Burton, Duane D.

AbstractBackgroundThis study compared prucalopride, a selective, prokinetic, 5‐HT4 receptor agonist, with polyethylene glycol 3350 + electrolytes (PEG3350), an osmotic laxative, on colonic motility parameters, primarily high‐amplitude propagating contractions (HAPCs) in patients with chronic constipation.MethodsThis randomized, cross‐over, reader‐blinded study was conducted at a single site in the USA. The study was open to men and women aged 18–75 years who met study inclusion criteria. Colonic manometry catheters were inserted the day before investigation. On the investigation days, patients received oral 2 mg prucalopride or 2 × 13.8 g PEG3350 in solution. The primary endpoint was HAPC count (threshold: mean amplitude ≥100 mmHg, propagation ≥20 cm [HAPC1]) in the 12 h after treatment administration. Analyses were also conducted at two co‐primary thresholds: mean amplitude ≥75 mmHg, propagation ≥20 cm (HAPC2); and mean amplitude ≥75 mmHg, propagation ≥10 cm (HAPC3). Secondary endpoints included HAPC area under the curve (AUC), contraction force, amplitude, duration, and propagation velocity.Key ResultsThirteen women were enrolled, with 12 completing the study. Significantly more HAPC1 (8.7 ± 2.06 vs 2.9 ± 2.06; p = 0.012) and HAPC2 (9.0 ± 2.11 vs 3.3 ± 2.11; p = 0.017) were observed in the 12‐h periods with prucalopride than with PEG3350. Prucalopride significantly increased mean propagation distance and velocity (HAPC2) and mean AUC, force, and amplitude (HAPC3) compared with PEG3350. Adverse events were mild or moderate.Conclusions & InferencesPrucalopride was superior to PEG3350 in inducing HAPCs in patients with chronic constipation.ClinicalTrials.gov number NCT01707667.

AbstractBackgroundGastrointestinal (GI) and non‐GI disorders are associated with altered intestinal permeability, which can be measured in vivo by urinary excretion after oral lactulose and mannitol ingestion. Inadvertent dietary consumption of 12Carbon (12C, regular) mannitol in food or from other sources may interfere with the test's interpretation. 13Carbon (13C) constitutes 1% of carbon in nature and 13C mannitol is a stable isotope. Our aim was to determine the performance of 13C mannitol for measurement of intestinal permeability.MethodsTen healthy volunteers underwent intestinal permeability assay using coadministered 12C mannitol, 13C mannitol and lactulose, followed by timed urine collections. Urinary sugar concentrations were measured using tandem high performance liquid chromatography–mass spectrometry.Key resultsWe found that 13C mannitol can be distinguishable from 12C mannitol on tandem mass spectrometry. In addition, 13C mannitol had ~20‐fold lower baseline contamination compared to 12C mannitol. We describe here the 13C mannitol assay method for the measurement of intestinal permeability.Conclusions & InferencesIn conclusion, 13C mannitol is superior to 12C mannitol for measurement of intestinal permeability. It avoids issues with baseline contamination and erratic excretions during the testing period.

ObjectiveTo examine the association of gene variants of uncoupling proteins (UCP)‐2 and −3 with obesity and gastrointestinal (GI) traits.MethodsIn 255 overweight or obese adults, the associations of gene variants in UCP‐2 (−3474, rs659366) and UCP‐3 (rs1626521, rs2075577, rs15763) with body weight (BW) and GI traits were studied. Gene variants were genotyped by TaqMan® assay. The associations of genotypes with BW and GI traits (gastric emptying, gastric volume, satiety by buffet meal, satiation by nutrient drink test and GI hormones) were assessed using ANOVA corrected for false detection rate (FDR).ResultsA novel UCP‐3 gene variant, rs1626521, was identified; it was associated with BW (P = 0.039), waist circumference (P = 0.035), and significantly higher postprandial gastric volume (P = 0.003) and calories ingested at buffet meal (P = 0.006, both significant with FDR). In a subgroup of 11 participants, rs1626521 was also associated with reduced mitochondrial bioenergetics efficiency in skeletal muscle (P = 0.051). In an in vitro study in HEK293 cells, rs1626521 reduced UCP‐3 protein expression (P = 0.049). Associations detected between other genotypes and GI traits were nonsignificant with FDR.ConclusionsA newly identified functional variant (rs1626521) in UCP‐3 affects postprandial gastric functions and satiety and may contribute to weight gain and alter human mitochondrial function.

To compare the effects of the κ-opioid agonist asimadoline and placebo on visceral sensation and gastrointestinal (GI) motor functions in humans, 91 healthy participants were randomized in a double-blind fashion to 0.15, 0.5, or 1.5 mg of asimadoline or placebo orally twice a day for 9 days. We assessed satiation (nutrient drink test), colonic compliance, tone, perception of colonic distension (barostat), and whole gut transit (scintigraphy). Treatment effect was assessed by analysis of covariance. Asimadoline increased nutrient drink intake ( P = 0.03). Asimadoline decreased colonic tone during fasting ( P = 0.03) without affecting postprandial colonic contraction, compliance, or transit. Gas scores in response to colonic distension were decreased with 0.5 mg of asimadoline at low levels (8 mmHg above operating pressure) of distension ( P = 0.04) but not at higher levels of distension. Asimadoline at 1.5 mg increased gas scores at 16 mmHg of distension ( P = 0.03) and pain scores at distensions of 8 and 16 mmHg ( P = 0.003 and 0.03, respectively) but not at higher levels of distension. Further studies of this compound in diseases with altered satiation or visceral sensation are warranted.

AbstractBackgroundA valid biomarker is ‘an indicator of normal biologic or pathogenic processes, or pharmacological responses to a therapeutic intervention’. There is no validated biomarker for irritable bowel syndrome (IBS). The aim of the study was to assess ability of three quantitative traits to identify treatable processes to discriminate between IBS‐diarrhea (IBS‐D) patients, IBS‐constipation (IBS‐C) patients and healthy volunteers (HV).MethodsIn 30 HV, 30 IBS‐C patients and 64 IBS‐D patients, we characterized bowel symptoms and quantitated pathophysiological mechanisms: bile acid (BA) synthesis (serum C4 and FGF19), fecal BA and fat, colonic transit (CT), and intestinal permeability (IP). We used multiple logistic regression and receiver‐operating characteristic (ROCAUC) to appraise three factors (fecal BA, CT, and IP) individually and in combination to identify discriminant targets for treatment in IBS.Key ResultsThere were significant associations between the three subgroups and symptoms reflecting bowel function and the quantitative traits. There were significant associations between fecal BA and CT at 48 h (r = 0.43; p < 0.001) and between fecal BA and IP (r = 0.23; p = 0.015). Individually, fecal BA and CT48 (but not IP) were significant independent predictors for distinguishing HV from IBS. In combination, they discriminated HV from IBS‐D patients (ROCAUC 0.70), HV from IBS‐C patients (ROCAUC 0.73), and IBS‐C patients from IBS‐D patients (ROCAUC 0.86). Colonic transit and fecal BA excretion together discriminate between healthy volunteers and IBS‐C patients or IBS‐D patients, or between the IBS subgroups with 75–90% specificity at 60% sensitivity.Conclusions & InferencesColonic transit and fecal BA individually and together constitute useful biomarkers to identify treatable mechanisms in IBS and to differentiate subgroups of IBS.

AbstractBackgroundNausea and vomiting are thought to result from upper gastrointestinal dysfunctions. Our clinical observations led to the hypothesis that colonic motor dysfunction is associated with nausea and vomiting.MethodsWe reviewed electronic medical records (EMR) of 149 patients presenting with complaints of nausea and/or vomiting in a tertiary gastroenterology practice to investigate the association with disorders of colonic motor or evacuation disorders. We extracted demographics, gastric emptying (GEin 149) and colonic transit (CTin 138) of solids, ascending colon emptying half‐time (ACt1/2), rectal evacuation by anorectal manometry (ARM) in 91 and balloon expulsion test (BE) in 55 patients. We estimated the proportions with delayedGEorCT, based on the 5th percentile ofGE(in 319) andCTin 220 healthy volunteers using same method.Key ResultsAmong 11 patients with nausea and/or vomiting with onlyGEmeasured, five had delayed and six normalGE. Among the 149 patients, 77 (52%) patients had evacuation disorders, confirmed by objective tests in 68 patients, and clinical examination in nine patients. In the 138 patients with bothGEandCTmeasured, 106 (76%) had both normalGEandCT, 11 (8%) only delayedGE, 16 (11%) normalGEwith delayedCT, and five (3%) delayedGEandCT. Among 21 patients (15%) with delayedCT, nine had slowACt1/2and 12 evacuation disorder.Conclusions & InferencesIn patients with chronic nausea and/or vomiting in gastroenterology practice, evaluation of colonic motility and rectal evacuation should be considered, since about half the patients have abnormal functions that conceivably contribute to the presenting nausea and/or vomiting.

Summary Background Daikenchuto, a Japanese herbal medicine used for post‐operative ileus and constipation, dose dependently stimulates gastrointestinal ( GI ) motility and decreases rectal compliance and sensation. Effects of TU ‐100 (commercial form of daikenchuto) in adults with constipation are unknown. Aim To compare the effects of oral TU ‐100, 2.5 g t.d.s. or 5 g t.d.s. and placebo t.d.s. on GI and colonic transit ( CT ), rectal compliance ( RC ) and sensation thresholds ( RST ), anal sphincter pressures ( ASP ) and bowel function in female patients with functional constipation ( FC ). Methods We conducted a single‐centre, randomised, parallel‐group, double‐blind, pharmacodynamic study; 45 female patients with FC without evidence of rectal evacuation disorder were assigned to 28 days' treatment with oral placebo or TU ‐100 (Tsumura USA, Princeton, NJ, USA). Demographic data and CT were measured at baseline and randomisation stratified by baseline CT (GC> or <1.9) and by BMI (<25 or ≥25 kg/m 2 ). At the end of treatment period, we measured GI and CT by scintigraphy, RST and RC by barostat, ASP by manometry, psychosensory sensations, bowel function by daily diary and quality of life ( QOL ). The study had power to detect effect sizes of 33% ( CT ), 40% ( RC ) and 46% ( RST ). Statistical analysis included BMI as covariate. Results TU ‐100 had no significant effects on GI or CT , RC , ASP , recto‐anal pressure difference, or RST . The 5 g t.d.s./day dose was associated with lower RST for first sensation and gas (unadjusted P : 0.045 and 0.024 respectively). There were no treatment effects on psychosensory symptoms, stool frequency, stool consistency or QOL . Conclusion Mechanisms underlying the observed clinical benefit of TU ‐100 remain unclear ( ClinicalTrials.gov NCT01139216).

AbstractBackgroundNon‐invasive single photon emission computed tomography (SPECT) has been validated as a test for postprandial gastric volume accommodation, with volumes measured twice over 30 min and averaged. The purpose of this study is to simplify the SPECT measurement of gastric accommodation.MethodsThe primary aim of this study was to compare two postprandial gastric volume measurements with data collected retrospectively from 443 patients and healthy volunteers who had undergone SPECT in the last decade. The differences in the two gastric volumes were compared in the entire group and each subgroup, and the correlation between the two measurements and their differences across a wide range of gastric volumes were plotted.Key ResultsThere was a median difference of <2% (P = 0.041) between postprandial scan 1 (757 mL) and scan 2 (743 mL), with significant correlation (rs = 0.859, P < 0.01) and excellent agreement (SD 60 mL) between the two scans across the entire range of observed postprandial gastric volumes.Conclusions & InferencesA single postprandial scan can detect gastric accommodation with the same accuracy as averaging two postprandial scans. These data support simplifying SPECT measurement of postprandial gastric volume with a scan in the first 15 min after a meal.

Abstract Background There is little information regarding gender‐specific measurements of colonic transit and anorectal function in patients with defecation disorders ( DD ). To compare overall colonic transit by gender in DD . Methods In 407 patients with constipation due to DD diagnosed by a single gastroenterologist (1994–2012), DD was characterized by anorectal manometry, balloon expulsion test, and colonic transit by scintigraphy. The primary endpoint was overall colonic transit (geometric center, GC ) at 24 h ( GC 24). Effects of gender in DD on colonic transit, and comparison with transit in 208 healthy controls were assessed by Mann–Whitney rank sum test. Secondary endpoints were maximum anal resting ( ARP ) and squeeze ( ASP ) pressures. We also tested association of the physiological endpoints among DD females by pregnancy history and among DD patients by colectomy history. Key Results The DD patients were 67 males (M) and 340 females (F). Significant differences by gender in DD patients were observed in GC 24 (median: M: 2.2; F: 1.8; P = 0.01), ARP (median: M: 87.8 mmHg; F: 82.4 mmHg; P = 0.04), and ASP (median: M: 182.4 mmHg; F: 128.7 mmHg; P < 0.001). GC 24 was slower in DD compared with same‐gender healthy controls. GC 24 did not differ among DD females by pregnancy history. Anorectal functions and upper GI transit did not differ among DD patients by colectomy history. Conclusions & Inferences Patients with DD have slower colonic transit compared with gender‐matched controls. Among DD patients, males have higher ARP and ASP , and females have slower colonic transit. Although the clinical significance of these differences may be unclear, findings suggest that interpretation of these tests in suspected DD should be based on same‐gender control data.

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 χ2test (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 (χ2P = 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.