various malignancies; however, they can cause immune-related hepatitis and enterocolitis. Patients on ICI may also develop upper gastrointestinal symptoms and undergo measurement of gastric emptying., Aims: Our aim was to review records of patients with gastroparesis following ICI therapy at two medical centers., Methods: We performed a retrospective review of all patients at Mayo Clinic and Brigham and Women's/Dana-Farber Cancer Center (BWH/DFCC) who underwent gastric scintigraphy for the assessment of symptoms of gastroparesis following ICI treatment up to January 2020. Clinical presentation, medical history, laboratory evaluation, imaging, treatment, and outcomes were retrieved from the records. Gastroparesis was diagnosed as delayed gastric emptying (GE) measured by gastric scintigraphy., Results: At Mayo Clinic, 2 patients (median age 59 years, 1 male [M], 1 female [F]) had delayed GE, while 4 patients (median age 53 years, 3M, 1F) had normal GE following ICI use. Of those with delayed GE (diagnosed after 38 and 2 months of ICI initiation), 1 patient was treated for non-Hodgkin's lymphoma and melanoma with ipilimumab; a second patient with breast cancer was treated with pembrolizumab. At BWH/DFCC, 2 patients (median age 56 years, 1M, 1F) had normal GE after ICI treatment, while a 62-year-old female with non-small cell lung cancer developed gastroparesis 3 months following initiation of nivolumab., Conclusion: This report documents gastroparesis as a potential adverse effect of ICI. Further studies should explore the potential for ICI therapy to damage anti-inflammatory macrophages that preserve the enteric neurons.

Background: Measurements of gastric emptying (GE) by scintigraphy in the pediatric population are based on adult standards. Due to radiation exposure, scintigraphy cannot be performed on healthy children to establish norms of GE in the pediatric population. Stable isotope breath tests (GEBTs) pose no such health risk to children. This study sought to determine the feasibility of a GEBT in children and to investigate whether GE may differ by age, gender, or body mass index (BMI)., Methods: Fifty healthy children 6 to 18 years underwent a 13 C-Spirulina platensis GEBT. Breath samples were obtained at baseline, every 15 min for 1 h, and at 30-min intervals for 3 h thereafter. Seventeen similarly aged patients with dyspeptic symptoms concurrently underwent scintigraphy and the GEBT., Key Results: Forty-six healthy subjects were included in the final analysis. Females had an overall slower rate of GE than did males. At nearly all timepoints, children with a BMI >85 th percentile had slower GE than normally weighted children. The GE rate of children aged 6-9 reached a maximum later than did the rate of older children. Thirteen patients undergoing scintigraphy were included in the comparative analysis. The agreement between scintigraphic and GEBT half-times as measured by the concordance correlation coefficient was 0.383 (95% CI: 0.02-0.65)., Conclusions and Inferences: GEBT was easily accomplished in healthy children. Differences of GE rates by age, gender, and BMI support the need for establishing pediatric standards of GE. One way to establish such standards may be through the use of a GEBT., (© 2021 John Wiley & Sons Ltd.)

Propofol and dexmedetomidine are popular used for sedation in ICU, however, inadequate attention has been paid to their effect on gastrointestinal tract (GIT) motility. Present study aimed to compare the effect of propofol and dexmedetomidine on GIT motility at parallel level of sedation and explore the possible mechanism. Male C57BL/6 mice (8-10 weeks) were randomly divided into control, propofol and dexmedetomidine group. After intraperitoneal injection of propofol or dexmedetomidine, comparable sedative level was confirmed by sedative score, physiological parameters and electroencephalogram (EEG). Different segments of GIT motility in vivo (gastric emptying, small intestine transit, distal colon bead expulsion, stool weight and number of fecal pellets, gastrointestinal transit and whole gut transit time) and colonic migrating motor complexes (CMMCs) pattern in vitro were evaluated. The Ca 2+ response of primary enteric glia was examined under the treatment of propofol or dexmedetomidine. There is little difference in physiological parameters and composite permutation entropy index (CPEI) between administration of 50 mg/kg propofol and 40 μg/kg dexmedetomidine, indicated that parallel level of sedation was reached. Data showed that propofol and dexmedetomidine had significantly inhibitory effect on GIT motility while dexmedetomidine was stronger. Also, the amplitude (ΔF/F0) of Ca 2+ response in primary enteric glia was attenuated after treated with the sedatives while the effect of dexmedetomidine was greater than propofol. These findings demonstrated that dexmedetomidine caused stronger inhibitory effects on GIT motility in sedative mice, which may involve impaired Ca 2+ response in enteric glia. Hence, dexmedetomidine should be carefully applied especially for potential GIT dysmotility patient.

Probiotics have been suggested to be effective for functional dyspepsia, but their effect on gastric motility is not clear. We evaluated the effect of Lactobacillus gasseri OLL2716 (LG21 strain) on mild to moderate delayed gastric emptying by a double-blind, parallel-group, placebo-controlled, randomized trial. Participants ( n = 28) were randomly assigned to ingest LG21 strain-containing yogurt (LG21 strain group) or LG21 strain-free yogurt (placebo group) for 12 weeks. The 13 C gastric emptying breath test was performed to measure the gastric emptying rate over time following ingestion of a liquid meal, and the time to reach the peak (Tmax) was used as an indicator of gastric emptying. We also measured the salivary amylase concentration, an indicator of autonomic dysfunction under stress. The per-protocol population ( n = 27, male n = 4, female n = 23) was evaluated for efficacy. When a ≥30% reduction in the difference between participant's Tmax and the Japanese mean Tmax was defined as an improvement, the odds ratio of improvement in delayed gastric emptying compared to placebo after 12 weeks was 4.1 (95% confidence interval, 0.8 to 20.2). Moreover, salivary amylase concentrations were significantly lower than in the placebo group, indicating an improvement in autonomic function. The present data were not enough to support the beneficial effects of the LG21 strain on delayed gastric emptying. However, if we define the odds ratio in further study investigated with a larger number of participants, LG21 strain might be expected to have some impact on delayed gastric emptying.

(1) Background: Whey protein lowers postprandial blood glucose in health and type 2 diabetes, by stimulating insulin and incretin hormone secretion and slowing gastric emptying. The branched-chain amino acids, leucine, isoleucine and valine, abundant in whey, may mediate the glucoregulatory effects of whey. We investigated the comparative effects of intragastric administration of leucine, isoleucine and valine on the plasma glucose, C-peptide and glucagon responses to and gastric emptying of a mixed-nutrient drink in healthy men. (2) Methods: 15 healthy men (27 ± 3 y) received, on four separate occasions, in double-blind, randomised fashion, either 10 g of leucine, 10 g of isoleucine, 10 g of valine or control, intragastrically, 30 min before a mixed-nutrient drink. Plasma glucose, C-peptide and glucagon concentrations were measured before, and for 2 h following, the drink. Gastric emptying of the drink was quantified using 13 C-acetate breath-testing. (3) Results: Amino acids alone did not affect plasma glucose or C-peptide, while isoleucine and valine, but not leucine, stimulated glucagon ( p < 0.05), compared with control. After the drink, isoleucine and leucine reduced peak plasma glucose compared with both control and valine (all p < 0.05). Neither amino acid affected early (t = 0-30 min) postprandial C-peptide or glucagon. While there was no effect on overall gastric emptying, plasma glucose at t = 30 min correlated with early gastric emptying ( p < 0.05). (4) Conclusion: In healthy individuals, leucine and isoleucine lower postprandial blood glucose, at least in part by slowing gastric emptying, while valine does not appear to have an effect, possibly due to glucagon stimulation.

Acute high-fat diet (aHFD) exposure induces a brief period of hyperphagia before caloric balance is restored. Previous studies have demonstrated that this period of regulation is associated with activation of synaptic N-methyl-D-aspartate (NMDA) receptors on dorsal motor nucleus of the vagus (DMV) neurons, which increases vagal control of gastric functions. Our aim was to test the hypothesis that activation of DMV synaptic NMDA receptors occurs subsequent to activation of extrasynaptic NMDA receptors. Sprague-Dawley rats were fed a control or high-fat diet for 3-5 days prior to experimentation. Whole-cell patch-clamp recordings from gastric-projecting DMV neurons; in vivo recordings of gastric motility, tone, compliance, and emptying; and food intake studies were used to assess the effects of NMDA receptor antagonism on caloric regulation. After aHFD exposure, inhibition of extrasynaptic NMDA receptors prevented the synaptic NMDA receptor-mediated increase in glutamatergic transmission to DMV neurons, as well as the increase in gastric tone and motility, while chronic extrasynaptic NMDA receptor inhibition attenuated the regulation of caloric intake. After aHFD exposure, the regulation of food intake involved synaptic NMDA receptor-mediated currents, which occurred in response to extrasynaptic NMDA receptor activation. Understanding these events may provide a mechanistic basis for hyperphagia and may identify novel therapeutic targets for the treatment of obesity.

Background: Postprandial falls in blood pressure (BP) are more common in older compared to younger individuals. The effects of protein compared to carbohydrates and fat on postprandial BP, and the relation to gastric emptying rates, are poorly studied., Objectives: To determine the effects of a whey protein compared to a control drink on systolic BP (SBP) and diastolic BP (DBP), and heart rate (HR) in healthy younger and older men, and to relate these effects to gastric emptying., Design: A pooled analyses of two randomized, double-blind, cross-over studies., Setting: Two acute clinical intervention studies with identical study design., Participants: Nineteen older (age: 74 ± 1 years, body mass index: 26 ± 1 kg/m 2 ) and 13 younger (23 ± 1 years, 24 ± 1 kg/m 2 ) healthy men., Intervention: A 70 g/280 kcal whey-protein or control (water with diet cordial, ~2 kcal) drink (450 ml)., Measurements: BP and HR were assessed with an automated device immediately before and at 3-min intervals after drink ingestion (0-180 min). Gastric emptying of the drinks was measured using 3D ultrasonography (0-180 min)., Results: Older versus younger men exhibited a greater fall in SBP (-23 ± 2 vs -15 ± 2 mmHg, p = 0.001) after whey-protein versus control, as BP did not change after the two drinks in younger men (p > 0.05). The nadir in SBP occurred later in the older than younger men (114 ± 11 vs 62 ± 14 min; p < 0.001), with SBP still apparently declining 180 min after whey-protein ingestion in the older men. The magnitude of the rise in HR was greater (p < 0.05) in the younger than older men., Conclusion: Following ingestion of 70 g whey protein, healthy older men exhibited a sustained fall in BP, despite an increase in HR, whereas in younger men there was no change in BP. BP may need to be monitored after high protein meals in older people at risk of postprandial hypotension., (© 2021 The American Geriatrics Society.)