The Acute Effect of Hydroxychloroquine Sulfate on Hunger, the Plasma Concentration of Orexigenic Peptides and Hedonic Food Intake: A Pilot Study.

The direct infusion of bitter solutions in the gastrointestinal tract can reduce the secretion of orexigenic hormones and influence appetite and food intake. We aimed to explore whether oral ingestion of the bitter tastant hydroxychloroquine sulfate can exert similar effects. Ten lean adult women were included in this double-blind, randomized, two-visit, crossover study. After an overnight fast, each volunteer received film-coated tablets containing 400 mg of hydroxychloroquine sulfate (Plaquenil®) or placebo. Plasma-ghrelin, -motilin, -insulin and blood-glucose concentrations were determined every 10 min before and 30 min after feeding; appetite was scored every 10 min. Hunger scores were investigated with a special interest 50-60 min after the ingestion of hydroxychloroquine sulfate, right before a rewarding chocolate milkshake was offered to drink ad libitum. Compared with the placebo, hydroxychloroquine sulfate tended to reduce hunger at the time of interest (p = 0.10). No effect was found upon subsequent milkshake intake. Motilin plasma concentrations were unaltered, but acyl-ghrelin plasma concentrations decreased after the ingestion of hydroxychloroquine sulfate (t = 40-50; p < 0.05). These data suggest that the oral intake of hydroxychloroquine sulfate tablets reduces subjective hunger via a ghrelin-dependent mechanism but does not affect motilin release, hedonic food intake or insulin levels in healthy women.

Physiological functions and potential clinical applications of motilin.

Motilin is a gastrointestinal hormone secreted by the duodenum. This peptide regulates a characteristic gastrointestinal contraction pattern, called the migrating motor complex, during the fasting state. Motilin also affects the pressure of the lower esophageal sphincter, gastric motility and gastric accommodation in the gastrointestinal tract. Furthermore, motilin induces bile discharge into the duodenum by promoting gallbladder contraction, pepsin secretion in the stomach, pancreatic juice and insulin secretion from the pancreas. In recent years, it has been shown that motilin is associated with appetite, and clinical applications are expected for diseases affected by food intake, e.g. obesity, by regulating motilin levels. Gastric acid and bile are the two major physiological regulators for motilin release. Caloric foods have varying effects on motilin levels, depending on their composition. Among non-caloric foods, bitter substances reduce motilin levels and are therefore expected to have an appetite-suppressing effect. Various motilin receptor agonists and antagonists have been developed but have yet to reach clinical use.

Gastrointestinal hormones and regulation of gastric emptying.

PURPOSE OF REVIEW: In this review, we evaluate recent findings related to the association between gastrointestinal hormones and regulation of gastric emptying. RECENT FINDINGS: Motilin and ghrelin, which act during fasting, promote gastric motility, whereas most of the hormones secreted after a meal inhibit gastric motility. Serotonin has different progastric or antigastric motility effects depending on the receptor subtype. Serotonin receptor agonists have been used clinically to treat dyspepsia symptoms but other hormone receptor agonists or antagonists are still under development. Glucagon-like peptide 1 agonists, which have gastric motility and appetite-suppressing effects are used as a treatment for obesity and diabetes. SUMMARY: Gastrointestinal hormones play an important role in the regulation of gastric motility. Various drugs have been developed to treat delayed gastric emptying by targeting gastrointestinal hormones or their receptors but few have been commercialized.

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

BACKGROUND: Aerosol spread is key to interpret the risk of viral contamination during clinical procedures such as esophageal high-resolution manometry (HRM). Installing an air purifier seems a legitimate strategy, but this has recently been questioned. METHODS: Patients undergoing an HRM procedure at the Leuven University Hospital were included in this clinical study. All subjects had to wear a surgical mask which was only lowered beneath the nose during the placement and removal of the nasogastric catheter. The number of aerosol particles was measured by a Lasair® II Particle Counter to obtain data about different particles sizes: 0.3; 0.5; 1.0; 3.0; 5.0; and 10.0 µm. Measurements were done immediately before the placement and the removal of the HRM catheter, and one and 5 min after. A portable air purifier with high-efficiency particle air filters was installed in the hospital room. KEY RESULTS: Thirteen patients underwent a manometry examination. The amount of 0.3 µm-sized particles was unaffected during the whole procedure. The larger particle sizes (1.0; 3.0; 5.0; and 10.0 µm) decreased when the catheter was positioned, but not 0.5 µm. During the HRM measurements itself, these numbers decreased further. Yet, 1 min after catheter removal a significant elevation of particles was seen, which did not recover within 5 min. CONCLUSIONS & INTERFERENCES: Based on this study, there is no evidence that filtration systems reduce aerosol particles properly during a clinical investigation.

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

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.

The Role of Gasotransmitters in Gut Peptide Actions.

Although gasotransmitters nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) receive a bad connotation; in low concentrations these play a major governing role in local and systemic blood flow, stomach acid release, smooth muscles relaxations, anti-inflammatory behavior, protective effect and more. Many of these physiological processes are upstream regulated by gut peptides, for instance gastrin, cholecystokinin, secretin, motilin, ghrelin, glucagon-like peptide 1 and 2. The relationship between gasotransmitters and gut hormones is poorly understood. In this review, we discuss the role of NO, CO and H2S on gut peptide release and functioning, and whether manipulation by gasotransmitter substrates or specific blockers leads to physiological alterations.

The gastrointestinal tract in hunger and satiety signalling.

BACKGROUND: Different peripheral pathways are implicated in the regulation of the food ingestion-digestion cycle. METHODS: Narrative review on gastrointestinal mechanisms involved in satiety and hunger signalling. RESULTS: Combined mechano- and chemoreceptors, peripherally released peptide hormones and neural pathways provide feedback to the brain to determine sensations of hunger (increase energy intake) or satiation (cessation of energy intake) and regulate the human metabolism. The gastric accommodation reflex, which consists of a transient relaxation of the proximal stomach during food intake, has been identified as a major determinant of meal volume, through activation of tension-sensitive gastric mechanoreceptors. Motilin, whose release is the trigger of gastric Phase 3, has been identified as the major determinant of return of hunger after a meal. In addition, the release of several peptide hormones such as glucagon-like peptide 1 (GLP-1), cholecystokinin as well as motilin and ghrelin contributes to gut-brain signalling with relevance to control of hunger and satiety. A number of nutrients, such as bitter tastants, as well as pharmacological agents, such as endocannabinoid receptor antagonists and GLP-1 analogues act on these pathways to influence hunger, satiation and food intake. CONCLUSION: Gastrointestinal mechanisms such as gastric accommodation and motilin release are key determinants of satiety and hunger.

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

Bitter tastants are recently introduced as potential hunger-suppressive compounds, the so-called "Bitter pill." However, the literature about bitter administration lacks consistency in methods and findings. We want to test whether hunger ratings and hormone plasma levels are affected by: 1) the site of administration: intragastrically (IG) or intraduodenally (ID), 2) the bitter tastant itself, quinine hydrochloride (QHCl) or denatonium benzoate (DB), and 3) the timing of infusion. Therefore, 14 healthy, female volunteers participated in a randomized, placebo-controlled six-visit crossover study. After an overnight fast, DB (1 µmol/kg), QHCl (10 µmol/kg), or placebo were given IG or ID via a nasogastric feeding tube. Blood samples were taken 10 min before administration and every 10 min after administration for a period of 2 h. Hunger was rated at the same time points on a visual analogue scale. ID bitter administration did not affect hunger sensations, motilin, or acyl-ghrelin release compared with its placebo infusion. IG QHCl infusion tended to suppress hunger increase, especially between 50 and 70 min after infusion, simultaneously with reduced motilin values. Here, acyl-ghrelin was not affected. IG DB did not affect hunger or motilin, however acyl-ghrelin levels were reduced 50-70 minutes after infusion. Plasma values of glucagon-like peptide 1 and cholecystokinin were too low to be properly detected or to have any physiological relevance. In conclusion, bitter tastants should be infused into the stomach to reduce hunger sensations and orexigenic gut peptides. QHCl has the best potential to reduce hunger sensations, and it should be infused 60 min before food intake.NEW & NOTEWORTHY Bitter tastants are a potential new weight-loss treatment. This is a noninvasive, easy approach, which should be received with considerable enthusiasm by the public. However, literature about bitter administration lacks consistency in methods and findings. We summarize how the compound should be given based on: the site of administration, the best bitter compound to use, and at what timing in respect to the meal. This paper is therefore a fundamental step to continue research toward the further development of the "bitter pill."

The bitter tastant denatonium benzoate has no influence on the number of transient lower esophageal sphincter relaxations in health.

BACKGROUND: Administration of a bitter compound can alter the intragastric pressure (IGP) after a meal. Additionally, a negative correlation between IGP and the number of transient lower esophageal sphincter relaxations (TLESRs) has been demonstrated. However, the effect of a bitter tastant on the number of TLESRs and subsequent reflux episodes has never been investigated and it is unclear whether bitter food items should be avoided in gastro-esophageal reflux disease. We hypothesize that bitter administration in healthy volunteers (HVs) will lead to an increase in the number of TLESRs. METHODS: After an overnight fast, 20 female HVs (36 years [21-63]) underwent a high-resolution impedance manometry (HRiM) measurement. After placement of the HRiM probe, 0.1 ml/kg of a 10 mM denatonium benzoate solution (bitter) or an identical volume of water (placebo) was administered directly into the stomach. The number of TLESRs and reflux episodes was quantified 30 min before and 2 h after consumption of a high caloric meal. KEY RESULTS: There was no significant difference in the number of TLESRs or reflux episodes between the bitter and placebo condition. Additionally, no differences were observed in the nature (gas or liquid) and extent of reflux events. Lower esophageal sphincter pressures dropped significantly in the first postprandial hour to start recovering slowly back to baseline values during the second postprandial hour (p < 0.0001), without any difference between both conditions. CONCLUSIONS & INTERFERENCES: Administration of the bitter tastant denatonium benzoate has no influence on the number of TLESRs or reflux episodes.

Gastric emptying of solutions containing the natural sweetener erythritol and effects on gut hormone secretion in humans: A pilot dose-ranging study.

AIM: To determine whether a dose-dependent effect in the stimulation of gut hormone release (plasma cholecystokinin [CCK], active glucagon-like peptide-1 [aGLP-1] and peptide tyrosine tyrosine [PYY]) is found for the natural sweetener erythritol. MATERIALS AND METHODS: Twelve healthy, lean volunteers received solutions with 10, 25 or 50 g erythritol, or tap water enriched with 13 C-sodium acetate on four study days via a nasogastric tube in this randomized (active treatments), placebo-controlled, double-blind, cross-over trial. Blood samples and breath samples (13 C-sodium acetate method for measurement of gastric emptying [GE]) were taken at regular intervals, and sensations of appetite and gastrointestinal symptoms were rated. RESULTS: We found (a) a dose-dependent stimulation of CCK, aGLP-1 and PYY, and slowing of GE, (b) no effect on blood glucose, insulin, motilin, glucagon or glucose-dependent insulinotropic polypeptide, (c) no effect on blood lipids and uric acid, and (d) no abdominal pain, nausea or vomiting. CONCLUSIONS: Solutions with 10 and 50 g of erythritol stimulated gut hormone release. Emptying of erythritol-containing solutions from the stomach was slower compared with placebo. There was no effect on plasma glucose, insulin, glucagon, blood lipids or uric acid. All doses were well tolerated.

Effect of the Natural Sweetener Xylitol on Gut Hormone Secretion and Gastric Emptying in Humans: A Pilot Dose-Ranging Study.

Sugar consumption is associated with a whole range of negative health effects and should be reduced and the natural sweetener xylitol might be helpful in achieving this goal. The present study was conducted as a randomized, placebo-controlled, double-blind, cross-over trial. Twelve healthy, lean volunteers received intragastric solutions with 7, 17 or 35 g xylitol or tap water on four separate days. We examined effects on: gut hormones, glucose, insulin, glucagon, uric acid, lipid profile, as well as gastric emptying rates, appetite-related sensations and gastrointestinal symptoms. We found: (i) a dose-dependent stimulation of cholecystokinin (CCK), active glucagon-like peptide-1 (aGLP-1), peptide tyrosine tyrosine (PYY)-release, and decelerated gastric emptying rates, (ii) a dose-dependent increase in blood glucose and insulin, (iii) no effect on motilin, glucagon, or glucose-dependent insulinotropic peptide (GIP)-release, (iv) no effect on blood lipids, but a rise in uric acid, and (v) increased bowel sounds as only side effects. In conclusion, low doses of xylitol stimulate the secretion of gut hormones and induce a deceleration in gastric emptying rates. There is no effect on blood lipids and only little effect on plasma glucose and insulin. This combination of properties (low-glycemic sweetener which stimulates satiation hormone release) makes xylitol an attractive candidate for sugar replacement.

A survey on the impact of the COVID-19 pandemic on motility and functional investigations in Europe and considerations for recommencing activities in the early recovery phase.

BACKGROUND: The COVID-19 pandemic, declared by WHO on March 13, 2020, had a major global impact on the healthcare system and services. In the acute phase, the presence of the SARS-CoV-2 virus in the aerodigestive tract limited activities in the gastroenterology clinic and procedures to emergencies only. Motility and function testing was interrupted and as we enter the recovery phase, restarting these procedures requires a safety-focused approach with adequate infection prevention for patients and healthcare professionals. METHODS: We summarized knowledge on the presence of the SARS-CoV-2 virus in the aerodigestive tract and the risk of spread with motility and functional testing. We surveyed 39 European centers documenting how the pandemic affected activities and which measures they are considering for restarting these measurements. We propose recommendations based on current knowledge as applied in our center. RESULTS: Positioning of catheters for gastrointestinal motility tests carries a concern for aerosol-borne infection of healthcare workers. The risk is low with breath tests. The surveyed centers stopped almost all motility and function tests from the second half of March. The speed of restarting and the safety measures taken varied highly. CONCLUSIONS AND INFERENCES: Based on these findings, we provided recommendations and practical relevant information for motility and function test procedures in the COVID-19 pandemic era, to guarantee a high-quality patient care with adequate infection prevention.

The Role of GI Peptides in Functional Dyspepsia and Gastroparesis: A Systematic Review.

Functional dyspepsia (FD) and gastroparesis (GP) are common disorders of the upper gastrointestinal tract. The pathophysiology of these conditions is likely to be heterogenous, and factors such as altered motility, sensitivity and response to nutrition have been identified as putative underlying mechanisms. Motility, sensitivity as well as responses to nutrition can be influenced or mediated by peptide hormones and serotonin released from the gastrointestinal mucosa. This review summarizes the role of GI peptides in functional dyspepsia and gastroparesis. In most studies, the levels of somatostatin, ghrelin, and motilin did not differ between healthy volunteers and FD or GP patients, but higher symptom burden was often correlated with higher peptide levels. Ghrelin and motilin receptor agonists showed promising results in improvement of the gastric emptying, but the link with improvement of symptoms is less predictable. Serotonin agonists have a potential to improve symptoms in both FD and idiopathic gastroparesis. Drugs acting on the GLP-1 and on the PYY receptors deserve further investigation. There is a need for systematic large scale studies.

Randomised clinical trial: the DPP-4 inhibitor, vildagliptin, inhibits gastric accommodation and increases glucagon-like peptide-1 plasma levels in healthy volunteers.

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inactivates glucagon-like peptide-1 (GLP-1). Whether DPP-4 inhibition affects GLP-1 metabolism and/or food intake in humans remains unknown. AIMS: To evaluate the effect of vildagliptin (DPP-4 inhibitor) on gastric accommodation and ad libitum food intake in healthy volunteers (HVs) METHODS: The effects of acute oral vildagliptin administration (50 mg) were evaluated in two randomised, placebo-controlled, single-blinded trials. Protocol 1 (n = 10, 32.3 ± 3 years, 23.4 ± 0.7 kg/m2 ): 60 min after treatment, a nutrient drink (270 kcal) was infused intragastrically and intragastric pressure (IGP) was measured for 1 h. Protocol 2 (n = 10, 24.3 ± 0.8 years, 22.3 ± 0.9 kg/m2 ): 60 min after treatment, HVs consumed one nutrient drink (300 kcal). Thirty minutes thereafter, HVs ate ad libitum from a free-choice buffet for 30 min. Blood was collected at several time points to measure active GLP-1 plasma levels. RESULTS: During the first 20 min after nutrient infusion, the drop in IGP was smaller after vildagliptin compared to placebo (treatment-by-time interaction effect: P = 0.008). No differences were seen on epigastric symptom scores. Planned contrast analysis showed that active GLP-1 levels were higher after vildagliptin compared to placebo (P = 0.018) only after nutrient ingestion. Total food intake (316.38 ± 58.89 g vs 399.58 ± 63.02 g, P = 0.359) and total caloric intake (594.77 ± 115.17 kcal vs 742.77 ± 107.10 kcal, P = 0.371) did not differ between treatments. CONCLUSIONS: Vildagliptin inhibits gastric accommodation without affecting epigastric symptom scoring in HVs. Active GLP-1 plasma levels were increased after vildagliptin treatment, but the increase was not sufficient to affect ad libitum food intake. The study was registered at Clincialtrials.gov (NCT 03500900).

Motilin: from gastric motility stimulation to hunger signalling.

After the discovery of motilin in 1972, motilin and the motilin receptor were studied intensely for their role in the control of gastrointestinal motility and as targets for treating hypomotility disorders. The genetic revolution - with the use of knockout models - sparked novel insights into the role of multiple peptides but contributed to a decline in interest in motilin, as this peptide and its receptor exist only as pseudogenes in rodents. The past 5 years have seen a major surge in interest in motilin, as a series of studies have shown its relevance in the control of hunger and regulation of food intake in humans in both health and disease. Luminal stimuli, such as bitter tastants, have been identified as modulators of motilin release, with effects on hunger and food intake. The current state of knowledge and potential implications for therapy are summarized in this Review.

A dynamic, sex-specific expression pattern of genes regulating thyroid hormone action in the developing zebra finch song control system.

The zebra finch (Taeniopygia guttata) song control system consists of several series of interconnected brain nuclei that undergo marked changes during ontogeny and sexual development, making it an excellent model to study developmental neuroplasticity. Despite the demonstrated influence of hormones such as sex steroids on this phenomenon, thyroid hormones (THs) - an important factor in neural development and maturation - have not been studied in this regard. We used in situ hybridization to compare the expression of TH transporters, deiodinases and receptors between both sexes during all phases of song development in male zebra finch. Comparisons were made in four song control nuclei: Area X, the lateral magnocellular nucleus of the anterior nidopallium (LMAN), HVC (used as proper name) and the robust nucleus of the arcopallium (RA). Most genes regulating TH action are expressed in these four nuclei at early stages of development. However, while general expression levels decrease with age, the activating enzyme deiodinase type 2 remains highly expressed in Area X, HVC and RA in males, but not in females, until 90days post-hatch (dph), which marks the end of sensorimotor learning. Furthermore, the L-type amino acid transporter 1 and TH receptor beta show elevated expression in male HVC and RA respectively compared to surrounding tissue until adulthood. Differences compared to surrounding tissue and between sexes for the other TH regulators were minor. These developmental changes are accompanied by a strong local increase in vascularization in the male RA between 20 and 30dph but not in Area X or HVC. Our results suggest that local regulation of TH signaling is an important factor in the development of the song control nuclei during the song learning phase and that TH activation by DIO2 is a key player in this process.