Debra Stephens

A randomized controlled trial of a probiotic combination VSL# 3 and placebo in irritable bowel syndrome with bloating.

Abstract  Aim:  To evaluate the effects of a combination probiotic on symptoms and colonic transit in patients with irritable bowel syndrome (IBS) and significant bloating.

Association of distinct α2 adrenoceptor and serotonin transporter polymorphisms with constipation and somatic symptoms in functional gastrointestinal disorders

Background: The role of genetics in the phenotypic manifestations of irritable bowel syndrome (IBS) is unclear. Our aims were: (1) to compare the prevalence of polymorphisms of alpha 2 (α2) adrenoceptors, norepinephrine transporter, and serotonin transporter protein (soluble carrier protein member 4 (SLC6A4)) promoter in patients with lower functional gastrointestinal disorders (FGID) and in healthy controls; and (2) to test associations of these genetic variations with symptoms of IBS and high somatic symptom scores. Methods: Validated bowel and somatic symptom questionnaires characterised the phenotype: 90 with IBS constipation (IBS-C), 128 IBS diarrhoea, 38 IBS alternating bowel function, and 20 chronic abdominal pain. Logistic regression analyses assessed associations of different polymorphisms for α2 adrenoceptor and SLC6A4 with IBS or chronic abdominal pain phenotypes and high somatic score. Results: Two distinct polymorphisms independently appeared to be associated with the phenotype IBS-C: α2C Del 322–325 (odds ratio (OR) 2.48 (95% confidence interval (CI) 0.98, 6.28); p = 0.05) and α2A −1291 (C→G) (OR 1.66 (95% CI 0.94, 2.92); p = 0.08) relative to wild-type. Overall, the α2C Del 322–325 polymorphism (alone or combined with other polymorphisms) was also significantly associated with a high somatic symptom score (OR 2.2 (95% CI 1.06, 4.64); p = 0.03). Combinations of polymorphisms were also associated with high somatic scores. Conclusion: Functionally distinct α2A and α2C adrenoceptor and serotonin transporter polymorphisms are associated with constipation and high somatic symptoms in patients with lower functional gastrointestinal disorders, although the strength of the genetic contribution to the phenotype is unclear.

Noninvasive measurement of gastric accommodation in patients with idiopathic nonulcer dyspepsia

Noninvasive measurement of gastric accommodation in patients with idiopathic nonulcer dyspepsia

A community-based, controlled study of the epidemiology and pathophysiology of dyspepsia

BACKGROUND & AIMS Dyspepsia is common in clinical practice and in the community. The relationship of the symptoms to meals and the pathophysiology in community dyspeptic patients is unclear. The purpose of this study was to measure symptoms, demographic features, and gastric motor and sensory functions associated with dyspepsia in the community. METHODS A Modified Bowel Disease Questionnaire was mailed to a random sample of Olmsted County, MN, residents. Dyspeptic patients and healthy controls identified among community respondents completed further questionnaires, Helicobacter pylori serology, gastric emptying by scintigraphy, gastric accommodation by 99mTc-single-photon emission computed tomography imaging, and postprandial symptoms and satiation by a nutrient drink test. RESULTS A total of 34.1% of community respondents reported dyspepsia within the past year, frequent (at least 25% of the time in the past year) in 17.5%, and 18.4% reported meal-related dyspepsia. Dyspepsia was frequent and related to meals in 10.8% of respondents. Compared with nondyspeptic controls, community dyspepsia was associated with higher aggregate symptom scores and bloating after a fully satiating meal. Community dyspepsia also was associated with higher somatization scores (P = .001), reporting of other somatic symptoms (P = .07), and general severity score on the symptom checklist 90 (P = .01), but not with disordered motor or sensory function. Gastric volumes, gastric emptying, and maximum tolerated volumes were not significantly different between community controls and dyspeptic patients. CONCLUSIONS Meal-related dyspepsia is an important component of dyspepsia in the community. Community dyspeptic patients have higher symptom scores after a fully satiating meal, consistent with gastric hypersensitivity. This is associated with higher somatization scores rather than disorders of gastric emptying or volumes.

A study of candidate genotypes associated with dyspepsia in a U.S. community.

BACKGROUND:The role of genetic predisposition to the development of dyspepsia is unclear. Recently, a significant association was reported with CC genotype of GNβ3.AIM:To explore the association of candidate genotypes altering adrenergic, serotonergic, CCKergic, and G protein functions, and dyspepsia in a sample from a U.S. community.METHODS:Dyspeptics and healthy controls were identified among community respondents who had been randomly selected to complete validated questionnaires. Other diseases were excluded by face-to-face history and physical examination. Polymorphisms of candidate genes for α2A, α2C, 5-HT1A, 5-HT2A, 5-HT2C, CCK-1 receptors and CCK promoter, GNβ3 protein, and SERT-promoter (SERT-P) were studied. The association between polymorphisms and meal-related or meal-unrelated dyspepsia, high somatic symptom scores, and somatization were evaluated using Fishers exact test.RESULTS:DNA was available from 41 dyspeptics and 47 healthy controls from Olmsted County. Community dyspepsia unrelated to meals was associated with both homozygous GNβ3 protein 825T and C alleles. There were no significant associations with meal-related dyspepsia. Using Rome II subgroups, the same genotype was associated with dysmotility-like and other dyspepsia. Higher somatization scores were not significantly associated with any of the candidate genes when considered as single factors.CONCLUSION:Meal-unrelated dyspepsia in a U.S. community study is associated with the homozygous 825T or C alleles of GNβ3 protein. Candidate genes controlling adrenergic, serotonergic, and CCKergic functions do not appear to be associated with dyspepsia.

Validation of a stable isotope gastric emptying test for normal, accelerated or delayed gastric emptying

To validate a 13C‐Spirulina platensis breath test for measurement of accelerated or delayed gastric emptying, we measured gastric emptying of egg containing 13C‐S. platensis and 99mTc‐sulphur colloid by breath 13 CO2 every 15 min over 3 h and scintigraphy every 15–30 min over 5 h in 57 healthy volunteers. Thirty‐three received no treatment, 10 received erythromycin, and 14 atropine. A generalized linear regression model predicted half‐emptying time by scintigraphy (t1/2S) from breath 13CO2 (t1/2B) data. Accuracy was assessed by standard deviation (SD) of differences between t1/2S and t1/2B and by receiver operating characteristic (ROC) curves. Regression models using breath samples at baseline, and 45, 90, 105 and 120 min, predicted t1/2B (mean ± SD) at 118 ± 59 min, similar to t1/2S (118 ± 67 min). Correlation between t1/2B and t1/2S was significant (r=0.88; P < 0.0001). Differences between t1/2S and t1/2B were: 18–19.2 min for t1/2 < 70–150 min, and 68.3 min for t1/2 > l50 min. Breath test detected abnormal emptying with a sensitivity of 86% and specificity of 80%. Thus, the 13C‐S. platensis test measures gastric emptying t1/2 for solids, which is accelerated or delayed to mimic a range of conditions from dumping syndrome to severe gastroparesis, with high sensitivity and specificity. Additional breath samples are needed to increase sensitivity in detecting accelerated gastric emptying.

Effect of a somatostatin analogue on gastric motor and sensory functions in healthy humans

Background: Pharmacological approaches to alter satiation may have an impact on functional upper gastrointestinal disorders and potentially change food intake in obesity. Aim: Our aim was to compare the effects of two doses of octreotide and placebo on postprandial symptoms, gastric accommodation, and gastric emptying using validated non-invasive techniques. Methods: In a randomised, parallel group, two dose, double blind, placebo controlled study, 39 healthy participants (13 per group) were randomised to 30 or 100 µg octreotide or placebo, administered subcutaneously, 30 minutes before each study. Studies were performed on three separate days and included scintigraphic gastric emptying of solids and liquids, 99mTc SPECT imaging to measure fasting stomach volume and gastric accommodation following a 300 ml Ensure meal, and a standardised nutrient drink test to measure maximum tolerated volume and postprandial symptoms. Results: Relative to placebo, both doses of octreotide delayed gastric emptying of solids (not liquids), increased fasting gastric volume, reduced the change in gastric volume post meal, and decreased the sensation of fullness after a satiating meal. Conclusion: The somatostatin analogue octreotide significantly alters human gastric functions, including inhibition of the normal reflex responses of gastric volume increase and emptying of the meal. These pharmacological effects suggest studies of the medication in disorders of satiation, including obesity and dyspepsia, are warranted.

Effect of female sex hormone supplementation and withdrawal on gastrointestinal and colonic transit in postmenopausal women

Abstract  Females are disproportionately affected by constipation, which is often aggravated during pregnancy. Bowel function also changes during the luteal phase of the menstrual cycle. The aim was to compare the effects of acute administration of female sex steroids on gastric emptying, small bowel transit and colonic transit in healthy postmenopausal subjects. A second aim was to determine whether withdrawal of the hormones was associated with a change in transit. Forty‐nine postmenopausal females were randomized to receive for 7 days 400 mg day−1 micronized progesterone, 0.2 mg day−1 oestradiol, combination of the two, or placebo. Treatment groups were balanced on age. Participants underwent whole gut transit measurement by scintigraphy using a 99m‐labeled technetium‐egg meal and 111‐labeled indium‐charcoal via a delayed‐release capsule. Transit measurement was repeated after withdrawal of the study medications. The primary endpoints were ascending colon (AC) emptying half‐life time (t1/2) and colonic geometric centre (GC) at 24 h. Secondary analysis variables were GC at 4 and 48 h, gastric emptying t1/2 and colonic filling at 6 h. There was a significant overall effect of progesterone on colonic transit with shorter AC emptying t1/2 and significantly greater colonic GC at 48 h. No transit endpoints were altered by oestradiol or combined hormonal treatment relative to placebo. Oestradiol and progesterone resulted in looser stool consistency. Withdrawal of the hormone supplement was not associated with significant alteration in transit. Micronized progesterone does not retard colonic transit in postmenopausal females.

Effect of Gastric Volume or Emptying on Meal-Related Symptoms After Liquid Nutrients in Obesity: A Pharmacologic Study

BACKGROUND & AIMS Altered postprandial satiation influences food intake in obesity. The aim of this study was to evaluate the contribution of gastric motor functions to intra- and postprandial symptoms in obese, otherwise healthy, people. METHODS In a randomized, parallel-group, double-blind design, 40 obese (body mass index>30 kg/m2) healthy volunteers (n=10/group) received intravenous saline (placebo), atropine (.02 mg/kg), or erythromycin (1 or 3 mg/kg) to alter gastric volume and emptying after liquid nutrient meals, measured by validated imaging methods. The nutrient drink test assessed the volume ingested at maximum satiation, and intra- and early postprandial symptoms. Relationships between gastric motor functions, meal size, and symptoms were assessed by using multiple regression. Circulating levels of candidate upper-gut hormones involved in satiation were measured. RESULTS Relative to placebo, atropine retarded gastric emptying and increased gastric volumes; erythromycin accelerated gastric emptying and reduced gastric volumes during fasting. Although similar maximal tolerated volumes were recorded across treatments, intra- and immediate postprandial symptoms were increased by these perturbations, particularly nausea and bloating. Upper-gut hormonal profiles generally reflected changes in gastric emptying. Regression analysis showed that fasting predrug gastric volume was a significant predictor of intra- and postprandial bloating. Change in gastric volume postdrug or postmeal did not contribute additionally to predicting intra- or postprandial symptoms. There was significant (negative) association between gastric emptying and fullness score, and significant (positive) association with hunger score 30 minutes postprandially. CONCLUSIONS In obese individuals, fasting gastric volumes and gastric emptying, but not postprandial gastric volumes, were associated with intra- and postprandial symptoms. Understanding the determinants of gastric volume may provide insights on mechanisms controlling satiation.

Effects of glucagon-like peptide-1 and feeding on gastric volumes in diabetes mellitus with cardio-vagal dysfunction

Abstract Glucagon‐like peptide‐1 (GLP‐1) increases gastric volume in humans possibly through the vagus nerve. Gastric volume response to feeding is preserved after vagal denervation in animals. We evaluated gastric volume responses to GLP‐1 and placebo in seven diabetic patients with vagal neuropathy in a crossover study. We also compared gastric volume response to feeding in diabetes with that in healthy controls. We measured gastric volume using SPECT imaging. Data are median (interquartile range). In diabetic patients, GLP‐1 did not increase gastric volume during fasting [5 mL (−3; 30)] relative to placebo [4 mL (−14; 50) P = 0.5], or postprandially [Δ postprandial minus fasting volume 469 mL (383; 563) with GLP‐1 and 452 mL (400; 493) with placebo P = 0.3]. Change in gastric volume over fasting in diabetic patients on placebo was comparable to that of healthy controls [452 mL (400; 493)], P = 0.5. In contrast to effects in health, GLP‐1 did not increase gastric volume in diabetics with vagal neuropathy, suggesting GLP‐1s effects on stomach volume are vagally mediated. Normal gastric volume response to feeding in diabetics with vagal neuropathy suggests that other mechanisms compensate for vagal denervation.