GI Motility Disorders Research Articles

Functional and GI Motility Disorders

Yale University School of Medicine, Section of Digestive Diseases, New Haven, CT The author declares that there is nothing to disclose.

A novel endoscopic prototype device for gastric full-thickness biopsy for the histopathologic diagnosis of GI neuromuscular pathology: in vivo porcine long-term survival study (with videos)

Many GI motility disorders are associated with underlying GI neuromuscular pathology, which requires full-thickness biopsies (FTB) for histopathologic diagnosis. Currently, none of the endoscopy-based attempts to obtain FTB specimens have proven suitable for routine use. This study evaluated a novel endoscopic prototype device (ED) for this purpose. To determine (1) the ability of the ED to obtain suitable FTB specimens, (2) associated complications, (3) feasibility of reliable defect closure, and (4) ability to evaluate intramural neuromuscular components. Preclinical proof-of-concept study in 30 pigs. Animal laboratory. Gastric FTB specimens were obtained with a circular cutter and anchor. The defect was closed by over-the-scope clips/T-tags. The resection site was inspected via laparoscopy. After 2 to 4 weeks, necropsy was carried out to evaluate late complications. Feasibility, safety, and closure rate of the procedure. FTB specimens were assessed by histology/immunohistochemistry to visualize enteric neuromusculature. A total of 29 of 30 procedures were successfully performed; one hemorrhage required endoscopic treatment. A total of 29 of 30 FTB specimens (mean diameter 9.1 mm) were retrieved in 7.1 ± 0.4 minutes (range 3.0-12.5 minutes), displaying optimal tissue quality. Defect closure took 10.8 ± 0.9 minutes (range 7.2-32 minutes). Laparoscopy did not reveal damage to adjacent organs. Necropsy showed well-healed scars at the resection site and no complications, peritonitis, or abscess formation. Histology showed smooth muscle layers and submucosal and myenteric ganglia. Survival animal pilot study, no patients. The novel ED enabled safe harvesting of well-preserved FTB specimens. Defect closure proved to be reliable. All neuromuscular structures relevant for histopathologic evaluation of GI neuromuscular pathology were demonstrated. Further studies are needed to verify the efficacy of this prototype device in the entire gut and in humans.

Stem cells for GI motility disorders

Currently available therapies for gastrointestinal motility conditions are often inadequate. Recent scientific advances, however, have facilitated the identification of neural stem cells as novel tools for cellular replenishment. Such cells can be generated from a number of tissue sources including the gut itself. Neural stem cells can readily be harvested from postnatal human gut including by conventional endoscopy, and in experimental transplantation studies appear capable of generating a neo-Enteric Nervous System. Current initiatives are addressing pre-clinical proof of concept studies in vivo utilising animal models of disease. Although definitive cell replenishment therapies for gut motility disorders appear to be an exciting and realistic prospect, even in the short-term, a number of challenges remain to be addressed before definitive clinical application.

Central oxytocin attenuates augmented gastric postprandial motility induced by restraint stress in rats

Restraint stress delays gastric emptying via uncoordinated motility pattern in rats. Central oxytocin has anxiolytic effects and attenuates the hypothalamic-pituitary-adrenal (HPA) axis in response to stress and facilitates stress-induced delayed gastric emptying. However, the role of central oxytocin in regulating gastric motility remains unknown. Postprandial gastric motility was recorded via a strain-gauge transducer, implanted on the antrum in Sprague–Dawley (SD) rats. To investigate whether central and peripheral oxytocin are involved in gastric motility, oxytocin (10 μg) was administered intracerebroventricularly (icv) and intraperitoneally (ip). Central and peripheral oxytocin administration did not affect the postprandial gastric motility under non-stressed conditions. Restraint stress augmented gastric contractions. Central administration of oxytocin, but not peripheral administration, abolished the augmented postprandial gastric contractions induced by restraint stress. Oxytocin facilitates stress-induced delayed gastric emptying via alleviating uncoordinated gastric motility. Oxytocin might be a candidate for the treatment of stress-induced GI motility disorders.

Comparison of GI Transit Parameters in Functional/Idiopathic Versus Constipation Predominant Irritable Bowel Syndrome (IBS) Patients Assessed by Wireless pH/Pressure Recording Capsule

Purpose: The SmartPill (SP) wireless pH/pressure recording capsule is utilized to assess gastric emptying (GET) small bowel transit time (SBTT) and colon transit time (CTT) in various GI motility disorders such as gastroparesis or chronic constipation (CC). Therefore, the aim of the study was to compare GET, SBTT, and CTT and whole gut transit time (WGTT) between two groups with chronic constipation: one group is diagnosed with functional (idiopathic) (FC) and another presents with IBS-C predominant symptoms, whereas a group of 39 healthy females served as the controls. Methods: In a multicenter CC study 63 constipated subjects (55 F, 8 M mean age 49 (range 21–79) were enrolled based on their Rome II criteria. 45 (73%) were identified with functional constipation (FC) and 18 (27%) had IBS-C as an etiological factor. Fasting subjects swallowed the SP capsule immediately after eating a caloric breakfast (Smart Bar, 260 kcal). They were then equipped with a recording system and diary pages were given to capture meal and symptoms status for the duration of the study. The WGTT was measured from the time of ingestion of the SP until an abrupt loss of recording signal was observed. The time from ingestion to rise of pH exceeding pH 4.0 was defined as GET and a sudden drop of 1 pH unit >5 min was regarded as ileo-cecal (I-C) arrival time. By subtracting GET from I-C time, SBTT and subsequently CTT were calculated. Based on statistical analysis with Mann-Whitney Test results are presented as median and 25–75% range. Results: The median WGTT in both CC groups was similar with 66 h (43–97 h) in FC group versus 65 h (29–119) IBS-C population (P= 0.958), which was significantly prolonged vs. normal female controls (P < 0.05) The CTT was numerically but not statistically different between FC and IBS-C patients 45 h (26–99 h) versus 58 h (20–108 h) (P= 0.802) respectively, but significantly slower then for female normal subjects (P < 0.05) The SBTT in these 2 groups of constipated patients was 4.3 h (3–5) vs. 4.0 h (3–4) (P= 0.465) and similar to results in healthy female volunteers where SBTT is <5 h. The GET in FC group 3.5 hours (3–4 h) was similar to and in IBS-C 3.4 hours (2–4 h) (P= 0.394) also within the normal limit for female controls (<5 hours. Conclusion: 1. From this study on chronic constipation in a female dominant population of patients, we conclude that WGTT and CTT are abnormally prolonged in both FC and IBS-C sub-groups of CC while GET and SBTT remain normal and are similar in both groups. 2. Although pathophysiological concepts may be different regarding the two entities, the GI transit parameters, specifically WGTT and CTT findings do not separate these two etiologies of constipation.

Feasibility of gastric electrical stimulation by percutaneous endoscopic transgastric electrodes

Gastric electrical stimulation has been used for the treatment of drug refractory GI motility disorders and for the treatment of obesity. Both these indications have involved surgical placement of gastric electrodes, which adds to the complexity and cost of the procedure. Endoscopic placement is therefore an attractive alternative approach for this therapy. Our purpose was to investigate the feasibility, safety, and efficacy of percutaneous endoscopic electrodes for gastric electrical stimulation. Experimental animal study in hound dogs. Percutaneous endoscopic transgastric electrode (PETE) placement was carried out by using a pair of gastric pacing wires attached to a percutaneous endoscopic gastrostomy tube. In addition, 4 pairs of gastric serosal electrodes were implanted surgically for comparison. The efficacy of the percutaneous endoscopic electrodes was defined by their ability to entrain gastric slow waves and the induction of dysrhythmia. (1) The PETE recorded gastric slow waves comparable to the serosal electrodes. (2) Gastric electrical stimulation with long pulses delivered by the PETE, at a frequency of 10% higher than the intrinsic gastric slow wave frequency, entrained gastric slow waves. (3) Gastric electrical stimulation delivered by the PETE, at a tachygastric frequency, induced gastric dysrhythmia. This was an animal study; however, its results are expected to be reproducible in humans, with PETE kept in place for even a longer duration than 6 to 8 weeks. PETE placement is both feasible and safe. PETEs are effective, having a potential for use in treatment of both gastroparesis and obesity.

In Vitro and Vivo Endoscopic Cellular Imaging of the Muscularis Propria

Background: Abnormalities of the muscularis propria occur in various diseases such as GI stromal tumors, achalasia and an array of GI motility disorders. Currently, muscle layer histological sampling and analysis is requisite for diagnosing neoplasias. Muscle layer diseases, especially motility disorders, are rarely associated with mortality or the need for surgical procedures. Muscle layer tissue acquisition for these clinical disorders is therefore difficult for both diagnosis and research. A minimally invasive repeatable endoscopic procedure for histological imaging of the muscularis propria is desirable.

Schuster atlas of gastrointestinal motility in health and disease, second editionedited by Marvin M. Schuster, Michael D. Crowell, and Kenneth L. Koch. 472 pp. $149.00. B.C. Decker Inc, Hamilton, London, 2002. ISBN 1-55009-104-2. Web address for ordering: www.bcdecker.com

Schuster atlas of gastrointestinal motility in health and disease, second editionedited by Marvin M. Schuster, Michael D. Crowell, and Kenneth L. Koch. 472 pp. $149.00. B.C. Decker Inc, Hamilton, London, 2002. ISBN 1-55009-104-2. Web address for ordering: www.bcdecker.com

Evaluation of autonomic and enteric nervous system may affect the outcome of therapy in patients with GI motility disorders

Evaluation of autonomic and enteric nervous system may affect the outcome of therapy in patients with GI motility disorders

Evaluation of autonomic and enteric nervous system may affect the therapy of patients with GI motility disorders

Evaluation of autonomic and enteric nervous system may affect the therapy of patients with GI motility disorders

Physiology and pathophysiology of the interstitial cells of Cajal: from bench to bedside. IV. Genetic and animal models of GI motility disorders caused by loss of interstitial cells of Cajal.

Several human motility disorders have been shown to be associated with loss or defects in interstitial cells of Cajal (ICC) networks. Because tissue samples for these studies were taken from patients with well-advanced motility problems, it is difficult to determine whether the loss of ICC is a cause or a consequence of the disease process. To establish the cause-and-effect relationship of ICC loss in motility disorders, it may be feasible to use animal models in which ICC are lost as motility dysfunction develops. Several models with defects in ICC networks have been developed, and these include animals with defects in the Kit signaling pathway (e.g., white-spotting mutants that have defects in Kit receptors; steel mutants that have mutations in stem cell factor, the ligand for Kit; and animals that are chronically treated with reagents that block Kit or downstream signaling proteins). ICC do not die when Kit signaling is blocked, rather, they redifferentiate into a smooth muscle-like phenotype. Diabetic animals (NOD/LtJ mice), animals with chronic bowel obstruction, and inflammatory bowel models also have defects in ICC networks that have been associated with motility disorders. By studying these models with molecular and genomic techniques it may be possible to determine the signals that cause loss of ICC and find ways of restoring ICC to dysfunctional tissues. This article discusses recent progress in the utilization of animal models to study the consequences of losing ICC on the development of motility disorders.

Treatment of Gi dysmotility in scleroderma with the new enterokinetic agent prucalopride

Scleroderma is a multisystem disorder frequently resulting in disturbed GI motility. Although, especially early in the disease, symptomatic improvement is achieved with prokinetic agents, more severe GI manifestations of scleroderma may be difficult to treat, leading to parenteral feeding and hospitalization. Recently, a new serotonin (5-HT 4) receptor agonist prucalopride was shown to have remarkable prokinetic properties, resulting in symptomatic improvement and increased frequency of defecation in patients with chronic functional constipation. Here we report two cases of scleroderma with GI manifestation in which previous prokinetic treatment failed, but where the patients were successfully treated with prucalopride. Our data suggest that prucalopride may be a promising and effective drug to treat GI motility disorders in scleroderma. However, further placebo-controlled double blind studies are needed for full documentation of the usefulness of prucalopride in patients with scleroderma.

Evaluation of autonomic and enteric measures can affect clinical care of patients with GI motility disorders

Evaluation of autonomic and enteric measures can affect clinical care of patients with GI motility disorders

Discovery of a potent, peripherally selective trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonist for the treatment of gastrointestinal motility disorders.

Structure-activity relationship studies were pursued within N-substituted-trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines in an effort to discover a peripherally selective opioid antagonist with high activity following systemic administration. Altering the size and the polarity of the N-substituent led to the discovery of 3 (LY246736). Compound 3 has high affinity for opioid receptors (Ki = 0.77, 40, and 4.4 nM for mu, kappa, and delta receptors, respectively). It is a potent mu receptor antagonist following parenteral and oral administration and distributes selectively (> 200-fold selectivity) to peripheral receptors. Thus, 3 has properties suitable for the clinical investigation of mu opioid receptor involvement in GI motility disorders.