Mechanisms underlying the laxative effect of lactulose: A randomized placebo-controlled trial showing increased small bowel water and motility unaltered by the 5-HT3 receptor antagonist, ondansetron.

BACKGROUND: Lactulose is a laxative which accelerates transit and softens stool. Our aim was to investigate its mechanism of action and use this model of diarrhea to investigate the anti-diarrheal actions of ondansetron. METHODS: A double-blind, randomized, placebo-controlled crossover study of the effect of ondansetron 8 mg in 16 healthy volunteers. Serial MRI scans were performed fasted and 6 h after a meal. Participants then received lactulose 13.6 g twice daily and study drug for a further 36 h. On Day 3, they had further serial MRI scans for 4 h. Measurements included small bowel water content (SBWC), colonic volume, colonic gas, small bowel motility, whole gut transit, and ascending colon relaxation time (T1AC), a measure of colonic water content. KEY RESULTS: Lactulose increased area under the curve (AUC) of SBWC from 0 to 240 min, mean difference 14.2 L · min (95% CI 4.1, 24.3), p = 0.009, and substantially increased small bowel motility after 4 h (mean (95% CI) 523 (457-646) a.u. to 852 (771-1178) a.u., p = 0.007). There were no changes in T1AC after 36 h treatment. Ondansetron did not significantly alter SBWC, small bowel motility, transit, colonic volumes, colonic gas nor T1AC, with or without lactulose. CONCLUSION & INFERENCES: Lactulose increases SBWC and stimulates small bowel motility; however, unexpectedly it did not significantly alter colonic water content, suggesting its laxative effect is not osmotic but due to stimulation of motility. Ondansetron's lack of effect on intestinal water suggests its anti-diarrheal effect is not due to inhibition of secretion but more likely altered colonic motility.

Demonstration of differences in colonic volumes, transit, chyme consistency, and response to psyllium between healthy and constipated subjects using magnetic resonance imaging.

BACKGROUND: In functional gastrointestinal disorders a lack of objective biomarkers limits evaluation of underlying mechanisms. We aimed to demonstrate the utility of magnetic resonance imaging for this task using psyllium, an effective constipation treatment, in patients and controls. METHODS: Two crossover studies: (i) adults without constipation (controls, n = 9) took three treatments in randomized order for 6 days - maltodextrin (placebo), psyllium 3.5 g t.d.s and 7 g t.d.s., (ii) adults with chronic constipation (patients, n = 20) took placebo and psyllium 7 g t.d.s. for 6 days. MRI was performed fasting and postprandially on day 6. Measurements included small bowel and ascending colon water content, colonic volume, transit time, and MR relaxometry (T1, T2) to assess colonic chyme. Stool water percentage was measured. RESULTS: 7 g psyllium t.d.s. increased fasting colonic volumes in controls from median 372 mL (IQR 284-601) to 578 mL (IQR 510-882), and in patients from median 831 mL (IQR 745-934) to 1104 mL (847-1316), P < .05. Mean postprandial small bowel water was higher in controls and patients after 7 g psyllium t.d.s. vs placebo. Whole gut transit was slower in patients than controls (P < .05). T1 of the descending colon chyme (fasting) was lower in patients (213 ms, 176-420) than controls (440 ms, 352-884, P < .05) on placebo, but increased by 7 g psyllium t.d.s. (590 ms, 446-1338), P < .001. Descending colon T1 correlated with baseline stool water content and stool frequency on treatment. CONCLUSIONS AND INFERENCES: MRI measurements can objectively demonstrate the mode of action of therapy targeting intestinal fluid content in constipation.

Cortical differences in diverticular disease and correlation with symptom reports.

BACKGROUND: Recent studies have shown that the brain of patients with gastrointestinal disease differ both structurally and functionally from that of controls. Highly somatizing diverticular disease (HSDD) patients were also shown to differ from low somatizing (LSDD) patients functionally. This study aimed to investigate how they differed structurally. METHODS: Four diseases subgroups were studied in a cross-sectional design: 20 patients with asymptomatic diverticular disease (ADD), 18 LSDD, 16 HSDD, and 18 with irritable bowel syndrome. We divided DD patients into LSDD and HSDD using a cutoff of 6 on the Patient Health Questionnaire 12 Somatic Symptom (PHQ12-SS) scale. All patients underwent a 1-mm isotropic structural brain MRI scan and were assessed for somatization, hospital anxiety, depression, and pain catastrophizing. Whole brain volumetry, cortical thickness analysis and voxel-based morphometry were carried out using Freesurfer and SPM. KEY RESULTS: We observed decreases in gray matter density in the left and right dorsolateral prefrontal cortex (dlPFC), and in the mid-cingulate and motor cortex, and increases in the left (19, 20) and right (19, 38) Brodmann Areas. The average cortical thickness differed overall across groups (P = .002) and regionally: HSDD > ADD in the posterior cingulate cortex (P = .03), HSDD > LSDD in the dlPFC (P = .03) and in the ventrolateral PFC (P < .001). The thickness of the anterior cingulate cortex and of the mid-prefrontal cortex were also found to correlate with Pain Catastrophizing (Spearman's ρ = 0.24, P = .043 uncorrected and Spearman's ρ = 0.25, P = .03 uncorrected). CONCLUSION & INFERENCES: This is the first study of structural gray matter abnormalities in diverticular disease patients. The data show brain differences in the pain network.

Systematic review of the evidence for sustained efficacy of dietary interventions for reducing appetite or energy intake.

We assessed evidence for changes in efficacy of food-based interventions aimed at reducing appetite or energy intake (EI), and whether this could be used to provide guidance on trial design. A systematic search identified randomized controlled trials testing sustained efficacy of diets, foods, supplements or food ingredients on appetite and/or EI. Trials had to include sufficient exposure duration (≥3 days) with appetite and/or EI measured after both acute and repeated exposures. Twenty-six trials met the inclusion criteria and reported data allowing for assessment of the acute and chronic effects of interventions. Most (21/26) measured appetite outcomes and over half (14/26) had objective measures of EI. A significant acute effect of the intervention was retained in 10 of 12 trials for appetite outcomes, and six of nine studies for EI. Initial effects were most likely retained where these were more robust and studies adequately powered. Where the initial, acute effect was not statistically significant, a significant effect was later observed in only two of nine studies for appetite and none of five studies for EI. Maintenance of intervention effects on appetite or EI needs to be confirmed but seems likely where acute effects are robust and replicable in adequately powered studies.

MRI assessment of the postprandial gastrointestinal motility and peptide response in healthy humans.

BACKGROUND: Feeding triggers inter-related gastrointestinal (GI) motor, peptide and appetite responses. These are rarely studied together due to methodological limitations. Recent MRI advances allow pan-intestinal, non-invasive assessment of motility in the undisturbed gut. This study aimed to develop a methodology to assess pan-intestinal motility and transit in a single session using MRI and compare imaging findings to GI peptide responses to a test meal and symptoms in a healthy volunteer cohort. METHODS: Fifteen healthy volunteers (29.3±2.7 years and BMI 20.1±1.2 kg m-2 ) underwent baseline and postprandial MRI scans, symptom questionnaires, and blood sampling (for subsequent GI peptide analysis, Glucagon-like peptide-1 [GLP-1], Polypeptide YY [PYY], Cholecystokinin [CCK]) at intervals for 270 minutes following a 400 g soup meal (204 kcal, Heinz, UK). Gastric volume, gall bladder volume, small bowel water content, small bowel motility, and whole gut transit were measured from the MRI scans. KEY RESULTS: (mean±SEM) Small bowel motility index increased from fasting 39±3 arbitrary units (a.u.) to a maximum of 87±7 a.u. immediately after feeding. PYY increased from fasting 98±10 pg mL-1 to 149±14 pg mL-1 at 30 minutes and GLP-1 from fasting 15±3 µg mL-1 to 22±4 µg mL-1 . CCK increased from fasting 0.40±0.06 pmol mL-1 to 0.94±0.1 pmol mL-1 . Gastric volumes declined with a T1/2 of 46±5 minute and the gallbladder contracted from a fasting volume of 19±2 mL-1 to 12±2 mL-1 . Small bowel water content increased from 39±2 mL-1 to 51±2 mL-1 postprandial. Fullness VAS score increased from 9±5 mm to 41±6 mm at 30 minutes postprandial. CONCLUSIONS AND INFERENCES: The test meal challenge was effective in inducing a change in MRI motility end-points which will improve understanding of the pathophysiological postprandial GI response.

Non-invasive quantification of small bowel water content by MRI: a validation study.

Substantial water fluxes across the small intestine occur during digestion of food, but so far measuring these has required invasive intubation techniques. This paper describes a non-invasive magnetic resonance imaging (MRI) technique for measuring small bowel water content which has been validated using naso-duodenal infusion. Eighteen healthy volunteers were intubated, with the tube position being verified by MRI. After a baseline MRI scan, each volunteer had eight 40 ml boluses of a non-absorbable mannitol and saline solution infused into their proximal small bowel with an MRI scan being acquired after each bolus. The MRI sequence used was an adapted magnetic resonance cholangiopancreatography sequence. The image data were thresholded to allow for intra- and inter-subject signal variations. The MRI measured volumes were then compared to the known infused volumes. This MRI technique gave excellent images of the small bowel, which closely resemble those obtained using conventional radiology with barium contrast. The mean difference between the measured MRI volumes and infused volumes was 2% with a standard deviation of 10%. The maximum 95% limits of agreement between observers were -15% to +17% while measurements by the same operator on separate occasions differed by only 4%. This new technique can now be applied to study alterations in small bowel fluid absorption and secretion due to gastrointestinal disease or drug intervention.

Assessment of motion of colonic contents in the human colon using MRI tagging.

BACKGROUND: We have previously reported a non-invasive, semi-automated technique to assess motility of the wall of the ascending colon (AC) using Magnetic Resonance Imaging. This study investigated the feasibility of using a tagged MRI technique to visualize and assess the degree of flow within the human ascending colon in healthy subjects and those suffering from constipation. METHODS: An open-labeled study of 11 subjects with constipation and 11 subjects without bowel disorders was performed. MRI scans were acquired fasted, then 60 and 120 minutes after ingestion of a 500 mL macrogol preparation. The amount of free fluid in the small and large bowel was assessed using a heavily T2-weighted MRI sequence. The internal movement of the contents of the AC was visualized using a cine tagged MRI sequence and assessed by a novel analysis technique. Comparisons were made between fasting and postprandial scans within individuals, and between the constipation and control groups. KEY RESULTS: Macrogol significantly increased the mobile, MR visible water content of the ascending colon at 60 minutes postingestion compared to fasted data (controls P=.001, constipated group P=.0039). The contents of the AC showed increased motion in healthy subjects but not in the constipated group with significant differences between groups at 60 minutes (P<.002) and 120 minutes (P<.003). CONCLUSIONS AND INFERENCES: This study successfully demonstrated the use of a novel MRI tagging technique to visualize and assess the motion of ascending colon contents following a 500 mL macrogol challenge. Significant differences were demonstrated between healthy and constipated subjects.

Clinical assessment of gastric emptying and sensory function utilizing gamma scintigraphy: Establishment of reference intervals for the liquid and solid components of the Nottingham test meal in healthy subjects.

BACKGROUND: Current investigations of stomach function are based on small test meals that do not reliably induce symptoms and analysis techniques that rarely detect clinically relevant dysfunction. This study presents the reference intervals of the modular "Nottingham test meal" (NTM) for assessment of gastric function by gamma scintigraphy (GSc) in a representative population of healthy volunteers (HVs) stratified for age and sex. METHODS: The NTM comprises 400 mL liquid nutrient (0.75 kcal/mL) and an optional solid component (12 solid agar-beads (0 kcal). Filling and dyspeptic sensations were documented by 100 mm visual analogue scale (VAS). Gamma scintigraphy parameters that describe early and late phase Gastric emptying (GE) were calculated from validated models. KEY RESULTS: Gastric emptying (GE) of the liquid component was measured in 73 HVs (male 34; aged 45±20). The NTM produced normal postprandial fullness (VAS ≥30 in 41/74 subjects). Dyspeptic symptoms were rare (VAS ≥30 in 2/74 subjects). Gastric emptying half-time with the Liquid- and Solid-component -NTM was median 44 (95% reference interval 28-78) minutes and 162 (144-193) minutes, respectively. Gastric accommodation was assessed by the ratio of the liquid-NTM retained in the proximal:total stomach and by Early phase emptying assessed by gastric volume after completing the meal (GCV0). No consistent effect of anthropometric measures on GE parameters was present. CONCLUSIONS AND INFERENCES: Reference intervals are presented for GSc measurements of gastric motor and sensory function assessed by the NTM. Studies involving patients are required to determine whether the reference interval range offers optimal diagnostic sensitivity and specificity.

Anticipation of thermal pain in diverticular disease.

BACKGROUND: The relative importance of peripheral nerve injury or central pain processing in painful diverticular disease (DD) is unclear. Functional magnetic resonance imaging (fMRI) has demonstrated that dysfunctional central pain processing predominates in irritable bowel syndrome (IBS). This study aims to identify anticipatory changes in symptomatic DD (SDD) compared to asymptomatic DD (ADD) and IBS patients. METHODS: Gastrointestinal symptoms and somatization were evaluated via the Patient Health Question-12 Somatic Symptom and the SDD group divided into low (≤6 [LSDD]) and high (≥7 [HSDD]) somatization. Cued painful cutaneous thermal stimuli were delivered to the left hand and foot during fMRI. Fixed effect group analysis of the 'cued' anticipatory phase was performed. KEY RESULTS: Within the right posterior insula, greater deactivation was found in the ADD compared to other groups. In emotion processing centers, anterior and middle insula, greater activation was identified in all patient compared to the ADD group, and in LSDD compared to IBS and HSDD groups. In comparison, amygdala deactivation was greater in ADD than the IBS and HSDD groups, and in LSDD vs HSDD groups. Descending nociceptive control centers, such as the superior medial frontal and orbitofrontal cortex, also showed greater deactivation in the ADD and LSDD compared to the HSDD and IBS groups. CONCLUSIONS & INFERENCES: The HSDD group have altered anticipatory responses to thermal pain, similar to IBS group. The LSDD are similar to ADD group. This suggests underlying differences in pain pathophysiology, and the need for individualized treatment strategies to target the cause of their chronic pain.

Development and validation of a large, modular test meal with liquid and solid components for assessment of gastric motor and sensory function by non-invasive imaging.

BACKGROUND: Current investigations of stomach function are based on small test meals that do not reliably induce symptoms and analysis techniques that rarely detect clinically relevant dysfunction. This study introduces the large 'Nottingham Test Meal' (NTM) for assessment of gastric motor and sensory function by non-invasive imaging. METHODS: NTM comprises 400 mL liquid nutrient (0.75 kcal/mL) and 12 solid agar-beads (0 kcal) with known breaking strength. Gastric fullness and dyspeptic sensations were documented by 100 mm visual analogue scale (VAS). Gastric emptying (GE) were measured in 24 healthy volunteers (HVs) by gastric scintigraphy (GS) and magnetic resonance imaging (MRI). The contribution of secretion to gastric volume was assessed. Parameters that describe GE were calculated from validated models. Inter-observer agreement and reproducibility were assessed. KEY RESULTS: NTM produced moderate fullness (VAS ≥30) but no more than mild dyspeptic symptoms (VAS <30) in 24 HVs. Stable binding of meal components to labels in gastric conditions was confirmed. Distinct early and late-phase GE were detected by both modalities. Liquid GE half-time was median 49 (95% CI: 36-62) min and 68 (57-71) min for GS and MRI, respectively. Differences between GS and MRI measurements were explained by the contribution of gastric secretion. Breaking strength for agar-beads was 0.8 N/m(2) such that median 25 (8-50) % intact agar-beads and 65 (47-74) % solid material remained at 120 min on MRI and GS, respectively. Good reproducibility for liquid GE parameters was present and GE was not altered by agar-beads. CONCLUSIONS & INFERENCES: The NTM provided an objective assessment of gastric motor and sensory function. The results were reproducible and liquid emptying was not affected by non-nutrient agar-beads. The method is potentially suitable for clinical practice.

Investigating the effects of an oral fructose challenge on hepatic ATP reserves in healthy volunteers: A (31)P MRS study.

BACKGROUND: Impaired homeostasis of hepatic ATP has been associated with NAFLD. An intravenous fructose infusion has been shown to be an effective challenge to monitor the depletion and subsequent recovery of hepatic ATP reserves using (31)P MRS. AIMS: The purpose of this study was to evaluate the effects of an oral rather than intravenous fructose challenge on hepatic ATP reserves in healthy subjects. METHODS: Self-reported healthy males were recruited. Following an overnight fast, baseline liver glycogen and lipid levels were measured using Magnetic Resonance Spectroscopy (MRS). Immediately after consuming a 500 ml 75 g fructose drink (1275 kJ) subjects were scanned continuously for 90 min to acquire dynamic (31)P MRS measurements of liver ATP reserves. RESULTS: A significant effect on ATP reserves was observed across the time course (P < 0.05). Mean ATP levels reached a minimum at 50 min which was markedly lower than baseline (80 ± 17% baseline, P < 0.05). Subsequently, mean values tended to rise but did not reach statistical significance above minimum. The time to minimum ATP levels across subjects was negatively correlated with BMI (R(2) = 0.74, P < 0.005). Rates of ATP recovery were not significantly correlated with BMI or liver fat levels, but were negatively correlated with baseline glycogen levels (R(2) = 0.7, P < 0.05). CONCLUSIONS: Depletion of ATP reserves can be measured non-invasively following an oral fructose challenge using (31)P MRS. BMI is the best predictor of postprandial ATP homeostasis following fructose consumption.

Colon wall motility: comparison of novel quantitative semi-automatic measurements using cine MRI.

BACKGROUND: Recently, cine magnetic resonance imaging (MRI) has shown promise for visualizing movement of the colonic wall, although assessment of data has been subjective and observer dependent. This study aimed to develop an objective and semi-automatic imaging metric of ascending colonic wall movement, using image registration techniques. METHODS: Cine balanced turbo field echo MRI images of ascending colonic motility were acquired over 2 min from 23 healthy volunteers (HVs) at baseline and following two different macrogol stimulus drinks (11 HVs drank 1 L and 12 HVs drank 2 L). Motility metrics derived from large scale geometric and small scale pixel movement parameters following image registration were developed using the post ingestion data and compared to observer grading of wall motion. Inter and intra-observer variability in the highest correlating metric was assessed using Bland-Altman analysis calculated from two separate observations on a subset of data. KEY RESULTS: All the metrics tested showed significant correlation with the observer rating scores. Line analysis (LA) produced the highest correlation coefficient of 0.74 (95% CI: 0.55-0.86), p < 0.001 (Spearman Rho). Bland-Altman analysis of the inter- and intra-observer variability for the LA metric, showed almost zero bias and small limits of agreement between observations (-0.039 to 0.052 intra-observer and -0.051 to 0.054 inter-observer, range of measurement 0-0.353). CONCLUSIONS & INFERENCES: The LA index of colonic motility derived from cine MRI registered data provides a quick, accurate and non-invasive method to detect wall motion within the ascending colon following a colonic stimulus in the form of a macrogol drink.

Colonic response to laxative ingestion as assessed by MRI differs in constipated irritable bowel syndrome compared to functional constipation.

BACKGROUND: Functional constipation (FC) and irritable bowel syndrome with constipation (IBS-C) share many symptoms but underlying mechanisms may be different. We have developed a magnetic resonance imaging (MRI) technique to measure intestinal volumes, transit, and motility in response to a laxative, Moviprep(®) . We aim to use these biomarkers to study the pathophysiology in IBS-C and FC. METHODS: Twenty-four FC and 24 IBS-C were studied. Transit was assessed using the weighted average position score (WAPS) of five MRI marker pills, taken 24 h before MRI scanning. Following baseline scan, participants ingested 1 L of Moviprep(®) followed by hourly scans. Magnetic resonance imaging parameters and bowel symptoms were scored from 0 to 4 h. KEY RESULTS: Weighted average position score for FC was 3.6 (2.5-4.2), significantly greater than IBS-C at 2.0 (1.5-3.2), p = 0.01, indicating slower transit for FC. Functional constipation showed greater fasting small bowel water content, 83 (63-142) mL vs 39 (15-70) mL in IBS-C, p < 0.01 and greater ascending colon volume (AC), 314 (101) mL vs 226 (71) mL in IBS-C, p < 0.01. FC motility index was lower at 0.055 (0.044) compared to IBS-C, 0.107 (0.070), p < 0.01. Time to first bowel movement following ingestion of Moviprep(®) was greater for FC, being 295 (116-526) min, compared to IBS-C at 84 (49-111) min, p < 0.01, and correlated with AC volume 2 h after Moviprep(®) , r = 0.44, p < 0.01. Using a cut-off >230 min distinguishes FC from IBS-C with low sensitivity of 55% but high specificity of 95%. CONCLUSION & INFERENCES: Our objective MRI biomarkers allow a distinction between FC and IBS-C.

Magnetic resonance imaging to evaluate gastrointestinal function.

Magnetic resonance imaging of gastrointestinal (GI) function has advanced substantially in the last few years. The ability to obtain high resolution images of the undisturbed bowel with tunable tissue contrast and using no ionizing radiation are clear advantages, particularly for children and women of reproductive age. Barriers to diffusion in clinical practice so far include the need to demonstrate clinical value and the burden of data processing. Both difficulties are being addressed and the technique is providing novel insights into both upper and lower GI disorders of function at an ever increasing rate.

Additive effects of gastric volumes and macronutrient composition on the sensation of postprandial fullness in humans.

BACKGROUND/OBJECTIVES: Intake of food or fluid distends the stomach and triggers mechanoreceptors and vagal afferents. Wall stretch and tension produces a feeling of fullness. Duodenal infusion studies assessing gastric sensitivity by barostat have shown that the products of fat digestion have a greater effect on the sensation of fullness and also dyspeptic symptoms than carbohydrates. We tested here the hypothesis that fat and carbohydrate have different effects on gastric sensation under physiological conditions using non-invasive magnetic resonance imaging (MRI) to measure gastric volumes. SUBJECTS/METHODS: Thirteen healthy subjects received a rice pudding test meal with added fat or added carbohydrate on two separate occasions and underwent serial postprandial MRI scans for 4.5 h. Fullness was assessed on a 100-mm visual analogue scale. RESULTS: Gastric half emptying time was significantly slower for the high-carbohydrate meal than for the high-fat meal, P=0.0327. Fullness significantly correlated with gastric volumes for both meals; however, the change from baseline in fullness scores was higher for the high-fat meal for any given change in stomach volume (P=0.0147), despite the lower energy content and faster gastric emptying of the high-fat meal. CONCLUSIONS: Total gastric volume correlates positively and linearly with postprandial fullness and ingestion of a high-fat meal increases this sensation compared with high-carbohydrate meal. These findings can be of clinical interest in patients presenting with postprandial dyspepsia whereby manipulating gastric sensitivity by dietary intervention may help to control digestive sensations.

Measurement of gastric meal and secretion volumes using magnetic resonance imaging.

MRI can assess multiple gastric functions without ionizing radiation. However, time consuming image acquisition and analysis of gastric volume data, plus confounding of gastric emptying measurements by gastric secretions mixed with the test meal have limited its use to research centres. This study presents an MRI acquisition protocol and analysis algorithm suitable for the clinical measurement of gastric volume and secretion volume. Reproducibility of gastric volume measurements was assessed using data from 10 healthy volunteers following a liquid test meal with rapid MRI acquisition within one breath-hold and semi-automated analysis. Dilution of the ingested meal with gastric secretion was estimated using a respiratory-triggered T1 mapping protocol. Accuracy of the secretion volume measurements was assessed using data from 24 healthy volunteers following a mixed (liquid/solid) test meal with MRI meal volumes compared to data acquired using gamma scintigraphy (GS) on the same subjects studied on a separate study day. The mean ± SD coefficient of variance between 3 observers for both total gastric contents (including meal, secretions and air) and just the gastric contents (meal and secretion only) was 3 ± 2% at large gastric volumes (>200 ml). Mean ± SD secretion volumes post meal ingestion were 64 ± 51 ml and 110 ± 40 ml at 15 and 75 min, respectively. Comparison with GS meal volumes, showed that MRI meal only volume (after correction for secretion volume) were similar to GS, with a linear regression gradient ± std err of 1.06 ± 0.10 and intercept -11 ± 24 ml. In conclusion, (i) rapid volume acquisition and respiratory triggered T1 mapping removed the requirement to image during prolonged breath-holds (ii) semi-automatic analysis greatly reduced the time required to derive measurements and (iii) correction for secretion volumes provided accurate assessment of gastric meal volumes and emptying. Together these features provide the scientific basis of a protocol which would be suitable in clinical practice.

Effect of experimental stress on the small bowel and colon in healthy humans.

BACKGROUND: Symptoms of irritable bowel syndrome (IBS) are frequently reported to be exacerbated by stress. Animal studies suggest that corticotrophin releasing hormone (CRH) mediates the effect of stress on the bowel. We have shown that stressed IBS patients with diarrhea have constricted small bowels. We hypothesized that we could mimic this effect by applying experimental stress in the form of either hand immersion in ice water or CRH injection in healthy volunteers (HV). METHODS: The postprandial effect of the cold pressor test (repeated hand immersion in ice cold water) and injection of CRH, were assessed vs control in two groups of 18 HVs. KEY RESULTS: CRH produced a significant rise from baseline salivary cortisol levels (p = 0.004) not seen with the cold pressor test. Small bowel water content (SBWC) fell postprandially on all four treatments. SBWC was significantly reduced by both stressors but CRH caused a greater effect (anova, p < 0.003 vs p = 0.02). Ascending colon (AC) volume was greater after CRH injection compared with saline (p = 0.002) but no differences were seen with the cold pressor test vs warm water. Postprandial increase in colon volume was also reduced by CRH which also increased the sensations of distension and bloating. CONCLUSIONS & INFERENCES: Two experimental stressors were shown to constrict the small bowel, mimicking the effect previously seen in IBS-D patients. CRH increased the volume of the AC. We speculate that stress accelerates transfer of water from the small bowel to the AC.

Effect of a novel 5-HT3 receptor agonist MKC-733 on upper gastrointestinal motility in humans.

BACKGROUND: Although 5-HT3 antagonists have been used to treat chemotherapy-induced emesis and diarrhoea-predominant irritable bowel syndrome, the effects of 5-HT3 agonists in humans are unknown. AIM: To determine the effect of MKC-733, a selective 5-HT3 receptor agonist, on upper gastrointestinal motility. METHODS: Oral MKC-733 (0.2, 1 and 4 mg) was compared with placebo in three randomized, double-blind, cross-over studies in healthy males. Antroduodenal manometry was recorded for 8 h during fasting and 3 h post-prandially (n = 12). Gastric emptying and small intestinal transit were determined by gamma-scintigraphy (n = 16). Gastric emptying, accommodation and antral motility were determined by echoplanar magnetic resonance imaging (n = 12). RESULTS: MKC-733 (4 mg) increased the number of migrating motor complexes recorded in the antrum and duodenum (P < 0.001), but had no effect on post-prandial motility. MKC-733 delayed scintigraphically assessed liquid gastric emptying (P = 0.005) and accelerated small intestinal transit (P = 0.038). Echoplanar magnetic resonance imaging confirmed the delayed gastric emptying (P < 0.001) and demonstrated a significant increase in cross-sectional area of the proximal stomach (P < 0.01). CONCLUSIONS: MKC-733 delays liquid gastric emptying in association with relaxation of the proximal stomach, stimulates fasting antroduodenal migrating motor complex activity and accelerates small intestinal transit.

Antral motility measurements by magnetic resonance imaging.

Magnetic resonance imaging has been recently proposed as a promising, noninvasive technique to assess the motility of the gastric antrum. However, so far the reproducibility and dependence on test meal composition has not been evaluated. In this study, snapshot echo-planar magnetic resonance imaging was used to measure the frequency, propagation speed and percentage occlusion of antral contractions in 28 healthy volunteers. They were fed either liquid (n=12), mixed liquid/solid (n=8) or mixed viscous/solid (n=8) nutrient (1350 kJ) test meals, and a total of 208 motility measurements were performed. No effect of meal type on antral motility parameters was observed. Antral contraction frequency was 3.0 +/- 0.2 min(-1) (mean +/- SD, n=164), propagation speed was 1.6 +/- 0.2 mm s(-1) (n=164) and the percentage occlusion was 58 +/- 14% (n=76). Overall, 21% of measurements did not provide useful antral motility data, because, in the supine position, the antrum was not filled by the test meal. Simple methods to overcome this and reduce scanning time to a minimum are proposed. The results show that the noninvasive magnetic resonance imaging evaluation of antral motility is accurate and reproducible and has potential to become a standard tool for such investigations.

Echo-planar imaging relaxometry to measure the viscosity of a model meal.

A method for measuring noninvasively the viscosity of a polysaccharide model meal using the known relationship between relaxation times and polysaccharide concentration in solution in vitro is presented. The aim is to develop a method for monitoring digesta viscosity in vivo, using EPI to capture the motion of the gastrointestinal lumen. The transverse relaxation rate T-12 of locust bean gum solutions was calibrated against the zero-shear viscosity at 37 degreesC. Differences in viscosity were distinguished significantly using T-12 measurements. T-12 and viscosity were insensitive to exposure to gastric juice and changes in pH, and the model meal was well received by volunteers and provided good contrast in vivo in EPI images. Therefore it would be possible to use this method to monitor the changes in meal viscosity within the gastric lumen in vivo.