Effects of ondansetron on symptoms during a gastric emptying study and enteral lipid challenge and on daily symptoms in diabetic gastroenteropathy.

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 T1/2. 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.

Small intestinal bacterial overgrowth in diabetic gastroenteropathy.

BACKGROUND: Although diabetic gastroenteropathy (DGE) is associated with small intestinal bacterial overgrowth (SIBO), most studies have evaluated SIBO with a hydrogen breath test, which may be affected by altered transit in DGE. The risk factors for the consequences of SIBO in DGE are poorly understood. We aimed to evaluate the prevalence of, risk factors for, and gastrointestinal symptoms associated with SIBO in patients with DGE. METHODS: In 75 patients with DGE and dyspepsia, we tested for SIBO (≥105 colony forming units /mL of aerobic and/or anaerobic bacteria in a duodenal aspirate) and assessed gastric emptying (GE) of solids, symptoms during a GE study and during an enteral lipid challenge (300 kcal/2 h), and daily symptoms with a Gastroparesis Cardinal Symptom Index diary for 2 weeks. Symptoms and GE were compared in patients with versus without SIBO. KEY RESULTS: Of 75 patients, 34 (45%) had SIBO, which was not associated with the use of proton pump inhibitors, daily symptoms, GE, or symptoms during a GE study. During enteral lipid challenge, severe nausea (p = 0.006), fullness (p = 0.02) and bloating (p = 0.009) were each associated with SIBO. Twenty patients (59%) with versus 13 (32%) without SIBO had at least one severe symptom during the lipid challenge (p = 0.006). CONCLUSIONS & INFERENCES: Among patients with DGE 45% had SIBO, which was associated with symptoms during enteral lipid challenge but not with delayed GE, symptoms during a GE study, or daily symptoms. Perhaps bacterial products and even fatty acids are recognized by and activate mast cells that drive the increased lipid sensitivity in SIBO.

Effects of liraglutide on gastrointestinal functions and weight in obesity: A randomized clinical and pharmacogenomic trial.

OBJECTIVE: This study aimed to determine the effects of a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide, and placebo subcutaneously over 16 weeks on weight and gastric functions and to evaluate associations of single-nucleotide polymorphisms in GLP1R (rs6923761) and TCF7L2 (rs7903146) with effects of liraglutide. METHODS: The study conducted a randomized, parallel-group, placebo-controlled, 16-week trial of liraglutide, escalated to 3 mg subcutaneously daily in 136 otherwise healthy adults with obesity. Weight, gastric emptying of solids (GES), gastric volumes, satiation, and body composition measured at baseline and after treatment were compared in two treatment groups using analysis of covariance. RESULTS: Liraglutide (n = 59) and placebo (n = 65) groups completed treatment. Relative to placebo, liraglutide increased weight loss at 5 and 16 weeks (both p < 0.05), slowed time to half GES (T1/2 ) at 5 and 16 weeks (both p < 0.001), and increased fasting gastric volume (p = 0.01) and satiation (p < 0.01) at 16 weeks. GES T1/2 was positively correlated with weight loss on liraglutide (both p < 0.001). After 16 weeks of liraglutide, GLP1R rs6923761 (AG/AA vs. GG) was associated with reduced percent body fat (p = 0.062), and TCF7L2 rs7903146 (CC vs. CT/TT) was associated with lower body weight (p = 0.015). CONCLUSIONS: Liraglutide, 3 mg, induces weight loss with delay in GES T1/2 and reduces calorie intake. Slowing GES and variations in GLP1R and TCF7L2 are associated with liraglutide effects in obesity.

Comprehensive characterization of antral and pyloric contractions by high resolution manometry: applied physiology in suspected gastroparesis.

Delayed gastric emptying may result from diverse pathophysiological mechanisms including antral hypomotility and pylorospasm. With increasing use of gastric peroral endoscopic myotomy and preliminary evidence of efficacy, our aim was to assess the motor functions of the distal antrum and pylorus in patients with symptoms of gastroparesis using high-resolution antropyloroduodenal manometry (HR-ADM). Sixteen patients with symptoms suggestive of gastroparesis underwent HR-ADM with 13 sensors, 1 cm apart, placed across the antropyloroduodenal (APD) junction and 2 sensors, 10 cm apart, in descending and distal duodenum. The 1-h postprandial motility was quantitated as contraction frequency/minute, average amplitude, and motility index (MI). Six healthy volunteers served as controls. In the patient group, the HR-ADM identified postprandial antral hypomotility, isolated pyloric pressure waves, and tonic elevation of baseline pressure in pylorus. Patients had significantly reduced frequency of the full-hour postprandial antral contractions/minute compared with healthy volunteers [1.52 (0.97, 1.67) vs. 2.04 (1.70, 2.67), P = 0.005], as well as reduced MI [9.65 (8.29, 10.31) vs. 11.04 (10.65, 11.63), P = 0.002]. The average contraction amplitude was numerically, but not significantly reduced [51.9 (21.9, 74.9) vs. 73.0 (59.8, 82.7), P = 0.14]. Bland-Altman plots showed similar distribution of antral contraction frequency and MI during the first and second postprandial 30-min periods for both patients and controls. High-resolution ADM can characterize a variety of postprandial antral contractile and pyloric motility dysfunctions. This technique shows promise to provide guidance for the selection of optimal treatment of patients with gastroparesis.NEW & NOTEWORTHY Current selection of different treatments for patients with gastroparesis is empiric or based on trial and error, though pyloric distensibility and diameter may predict response to pyloric interventions. High-resolution antropyloroduodenal manometry (HR-ADM) can characterize a variety of postprandial antral contractile and pyloric motility dysfunctions in patients with suspected gastroparesis. HR-ADM shows promise to provide guidance for selection and individualization of treatments such as prokinetic agents or pyloric interventions for patients with gastroparesis based on documented pathophysiology.

Defining normal pouch function in patients with ileal pouch-anal anastomosis: a pilot study.

BACKGROUND: Most patients experience good functional outcomes following ileal pouch-anal anastomosis (IPAA) for ulcerative colitis. AIM: We aimed to determine if asymptomatic patients with an IPAA had findings consistent with normal defecation on standard objective anorectal tests. METHODS: Patients 18-65 years old with IPAA and self-reported healthy pouch function were recruited. Patients with chronic pouchitis, Crohn's disease, anastomotic stricture, or indication for IPAA other than ulcerative or indeterminate colitis were excluded. Patients underwent an interview with an abbreviated Rome Questionnaire followed by high-resolution ano-pouch manometry, balloon expulsion test, pouch barostat, and magnetic resonance (MR) defecography. RESULTS: Twenty patients completed all testing. Six patients were excluded from the final analysis due to symptoms suggestive of pouch evacuation disorder on the abbreviated Rome Questionnaire (n = 2), structural abnormality on MR imaging (n = 3), or both (n = 1). Of the remaining 14 patients, mean anal resting pressure during high-resolution manometry was 72 ± 16 mmHg, mean anal squeeze pressure was 247 ± 69 mmHg, and mean pouch-anal gradient during the simulated evacuation was -27 ± 37 mmHg. The meantime to balloon expulsion was 54 seconds. During dynamic MR defecography, the mean descent of ano-pouch junction was 2.6 cm, and mean pouch evacuation was 44.5% and 74.2% pre- and posttoilet phase, respectively. CONCLUSIONS: A substantial proportion of patients with IPAA and self-reported healthy pouch function have anatomic and/or functional abnormalities of the pouch. In asymptomatic IPAA patients with an anatomically normal pouch, we have proposed normal parameters for high-resolution ano-pouch manometry, time to balloon expulsion, pouch barostat, and MR defecography.

Gastric accommodation influences proximal gastric and total gastric emptying in concurrent measurements conducted in healthy volunteers.

Gastric emptying and gastric accommodation play a role in generation of upper gastrointestinal symptoms. Although both functions have been measured simultaneously using MRI or 99mTc SPECT methodology, the correlation of these two functions has not been evaluated simultaneously using a solid and liquid meal. To study relationships of whole or proximal stomach volumes to emptying, we concurrently measured postprandial gastric accommodation and emptying (over 4 h) of a 111In-labeled mixed solid and liquid meal. A semiautomated method allowing selection of a segmentation threshold based on a grayscale image was used to measure volume of the proximal half of the stomach, defined as the top half of axial slices along the vertical length of the stomach. A correction factor derived from phantom studies was applied for upscatter from the 99mTc to the 111In window. Relationships of time to emptying 10%, 25%, 50%, and 75% of the meal to fasting and postprandial gastric volumes were evaluated using Spearman correlation. Whole stomach fed and accommodation volumes were significantly correlated with all gastric emptying times (10%, 25%, and 50%). Proximal stomach fed volumes were similarly associated with 50% and 75% proximal gastric emptying. Fed proximal gastric volume was associated with 50% and 75% whole gastric emptying. Fed proximal accommodation volume was associated with 50% gastric emptying. Fasting gastric volumes were not significant determinants of emptying rates. In conclusion, postprandial gastric accommodation is significantly associated with the rate of gastric emptying, with higher gastric volumes associated with prolongation of emptying. Novel methods to measure proximal gastric accommodation and correct for radioisotope upscatter are described.NEW & NOTEWORTHY In vivo human studies evaluated concurrently the volume of the stomach during fasting and after a solid and liquid meal using a new SPECT-based method. Although fasting gastric volumes did not impact the rates of gastric emptying, both postprandial and accommodation volumes of the whole and proximal stomach were significantly correlated with gastric emptying. Larger stomach volumes were associated with slower gastric emptying.

Associations of gastric volumes, ingestive behavior, calorie and volume intake, and fullness in obesity.

Whereas gastric emptying significantly predicts calorie intake, the association between gastric capacity and satiation and satiety is unclear. To study the associations between gastric volumes and ingestive behaviors with satiation and satiety in obesity, 62 healthy adult obese patients (57 female) with no eating disorders underwent measurements of satiety, as determined by kilocalories of ingestion at a buffet meal, and satiation by volume to comfortable fullness (VTF) and maximum tolerated volume (MTV), while drinking Ensure (30 mL/min). Fasting and postprandial gastric volumes were measured by validated single-photon emission computed tomography. We also measured eating [Weight Efficacy Life-Style Questionnaire score (WEL)] and exercise behaviors associated with obesity. Spearman correlation-assessed relationships of measured traits and linear regression analysis to identify predictors of satiation or satiety. The participants were aged 38 ± 10.1 yr and the body mass index (BMI) 36.8 ± 4.8 kg/m2. Fasting gastric volume was significantly correlated with VTF (rs = 0.3, P = 0.03), but not with MTV or buffet meal kilocalorie ingestion. Regression analysis identified sex (P = 0.02, with males having significantly higher fasting gastric volume) and fasting gastric volume (0.04) as predictors of higher VTF. An increase in fasting gastric volume of 50 mL resulted in a 6-mL increase in VTF. Buffet meal intake was inversely related to the ability to resist the urge to eat; factors associated with ingestive behavior (increase in total WEL score) significantly correlated with satiety and gastric accommodation (P < 0.05). Gastric capacity during fasting is associated with calorie intake to the point of comfortable fullness; factors associated with ingestive behavior are associated with satiety and gastric accommodation.NEW & NOTEWORTHY Buffet meal intake was inversely related to the ability to resist the urge to overeat. Factors associated with ingestive behavior significantly correlated with satiety and gastric accommodation. Gastric capacity during fasting is associated with calorie intake to the point of comfortable fullness; factors associated with ingestive behavior are associated with satiety and gastric accommodation.

GLP-1 Analog Modulates Appetite, Taste Preference, Gut Hormones, and Regional Body Fat Stores in Adults with Obesity.

PURPOSE: Obesity is associated with alterations in appetite, gastrointestinal hormone levels and excessive fat mass. We previously published a double-blind, placebo-controlled, randomized, 16-week trial on effects of once-daily glucagon-like peptide-1 (GLP-1) analog, liraglutide on weight, satiation, and gastric functions in obese volunteers. The aim of this substudy is to compare to placebo the effects of liraglutide on appetite, taste preference, regional body fat stores, and anthropometric measurements. METHODS: Forty obese adults received standard instruction for weight management, monthly behavioral intervention utilizing motivational interviews, and 16-week treatment of once-daily liraglutide (escalated to 3 mg SQ daily). At baseline and 16 weeks, the following were measured: appetite and taste preferences rated every 30 min for 5 h after ingesting 300 mL Ensure®; maximal tolerated volume (MTV) with a nutrient drink test; fasting and postprandial bioactive GLP-1 (7-36) and peptide YY (PYY) levels; total and regional body fat with dual-energy X-ray absorptiometry, and waist and hip circumference. RESULTS: Thirty-five participants (17 liraglutide; 18 placebo) completed the trial. Compared to placebo group, liraglutide group had significant reductions in MTV; prospective food consumption score; desire to eat something sweet, salty, savory or fatty; and an increase in perceived fullness. Postprandial plasma levels of GLP-1 decreased and PYY levels increased with liraglutide relative to baseline. Significant reductions in total body, trunk, and upper and lower body fat without reduction in lean body mass were observed. CONCLUSION: Liraglutide 3 mg SQ modulates appetite, taste preference, gut hormones, and regional body fat stores in adults with obesity without reduction in lean body mass.

Effects of liraglutide on weight, satiation, and gastric functions in obesity: a randomised, placebo-controlled pilot trial.

BACKGROUND: Liraglutide, a long-acting GLP-1 receptor agonist, is approved for treatment of obesity; however, the mechanisms of action of liraglutide are incompletely understood. We compared effects of liraglutide versus placebo on gastric motor functions, satiation, satiety, and weight in obese individuals over 16 weeks. METHODS: We did a randomised, double-blind, placebo-controlled pilot trial at a single centre (Mayo Clinic, Rochester, MN, USA). Participants were randomly allocated (1:1) by a computer generated randomisation schedule with no stratification to receive subcutaneous liraglutide (3·0 mg) or placebo, with standardised nutritional and behavioural counselling. Allocation was concealed from participants and study investigators. Otherwise healthy, local residents aged 18-65 years with body-mass index (BMI) 30 kg/m2 or higher were included. Liraglutide or placebo was escalated by 0·6 mg/day each week for 5 weeks and continued until week 16. The primary outcome was change in gastric emptying (delay relative to baseline) of solids T1/2 (time taken for half the radiolabelled meal to empty from the stomach), measured at 5 weeks and 16 weeks in all patients who received at least one dose of study drug, with missing data imputed. Secondary outcomes included weight loss at weeks 5 and 16, satiation (volume to fullness and maximum tolerated volume), satiety, and fasting and postprandial gastric volumes at 16 weeks. This trial is registered with ClinicalTrials.gov, number NCT02647944, and is closed to new participants. FINDINGS: Between Dec 18, 2015, and Sept 1, 2016, 40 adults were enrolled and randomly allocated (19 to the liraglutide group; 21 to the placebo group). Compared with placebo, liraglutide delayed gastric emptying of solids at 5 weeks (median 70 min [IQR 32 to 151] vs 4 min [-21 to 18]; p<0·0001) and 16 weeks (30·5 min [-11 to 54] vs -1 min [-19 to 7]; p=0·025). There was also significantly greater weight loss in the liraglutide group than in the placebo group (at 5 weeks: median 3·7 kg [IQR 2·8 to 4·8] vs 0·6 kg [-0·3 to 1·4], p<0·0001; at 16 weeks: 5·3 kg [5·2 to 6·8] vs 2·5 kg [0·1 to 4·2], p=0·0009). Satiation, as assessed by maximum tolerated volume at 16 weeks, was lower in the liraglutide group (median 750 mL [IQR 651 to 908]) compared with the placebo group (1126 mL [944-1185]; p=0·054). No significant differences were noted between groups in terms of volume to fullness, satiety, or fasting and postprandial gastric volumes at week 16. Post-hoc analysis showed that the T1/2 of gastric emptying of solids at 5 weeks correlated with change in weight loss at week 16 with liraglutide (Rs 0·567, p=0·018). Nausea was the most common adverse event in the liraglutide group (12 of 19) compared with placebo (four of 21). INTERPRETATION: Effects of liraglutide on weight loss are associated with delay in gastric emptying of solids; measurement of gastric emptying (eg, at 5 weeks of treatment) may be a biomarker of responsiveness and may help to select individuals for prolonged treatment with this class of drug. FUNDING: US National Institutes of Health grant R56-DK67071.

Effects of Rifaximin on Transit, Permeability, Fecal Microbiome, and Organic Acid Excretion in Irritable Bowel Syndrome.

OBJECTIVES: Rifaximin relieves irritable bowel syndrome (IBS) symptoms, bloating, abdominal pain, and loose or watery stools. Our objective was to investigate digestive functions in rifaximin-treated IBS patients. METHODS: In a randomized, double-blind, placebo-controlled, parallel-group study, we compared the effects of rifaximin, 550 mg t.i.d., and placebo for 14 days in nonconstipated IBS and no evidence of small intestinal bacterial overgrowth (SIBO). All subjects completed baseline and on-treatment evaluation of colonic transit by scintigraphy, mucosal permeability by lactulose-mannitol excretion, and fecal microbiome, bile acids, and short chain fatty acids measured on random stool sample. Overall comparison of primary response measures between treatment groups was assessed using intention-to-treat analysis of covariance (ANCOVA, with baseline value as covariate). RESULTS: There were no significant effects of treatment on bowel symptoms, small bowel or colonic permeability, or colonic transit at 24 h. Rifaximin was associated with acceleration of ascending colon emptying (14.9±2.6 h placebo; 6.9±0.9 h rifaximin; P=0.033) and overall colonic transit at 48 h (geometric center 4.0±0.3 h placebo; 4.7±0.2 h rifaximin; P=0.046); however, rifaximin did not significantly alter total fecal bile acids per g of stool or proportion of individual bile acids or acetate, propionate, or butyrate in stool. Microbiome studies showed strong associations within subjects, modest associations with time across subjects, and a small but significant association of microbial richness with treatment arm (rifaximin vs. treatment). CONCLUSIONS: In nonconstipated IBS without documented SIBO, rifaximin treatment is associated with acceleration of colonic transit and changes in microbial richness; the mechanism for reported symptomatic benefit requires further investigation.

Increased nutrient sensitivity and plasma concentrations of enteral hormones during duodenal nutrient infusion in functional dyspepsia.

OBJECTIVES: Functional dyspepsia is predominantly attributed to gastric sensorimotor dysfunctions. The contribution of intestinal chemosensitivity to symptoms is not understood. We evaluated symptoms and plasma hormones during enteral nutrient infusion and the association with impaired glucose tolerance and quality-of-life (QOL) scores in patients with functional dyspepsia vs. healthy controls. METHODS: Enteral hormonal responses and symptoms were measured during isocaloric and isovolumic dextrose and lipid infusions into the duodenum in 30 patients with functional dyspepsia (n=27) or nausea and vomiting (n=3) and 35 healthy controls. Infusions were administered in randomized order over 120 min each, with a 120-min washout. Cholecystokinin, glucose-dependent insulinotropic peptide, glucagon-like peptide 1 (GLP1), and peptide YY were measured during infusions. RESULTS: Moderate or more severe symptoms during lipid (4 controls vs. 14 patients) and dextrose (1 control vs. 12 patients) infusions were more prevalent in patients than controls (P≤0.01), associated with higher dyspepsia symptom score (P=0.01), worse QOL (P=0.01), and greater plasma hormone concentrations (e.g., GLP1 during lipid infusion). Moderate or more severe symptoms during enteral infusion explained 18%, and depression score explained 21%, of interpatient variation in QOL. Eight patients had impaired glucose tolerance, associated with greater plasma GLP1 and peptide YY concentrations during dextrose and lipid infusions, respectively. CONCLUSIONS: Increased sensitivity to enteral dextrose and lipid infusions was associated with greater plasma enteral hormone concentrations, more severe daily symptoms, and worse QOL in functional dyspepsia. These observations are consistent with the hypothesis that enteral hormones mediate increased intestinal sensitivity to nutrients in functional dyspepsia.

Cannabinoid receptor 1 gene and irritable bowel syndrome: phenotype and quantitative traits.

Genetic variations in metabolism of endocannabinoids and in CNR1 (gene for cannabinoid 1 receptor) are associated with symptom phenotype, colonic transit, and left colon motility in irritable bowel syndrome (IBS). Our aim was to evaluate associations between two variations in CNR1 genotype (rs806378 and [AAT]n triplets) with symptom phenotype, small bowel and colonic transit, and rectal sensations in 455 patients with IBS and 228 healthy controls. Small bowel and colonic transit were measured by scintigraphy, rectal sensation by isobaric distensions. Associations with genotype were assessed by χ(2) test (symptom phenotype) and ANCOVA (quantitative traits) based on a dominant genetic model. Significant association of CNR1 rs806378 (but not CNR1 [AAT]n) genotype and symptom phenotype was observed (χ(2) P = 0.028). There was significant association of CNR1 rs806378 (P = 0.014; CC vs. CT/TT) with colonic transit in IBS-diarrhea (IBS-D) group; the TT group had the fastest colonic transit at 24 and 48 h. There was significant overall association of CNR1 rs806378 with sensation rating of gas (P = 0.025), but not pain; the strongest associations for gas ratings were in IBS-D (P = 0.002) and IBS-alternating (P = 0.025) subgroups. For CNR1 (AAT)n, gene-by-phenotype interactions were observed for colonic transit at 24 (P = 0.06) and 48 h (P = 0.002) and gas (P = 0.046, highest for IBS-D, P = 0.034), but not pain sensation; the strongest association with transit was in controls, not in IBS. These data support the hypothesis that cannabinoid receptors may play a role in control of colonic transit and sensation in humans and deserve further study as potential mediators or therapeutic targets in lower functional gastrointestinal disorders.

The role of autonomic testing in the differentiation of Parkinson's disease from multiple system atrophy.

Differentiation of idiopathic Parkinson's disease (PD) from multiple system atrophy (MSA) can be difficult. Methods devised to help distinguish the two disorders include standardized autonomic testing and cardiac imaging with iodine-123 meta-iodobenzylguanidine myocardial scintigraphy. MSA patients had more severe adrenergic and overall autonomic dysfunction when compared to control and PD patients. Area of anhidrosis on thermoregulatory sweat test was greater in MSA (67.4±12.42, p<0.001) versus PD patients (area of anhidrosis, 1.7±2.96). Postganglionic cardiac sympathetic innervation (iodine-123 meta-iodobenzylguanidine) expressed as heart to mediastinal ratio was significantly lower in Parkinson's disease patients (1.4±0.40, p=0.025) compared to controls (2.0±0.29), but not in multiple system atrophy (2.0±0.76). These findings indicate that autonomic dysfunction is generalized and predominantly preganglionic in multiple system atrophy, and postganglionic in Parkinson's disease. In our hands the thermoregulatory sweat test provides the best distinction between MSA and PD. However further confirmatory studies using larger patient numbers are required. Currently a combination of clinical judgment and autonomic testing is recommended to help differentiate MSA and PD.

Urine sugars for in vivo gut permeability: validation and comparisons in irritable bowel syndrome-diarrhea and controls.

Mucosal barrier dysfunction contributes to gastrointestinal diseases. Our aims were to validate urine sugar excretion as an in vivo test of small bowel (SB) and colonic permeability and to compare permeability in patients with irritable bowel syndrome-diarrhea (IBS-D) to positive and negative controls. Oral lactulose (L) and mannitol (M) were administered with (99m)Tc-oral solution, (111)In-oral delayed-release capsule, or directly into the ascending colon (only in healthy controls). We compared L and M excretion in urine collections at specific times in 12 patients with IBS-D, 12 healthy controls, and 10 patients with inactive or treated ulcerative or microscopic colitis (UC/MC). Sugars were measured by high-performance liquid chromatography-tandem mass spectrometry. Primary endpoints were cumulative 0-2-h, 2-8-h, and 8-24-h urinary sugars. Radioisotopes in the colon at 2 h and 8 h were measured by scintigraphy. Kruskal-Wallis and Wilcoxon tests were used to assess the overall and pairwise associations, respectively, between group and urinary sugars. The liquid in the colon at 2 h and 8 h was as follows: health, 62 ± 9% and 89 ± 3%; IBS-D, 56 ± 11% and 90 ± 3%; and UC/MC, 35 ± 8% and 78 ± 6%, respectively. Liquid formulation was associated with higher M excretion compared with capsule formulation at 0-2 h (health P = 0.049; IBS-D P < 0.001) but not during 8-24 h. UC/MC was associated with increased urine L and M excretion compared with health (but not to IBS-D) at 8-24 h, not at 0-2 h. There were significant differences between IBS-D and health in urine M excretion at 0-2 h and 2-8 h and L excretion at 8-24 h. Urine sugars at 0-2 h and 8-24 h reflect SB and colonic permeability, respectively. IBS-D is associated with increased SB and colonic mucosal permeability.

HLA-DQ genotype is associated with accelerated small bowel transit in patients with diarrhea-predominant irritable bowel syndrome.

BACKGROUND: Colonic transit (CT) is accelerated in 46% of patients with diarrhea-predominant irritable bowel syndrome (IBS-D). Improvement in IBS-D with gluten withdrawal is associated with human leukocyte antigen (HLA)-DQ2 positivity; the mechanism of improvement is unclear. OBJECTIVE: To determine if HLA-DQ2-positive or HLA-DQ8-positive patients with IBS-D have faster small bowel (SB) or CT than HLA-DQ2-negative and HLA-DQ8-negative patients. MATERIALS AND METHODS: Among 94 patients with IBS-D, who previously provided DNA samples, 64 had undergone validated measurements of CT [geometric center at 24 h (GC24)]; 50 of the patients also had measurement of gastric emptying (GE) and 54 of SB transit (colonic filling at 6 h). HLA-DQ status was determined by tag single nucleotide polymorphism approach. Associations of colonic filling at 6 h and GC24 with HLA-DQ2 and HLA-DQ8 status were assessed using analysis of covariance, adjusting for BMI. RESULTS: Mean age was 40.8±1.6 years; 98.5% were females. In 60 of the 64 patients, celiac disease was excluded by serology or histology. There were no significant differences in age or BMI among the different HLA-DQ groups. Independently, patients positive for HLA-DQ2 had numerically greater colonic filling at 6 h compared with HLA-DQ2-negative (P=0.065), and those positive for HLA-DQ8 had greater colonic filling at 6 h compared with HLA-DQ8-negative patients (P=0.021). Gastric emptying was not associated with HLA-DQ2 and HLA-DQ8 status. Patients positive for both HLA-DQ2 and HLA-DQ8 had greater colonic filling at 6 h (P=0.013) and numerically higher, but not significant, GC24 (P=0.38) compared with HLA-DQ2-negative and HLA-DQ8-negative patients. CONCLUSION: Patients with IBS-D positive for HLA-DQ8 or for both HLA-DQ2 and HLA-DQ8 have faster SB transit. The mechanism of the accelerated SB transit and the effect of gluten withdrawal on SB function in IBS-D deserve further investigation.

A preliminary candidate genotype-intermediate phenotype study of satiation and gastric motor function in obesity.

Stomach motility contributes significantly to fullness sensation while eating and cessation of food intake in humans. Genes controlling adrenergic and serotonergic mechanisms (ADRA2A, GNB3, and SLC6A4) affect gastric emptying (GE), volume (GV), and satiation. Fat mass and obesity-associated gene (FTO) is linked with satiety. Our aim was to examine the association of these candidate genes with stomach functions that signal postprandial fullness: GE, GV, and maximum tolerated volume (MTV). These biomarkers constitute a component of the intermediate phenotype of satiation. A total of 62 overweight or obese participants underwent genotyping of the candidate genes, and validated measurements of GE of solids and liquids by scintigraphy, fasting and postprandial change in GV by SPECT (single photon emission computed tomography), and MTV by nutrient drink test. These markers of satiation were compared for 38 genetic variants in ADRA2A, ADR2C, ADRB3, uncoupling protein (UCP)-2 and -3, GNB3, FTO, and SLC6A4 using a recessive model of inheritance. ADRA2A, ADR2C, UCP-3, GNB3, and FTO loci were significantly associated with the intermediate phenotype markers of satiation: ADR2C (Ins-Del322_325) with accelerated GE; GNB3 (rs1047776) with delayed GE; ADRA2A (rs491589 and rs553668) and GNB3 (rs2269355, rs10849527, and rs3759348) with decreased postprandial GV; ADRA2A (rs3750625) and GNB3 (rs4963517 and rs1129649) with increased postprandial GV; UCP-3 (rs1685356) with increased MTV, and FTO (rs9939609) decreased MTV. Genetic susceptibility to postprandial satiation can be identified through intermediate phenotype markers. With independent validation, these markers may guide patient selection of weight-loss therapies directed at gastric motor functions.

Do corticotropin releasing factor-1 receptors influence colonic transit and bowel function in women with irritable bowel syndrome?

Corticotropin releasing factor (CRF), a mediator of stress response, alters gastrointestinal (GI) functions. Stress-related changes in colonic motility are blocked by selective CRF(1) receptor antagonists. Our aim was to assess whether modulation of central and peripheral CRF(1) receptors affects colonic transit and bowel function in female patients with diarrhea-predominant irritable bowel syndrome (D-IBS). This randomized, double-blind, placebo-controlled, 2-wk study evaluated the effects of oral pexacerfont (BMS-562086), a selective CRF(1) receptor antagonist, 25 and 100 mg qd, on GI and colonic transit of solids [by validated scintigraphy with primary end point colonic geometric center (GC) at 24 h] and bowel function (by validated daily diaries) in 39 women with D-IBS. The 100-mg dose was comparable to a dose that inhibited colonic motility in stressed rats. Treatment effects were compared by analysis of covariance with baseline colonic transit as covariate. The study had 80% power (alpha = 0.05) to detect clinically meaningful (26%) differences in colonic transit. Thirty-nine of 55 patients fulfilled eligibility criteria (9 screen failures, 5 baseline GC24 outside prespecified range). At baseline, three treatment groups had comparable age, body mass index, and GC 24 h. Significant effects of pexacerfont relative to placebo were not detected on colonic GC24 (P = 0.53), gastric emptying, orocecal transit, ascending colon emptying half-time, and stool frequency, consistency, and ease of passage. No safety issues were identified. We conclude that in women with D-IBS, pexacerfont, 25 or 100 mg qd, does not significantly alter colonic or other regional transit or bowel function. The role of central and peripheral CRF(1) receptors in bowel function in D-IBS requires further study.

Feasibility and application of 3-dimensional ultrasound for measurement of gastric volumes in healthy adults and adolescents.

OBJECTIVES: Abnormal gastric accommodation to a meal results in dyspepsia. Current methods to measure gastric volume (GV) are invasive or involve ionizing radiation. The aims of this study were to compare fasting and postprandial (PP) GVs measured by (99m)Tc-single photon emission computed tomography (SPECT) and 3-dimensional ultrasound (3D-US) in adults, to assess the performance characteristics of 3D-US measurement of GV during fasting and postprandially, and to develop normative data of GVs in 24 healthy adolescents. PATIENTS AND METHODS: Eleven adults underwent SPECT and 3D-US simultaneously to measure GV, and a second 3D-US alone within 1 week of the first study. Twenty-four adolescents underwent 1 3D-US measurement. Each study included fasting, a 300-mL Ensure meal, and 0 to 30-minute PP GV measurements. RESULTS: 3D-US identifies GV accommodation to 300mL Ensure. Delta (0-30 minutes average PP fasting) GV was 444mL (median, interquartile range [IQR]=422, 534) for 3D-US and 543mL (median, IQR=486, 564) for SPECT (P=0.15). There were larger interindividual coefficients of variation for GV by 3D-US (60.3% fasting and 21.3% average PP) compared with 19% fasting and 9.2% PP for SPECT. Intraindividual coefficients of variation for the 2 3D-US measurements in adults were 84% fasting and 44% average PP. The estimated GVs for the adolescent group (median [25th-75th IQR]) were 33 (18-53)mL fasting, 330 (284-357)mL 30 minutes PP, and 281 (240-324)mL for delta GV. CONCLUSIONS: 3D-US is a promising method to measure GV accommodation to a meal. Large coefficients of variation reflect the learning stage in development of this promising technique.