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."

High-resolution manometry reveals different effect of polyethylene glycol, bisacodyl, and prucalopride on colonic motility in healthy subjects: An acute, open label, randomized, crossover, reader-blinded study with potential clinical implications.

BACKGROUND: Polyethylene glycol (PEG), bisacodyl, and prucalopride have been reported to be more effective than placebo in treating patients with constipation but about 50% of the patients still do not respond to these medications. Only bisacodyl and prucalopride are expected to directly stimulate the colonic motility in humans in vivo. As no previous study has done this, the aim of the study was to investigate the effect of PEG, bisacodyl, and prucalopride as compared to placebo on colonic motility assessed by means of the high-resolution manometry (HRM) in healthy subjects. METHODS: Ten healthy subjects have been enrolled in an acute, open label, randomized, reader-blinded, crossover study and requested to undergo a colonoscopy-assisted HRM measuring their colonic motility before and after oral administration of 13.8 g (two doses) PEG, 10 mg bisacodyl, 2 mg prucalopride, and placebo. KEY RESULTS: In the human prepared colon, oral administration of PEG significantly increases the number of low-amplitude long distance propagating contractions (p = 0.007 vs placebo) while bisacodyl significantly increases the number of high-amplitude propagating contractions (HAPCs) (all p < 0.01 vs PEG, prucalopride, and placebo). Prucalopride has no major effect on the number of propagating contractions but increases HAPCs amplitude (p = 0.01). CONCLUSIONS & INFERENCES: In humans, PEG, prucalopride, and bisacodyl have distinct effects on colonic motility. This information has clinical implication, as it indicates that the combination of prucalopride and bisacodyl, normally not considered in clinical practice, could be effective in treating patients with constipation refractory to single medications.

Manometric demonstration of duodenal/jejunal motor function consistent with the duodenal brake mechanism.

BACKGROUND: High-resolution manometric studies below the stomach are rare due to technical limitations of traditional manometry catheters. Consequently, specific motor patterns and their impact on gastric and small bowel function are not well understood. High-resolution manometry was used to record fed-state motor patterns in the antro-jejunal segment and relate these to fasting motor function. METHODS: Antro-jejunal pressures were monitored in 15 healthy females using fiber-optic manometry (72 sensors at 1 cm intervals) before and after a high-nutrient drink. KEY RESULTS: Postprandial motility showed a previously unreported transition point 18.8 cm (range 13-28 cm) beyond the antro-pyloric junction. Distal to the transition, a zone of non-propagating, repetitive pressure events (11.5 ± 0.5 cpm) were dominant in the fed state. We have named this activity, the duodeno-jejunal complex (DJC). Continuous DJC activity predominated, but nine subjects also exhibited intermittent clusters of DJC activity, 7.4 ± 4.9/h, lasting 1.4 ± 0.55 minutes, and 3.8 ± 1.2 minutes apart. DJC activity was less prevalent during fasting (3.6 ± 3.3/h; P = .04). 78% of fed and fasting state propagating antro-duodenal pressure events terminated proximally or at the transition point and were closely associated with DJC clusters. CONCLUSIONS AND INFERENCES: High-resolution duodeno-jejunal manometry revealed a previously unrecognized transition point and associated motor pattern extending into the jejunum, consistent with the duodenal brake previously identified fluoroscopically. Timing suggests DJC activity is driven by chyme stimulating duodenal mucosal chemosensors. These findings indicate that the duodenum and proximal jejunum consists of two major functional motor regions.

Exploring the impact of real-life dosing conditions on intraluminal and systemic concentrations of atazanavir in parallel with gastric motility recording in healthy subjects.

This work strived to explore gastrointestinal (GI) dissolution, supersaturation and precipitation of the weakly basic drug atazanavir in humans under different 'real-life' intake conditions. The impact of GI pH and motility on these processes was thoroughly explored. In a cross-over study, atazanavir (Reyataz®) was orally administered to 5 healthy subjects with (i) a glass of water, (ii) a glass of Coca-Cola® and (iii) a glass of water under hypochlorhydric conditions (induced by concomitant intake of a proton-pump inhibitor (PPI)). After intake, GI fluids were aspirated from the stomach and the duodenum and, subsequently, analyzed for atazanavir. In parallel, blood samples were collected to assess systemic concentrations. In general, the results of this study revealed that the acidic gastric pH in combination with gastric residence time played a crucial role in the dissolution of atazanavir along the GI tract. After intake of atazanavir with a glass of water (i.e., reference condition), complete gastric dissolution was observed. After GI transfer, supersaturation was noticed for a limited amount of time (1.25 h). With respect to the Coca-Cola® condition, complete gastric dissolution was also observed. A delay in gastric emptying, highly likely caused by the caloric content (101 kcal), was responsible for delayed arrival of atazanavir into the upper small intestine, creating a longer time window of supersaturated concentrations in the duodenal segment (3.25 h) compared to the water condition. The longer period of supersaturated concentrations resulted in a slightly higher systemic exposure of atazanavir compared to the condition when atazanavir was taken with a glass of water. A remarkable observation was the creation (when the drug was given in the migrating motor complex (MMC) phase 2) or maintenance (when the drug was given in MMC phase 1) of a quiescent phase for up to 80 min. With respect to the PPI condition, negligible gastric and intestinal concentrations were observed, resulting in minimal systemic exposure for all subjects. It can be concluded that gastric pH and residence time play a pivotal role in the intestinal disposition of atazanavir in order to generate sufficiently high concentrations further down in the intestinal tract for a sufficient period of time, thus creating a beneficial driving force for intestinal absorption.

Acute administration of fructans increases the number of transient lower esophageal sphincter relaxations in healthy volunteers.

INTRODUCTION: Dietary measures are often advised to patients with gastro-esophageal reflux disease (GERD). Fermentable Oligo-, Di-, Mono-saccharides and Polyols (FODMAPs) induce lower gastrointestinal (GI) symptoms. However, their effects on esophageal motility, including transient lower esophageal sphincter relaxations (TLESRs), reflux events and GERD symptoms are unknown. We investigated the effect of acute administration of two FODMAPs, fructose, and fructans, on the number of TLESRs, reflux episodes and symptom perception in healthy volunteers (HVs). MATERIALS: After an overnight fast, 20 HVs (10 males; 32.6 ± 2.8 years) underwent a high-resolution impedance manometry. The number of TLESRs and reflux episodes was quantified during five hours after consumption of a high-caloric meal (740 kcal) enriched with 40 g of either fructose, fructans or glucose (as placebo). Results were analyzed using mixed models. RESULTS: There was a trend for a change in the number of TLESRs between the three conditions (P = .06). Post hoc analysis revealed a trend toward a higher number of TLESRs in the fructan condition compared with placebo (Pcorr  = .06). Acute administration of fructose did not influence the number of TLESRs. The total number of reflux events was not affected by either FODMAP condition. Lower esophageal sphincter (LES) pressures dropped significantly in the first postprandial hour to recover slowly back to baseline values (P < .0001), without any difference in LES pressure between the three conditions. CONCLUSION: Ingestion of fructans increased the number of TLESRs slightly compared with placebo. The effect of FODMAPs such as fructans or a low FODMAP diet on reflux parameters in GERD patients remains to be investigated.

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.

Obesity alters adrenergic and chemosensory signaling pathways that regulate ghrelin secretion in the human gut.

Chemosensory signaling in organs such as the mouth and gut contributes to the mechanisms that control metabolism. We investigated the chemosensory pathways that regulate secretion of the hunger hormone ghrelin in response to neurotransmitters, bitter and sweet tastants at the cellular level in the human gut mucosa, and the disturbances in this regulatory pathway induced by obesity. Obesity impaired ghrelin protein production and adrenalin-induced ghrelin secretion in fundic cells, which was counterbalanced by somatostatin. Bitter agonists selective for taste receptor type 2 (TAS2Rs), TAS2R5 and TAS2R10 stimulated ghrelin secretion in fundic cells. The stimulatory effect of the broadly tuned bitter agonist, denatonium benzoate, was selectively blunted by obesity in the small intestine but not in the fundus. Luminal glucose concentrations inhibited ghrelin secretion via sodium-dependent glucose cotransporter and taste receptor type 1 member 3. Obesity altered the sensitivity of the ghrelin cell to glucose in the small intestine but not in the fundus. Sweet taste receptor activation inhibited bitter taste signaling of the ghrelin cell. In conclusion, obesity impairs the sympathetic drive that controls ghrelin release in the fundus and affects the sensitivity of the ghrelin cell to bitter and sweet stimuli in the small intestine but not in the fundus. Region-selective targeting of gut taste receptors in obesity is indicated.-Wang, Q., Liszt, K. I., Deloose, E., Canovai, E., Thijs, T., Farré, R., Ceulemans, L. J., Lannoo, M., Tack, J., Depoortere, I. Obesity alters adrenergic and chemosensory signaling pathways that regulate ghrelin secretion in the human gut.

Intragastric quinine administration decreases hedonic eating in healthy women through peptide-mediated gut-brain signaling mechanisms.

Objectives: Intragastric bitter tastants may decrease appetite and food intake. We aimed to investigate the gut-brain signaling and brain mechanisms underlying these effects.Methods: Brain responses to intragastric quinine-hydrochloride (QHCl, 10 µmol/kg) or placebo infusion were recorded using functional magnetic resonance imaging in 15 healthy women. Appetite-related sensations, plasma levels of gastrointestinal hormones and hedonic food intake (ad libitum drink test) were assessed.Results: Lower octanoylated ghrelin (P<0.04), total ghrelin (P<0.01), and motilin (P<0.01) plasma levels were found after QHCl administration, along with lower prospective food consumption ratings (P<0.02) and hedonic food intake (P<0.05). QHCl increased neural activity in the hypothalamus and hedonic (anterior insula, putamen, caudate, pallidum, amygdala, anterior cingulate cortex, orbitofrontal cortex, midbrain) regions, but decreased activity in the homeostatic medulla (all pFWE-corrected<0.05). Differential brain responses to QHCl versus placebo covaried with subjective and hormonal responses and predicted differences in hedonic food intake.Discussion: Intragastric QHCl decreases prospective and actual food intake in healthy women by interfering with homeostatic and hedonic brain circuits in a ghrelin- and motilin-mediated fashion. These findings suggest a potential of bitter tastants to reduce appetite and food intake, through the gut-brain axis.

The optimal order of stimulation modalities and reproducibility of the multimodal esophageal stimulation paradigm.

BACKGROUND: Esophageal hypersensitivity can be triggered by different stimuli. We use a multimodal stimulation model to study esophageal sensitivity to four sensory modalities: thermal, mechanical, electrical, and chemical stimulation. The optimal order of these stimulations needs further validation. METHODS: Esophageal sensitivity to thermal (heated saline solution), mechanical (balloon distention), electrical (block pulses with electrodes), and chemical stimulation (acid solution, 0.1 N HCl) was assessed in 10 subjects. In one session, thermal stimulation was performed first, followed by mechanical stimulation ("original protocol"). In a second session, mechanical stimulation was performed first, followed by temperature stimulation ("reversed protocol"). Besides, the impact of balloon distention speed (25 mL/min vs 50 mL/min) during mechanical stimulation was evaluated. Secondly, in order to establish reproducibility, independent control sessions of multimodal stimulations in 15 healthy volunteers were used retrospectively. KEY RESULTS: A significant difference in pain perception threshold for thermal stimulation was found between the original and reversed protocol (P = 0.046), indicating that mechanical stimulation can sensitize the esophagus to thermal stimulation. Balloon distention rate had no impact on sensitivity thresholds for mechanical stimulation. Concerning the reproducibility, there were no differences for thermal, mechanical, electrical, and chemical stimulation in any of the control sessions. CONCLUSIONS: The optimal order of the multimodal stimulation protocol was to start with the thermal stimulation, followed by mechanical, electrical, and chemical stimulation. The optimal balloon distention rate was 25 mL/min. Multimodal esophageal stimulation generates reproducible perception scores in health and therefore provides a reliable method to assess esophageal sensitivity changes after interventions that may alter esophageal sensitivity.

Effects of caloric and noncaloric sweeteners on antroduodenal motility, gastrointestinal hormone secretion and appetite-related sensations in healthy subjects.

Background: Activation of gastrointestinal (GI) sweet taste receptors by caloric sweeteners triggers secretion of anorexigenic and inhibition of orexigenic GI hormones to regulate food intake. The effect of noncaloric sweeteners on these mechanisms is controversial. We have recently shown that motilin-induced gastric phase III contractions signal hunger feelings, thereby identifying GI motility, and its regulatory hormone motilin, as novel players in food intake regulation. Objective: The objective of the present study was to determine the effect of caloric and noncaloric sweeteners on GI motility, GI hormone secretion, and hunger in humans. Design: The study was a randomized, double-blind, crossover trial. Twelve healthy volunteers underwent 4 gastroduodenal manometry recordings in which the occurrence of phase III contractions was followed by the intragastric (i.g.) administration of 250 mL tap water or equisweet caloric (1) 50 g glucose and 2) 25 g fructose) and noncaloric sweeteners [220 mg acesulfame-K (ace-K)] dissolved in 250 mL tap water. Measurement continued until ≥1 subsequent phase III. Blood samples were collected for the measurement of GI hormones. Visual analog scales were used to rate hunger and satiety feelings. Response curves were analyzed using (generalized) linear mixed models. Results: We found: 1) an inhibitory effect of the 2 caloric sweeteners on antral motility (P < 0.01), but no effect after ace-K, 2) an inhibitory effect of the 2 caloric sweeteners on motilin secretion (P < 0.01), but no effect after ace-K, 3) an early increase in cholecystokinin (CCK) secretion after the 2 caloric sweeteners (P < 0.01), but no effect after ace-K, and 4) an initial stronger decrease in hunger feelings and stronger increase in satiety after ace-K (P < 0.05), followed by a steeper return of hunger and decrease of satiety after ace-K (P < 0.05). Conclusions: Our results demonstrate, for the first time to our knowledge, that the caloric sweeteners glucose and fructose, but not the noncaloric sweetener ace-K, inhibit motilin secretion and antral motility while increasing CCK secretion. This trial was registered at clinicaltrials.gov as NCT02891525.

Effect of motilin receptor activation on food intake and food timing.

Background: Motilin plasma concentrations are positively correlated with hunger ratings during the fasting state. Moreover, the motilin agonist erythromycin stimulates meal requests. Objectives: The first aim of the study was to evaluate the effect of erythromycin on ad libitum food intake. The second aim was to study the involvement of endogenous motilin and octanoylated ghrelin on voluntary meal initiations. Design: Study 1: Fourteen healthy participants were studied twice after an overnight fast. Intravenous administration of placebo (saline) or erythromycin (40 mg) was given in a double-blind randomized order. Participants had the opportunity to eat ad libitum from an excess free-choice buffet (2330 kcal) for the duration of 1 h. The primary outcome was total caloric intake. Study 2: Thirteen healthy participants were studied after an overnight fast. Baseline blood samples were collected before a breakfast (245 kcal). After a rest period of 90 min, blood samples were collected every 15 min for a duration of 5 h. During this period, volunteers could request small meal portions (164 kcal/serving) at time points of their choosing and unlimited in numbers. The primary outcome was the determination of plasma concentrations before postbreakfast spontaneous meal requests. Results: Ad libitum food intake did not differ between placebo and erythromycin groups (difference compared with placebo: 79 kcal; 95% CI: -245.9, 403.97 kcal; P = 0.3). Octanoylated ghrelin concentrations before spontaneous meal requests were, on average, 36% (95% CI: 5.8%, 65.7%; P = 0.02) higher than values before breakfast, whereas motilin concentrations did not increase (6% increase: 95% CI: -5.9%, 17.2% increase; P = 0.3). Conclusions: Motilin receptor stimulation during the fasting state does not affect total caloric intake nor does endogenous motilin stimulate meal requests after breakfast in the current study population. This trial was registered at www.clinicaltrials.gov as NCT03024879.

The motilin agonist erythromycin increases hunger by modulating homeostatic and hedonic brain circuits in healthy women: a randomized, placebo-controlled study.

The motilin agonist, erythromycin, induces gastric phase III of the migrating motor complex, which in turn generates hunger peaks. To identify the brain mechanisms underlying these orexigenic effects, 14 healthy women participated in a randomized, placebo-controlled crossover study. Functional magnetic resonance brain images were acquired for 50 minutes interprandially. Intravenous infusion of erythromycin (40 mg) or saline started 10 minutes after the start of scanning. Blood samples (for glucose and hormone levels) and hunger ratings were collected at fixed timepoints. Thirteen volunteers completed the study, without any adverse events. Brain regions involved in homeostatic and hedonic control of appetite and food intake responded to erythromycin, including pregenual anterior cingulate cortex, anterior insula cortex, orbitofrontal cortex, amygdala, caudate, pallidum and putamen bilaterally, right accumbens, hypothalamus, and midbrain. Octanoylated ghrelin levels decreased, whereas both glucose and insulin increased after erythromycin. Hunger were higher after erythromycin, and these differences covaried with the brain response in most of the abovementioned regions. The motilin agonist erythromycin increases hunger by modulating neurocircuitry related to homeostatic and hedonic control of appetite and feeding. These results confirm recent behavioural findings identifying motilin as a key orexigenic hormone in humans, and identify the brain mechanisms underlying its effect.

The Effect of Sparkling Water on Intraluminal Formulation Behavior and Systemic Drug Performance.

In the context of mediating intra- and interindividual variability in systemic drug exposure after oral drug administration, this small-scale, crossover study aimed to investigate the effect of drug intake with sparkling water on fasted state gastric motor function and subsequent (variability in) intraluminal and systemic drug disposition. For this purpose, healthy human volunteers were asked to ingest a conventional paracetamol tablet with either tap or sparkling water, after which antroduodenal motility and intraluminal and systemic drug disposition were monitored as a function of time. Ingestion of sparkling water led to the occurrence of transient pressure events in the upper gastrointestinal tract for all volunteers, although the duration and frequency of the observed effect were subject to variability. Based on systemic drug disposition parameters, drug intake with sparkling water resulted in a trend toward faster and less variable absorption of paracetamol from the gastrointestinal tract. Faster and less variable intragastric tablet disintegration, due to (i) a direct effect (i.e., in vivo dissolution rate) and (ii) an indirect effect (i.e., gastrointestinal motility) of sparkling water, is likely to contribute to this observation.

Intragastric infusion of denatonium benzoate attenuates interdigestive gastric motility and hunger scores in healthy female volunteers.

Background: Denatonium benzoate (DB) has been shown to influence ongoing ingestive behavior and gut peptide secretion.Objective: We studied how the intragastric administration of DB affects interdigestive motility, motilin and ghrelin plasma concentrations, hunger and satiety ratings, and food intake in healthy volunteers.Design: Lingual bitter taste sensitivity was tested with the use of 6 concentrations of DB in 65 subjects. A placebo or 1 µmol DB/kg was given intragastrically to assess its effect on fasting gastrointestinal motility and hunger ratings, motilin and ghrelin plasma concentrations, satiety, and caloric intake.Results: Women (n = 39) were more sensitive toward a lingual bitter stimulus (P = 0.005) than men (n = 26). In women (n = 10), intragastric DB switched the origin of phase III contractions from the stomach to the duodenum (P = 0.001) and decreased hunger ratings (P = 0.04). These effects were not observed in men (n = 10). In women (n = 12), motilin (P = 0.04) plasma concentrations decreased after intragastric DB administration, whereas total and octanoylated ghrelin were not affected. The intragastric administration of DB decreased hunger (P = 0.008) and increased satiety ratings (P = 0.01) after a meal (500 kcal) in 13 women without affecting gastric emptying in 6 women. Caloric intake tended to decrease after DB administration compared with the placebo (mean ± SEM: 720 ± 58 compared with 796 ± 45 kcal; P = 0.08) in 20 women.Conclusions: Intragastric DB administration decreases both antral motility and hunger ratings during the fasting state, possibly because of a decrease in motilin release. Moreover, DB decreases hunger and increases satiety ratings after a meal and shows potential for decreasing caloric intake. This trial was registered at clinicaltrials.gov as NCT02759926.

Pan-Colonic Pressurizations Associated With Relaxation of the Anal Sphincter in Health and Disease: A New Colonic Motor Pattern Identified Using High-Resolution Manometry.

OBJECTIVES: Only a few studies have applied high-resolution manometry (HRM) to the study of colonic motility in adults and none of them have concurrently evaluated colonic and anal motor activity. The aim of the study was to evaluate colonic and anal motor activity by means of HRM in healthy subjects. As the present study revealed the presence of a new colonic motor pattern (pan-colonic pressurizations) in healthy subjects, three additional studies were conducted: the first and the second to exclude that this motor event results from an artifact due to abdominal wall contraction and to confirm its modulation by cholinergic stimulation, and the third, as pilot study, to test the hypothesis that this colonic pattern is defective in patients with chronic constipation refractory to current pharmacological treatments. METHODS: In both volunteers and patients the HRM catheter was advanced proximally during colonoscopy. RESULTS: In all subjects, pressure increases of 15±3 mm Hg and 24±4 s simultaneously occurring in all colonic sensors (pan-colonic pressurizations) and associated with anal sphincter relaxation were identified. Subjects had 85±38 pan-colonic pressurizations, which increased significantly during meal (P=0.007) and decreased afterward (P=0.01), and were correlated with feelings of and desire to evacuate gas. The mean number of propagating sequences was 47±39, and only retrograde increased significantly postprandially (P=0.01). Pan-colonic pressurizations differed from strain artifacts and significantly increased after prostigmine. In patients pan-colonic pressurizations were significantly reduced as compared with volunteers. CONCLUSIONS: Pan-colonic pressurizations associated with relaxations of the anal sphincter represent a new colonic motor pattern that seems to be defective in patients with treatment-refractory chronic constipation and may have a role in the transport of colonic gas and in the facilitation of the propagating sequence-induced colonic transport.

The motilin receptor agonist erythromycin stimulates hunger and food intake through a cholinergic pathway.

BACKGROUND: Motilin-induced phase III contractions have been identified as a hunger signal. These phase III contractions occur as part of the migrating motor complex (MMC), a contractility pattern of the gastrointestinal tract during fasting. The mechanism involved in this association between subjective hunger feelings and gastrointestinal motility during the MMC is largely unknown, however, as is its ability to stimulate food intake. OBJECTIVES: We sought to 1) investigate the occurrence of hunger peaks and their relation to phase III contractions, 2) evaluate whether this relation was cholinergically driven, and 3) assess the ability of the motilin receptor agonist erythromycin to induce food intake. DESIGN: An algorithm was developed to detect hunger peaks. The association with phase III contractions was studied in 14 healthy volunteers [50% men; mean ± SEM age: 25 ± 2 y; mean ± SEM body mass index (BMI; in kg/m(2)): 23 ± 1]. The impact of pharmacologically induced phase III contractions on the occurrence of hunger peaks and the involvement of a cholinergic pathway were assessed in 14 healthy volunteers (43% men; age: 29 ± 3 y; BMI: 23 ± 1). Last, the effect of erythromycin administration on food intake was examined in 15 healthy volunteers (40% men; age: 28 ± 3 y; BMI: 22 ± 1). RESULTS: The occurrence of hunger peaks and their significant association with phase III contractions was confirmed (P < 0.0001). Pharmacologically induced phase III contractions were also significantly associated with hunger peaks (P < 0.05), and this association involved a cholinergic pathway. Administering erythromycin significantly stimulated food intake compared with placebo (53% ± 13% compared with 10% ± 5%; P < 0.05). CONCLUSIONS: Motilin-induced phase III contractions induced hunger feelings through a cholinergic pathway. Moreover, erythromycin stimulated food intake, suggesting a physiologic role of motilin as an orexigenic signal from the gastrointestinal tract. This trial was registered at www.clinicaltrials.gov as NCT02633579.

Redefining the functional roles of the gastrointestinal migrating motor complex and motilin in small bacterial overgrowth and hunger signaling.

During the fasting state the upper gastrointestinal tract exhibits a specific periodic migrating contraction pattern that is known as the migrating motor complex (MMC). Three different phases can be distinguished during the MMC. Phase III of the MMC is the most active of the three and can start either in the stomach or small intestine. Historically this pattern was designated to be the housekeeper of the gut since disturbances in the pattern were associated with small intestinal bacterial overgrowth; however, its role in the involvement of hunger sensations was already hinted in the beginning of the 20th century by both Cannon (Cannon W, Washburn A. Am J Physiol 29: 441-454, 1912) and Carlson (Carlson A. The Control of Hunger in Health and Disease. Chicago, IL: Univ. of Chicago Press, 1916). The discovery of motilin in 1973 shed more light on the control mechanisms of the MMC. Motilin plasma levels fluctuate together with the phases of the MMC and induce phase III contractions with a gastric onset. Recent research suggests that these motilin-induced phase III contractions signal hunger in healthy subjects and that this system is disturbed in morbidly obese patients. This minireview describes the functions of the MMC in the gut and its regulatory role in controlling hunger sensations.