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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Dual registration of abdominal motion for motility assessment in free-breathing data sets acquired using dynamic MRI.

At present, registration-based quantification of bowel motility from dynamic MRI is limited to breath-hold studies. Here we validate a dual-registration technique robust to respiratory motion for the assessment of small bowel and colonic motility. Small bowel datasets were acquired in breath-hold and free-breathing in 20 healthy individuals. A pre-processing step using an iterative registration of the low rank component of the data was applied to remove respiratory motion from the free breathing data. Motility was then quantified with an existing optic-flow (OF) based registration technique to form a dual-stage approach, termed Dual Registration of Abdominal Motion (DRAM). The benefit of respiratory motion correction was assessed by (1) assessing the fidelity of automatically propagated segmental regions of interest (ROIs) in the small bowel and colon and (2) comparing parametric motility maps to a breath-hold ground truth. DRAM demonstrated an improved ability to propagate ROIs through free-breathing small bowel and colonic motility data, with median error decreased by 90% and 55%, respectively. Comparison between global parametric maps showed high concordance between breath-hold data and free-breathing DRAM. Quantification of segmental and global motility in dynamic MR data is more accurate and robust to respiration when using the DRAM approach.

Stimulation of colonic motility by oral PEG electrolyte bowel preparation assessed by MRI: comparison of split vs single dose.

BACKGROUND: Most methods of assessing colonic motility are poorly acceptable to patients. Magnetic resonance imaging (MRI) can monitor gastrointestinal motility and fluid distributions. We predicted that a dose of oral polyethylene glycol (PEG) and electrolyte solution would increase ileo-colonic inflow and stimulate colonic motility. We aimed to investigate the colonic response to distension by oral PEG electrolyte in healthy volunteers (HVs) and to evaluate the effect of single 2 L vs split (2 × 1 L) dosing. METHODS: Twelve HVs received a split dose (1 L the evening before and 1 L on the study day) and another 12 HVs a single dose (2 L on the main study day) of PEG electrolyte. They underwent MRI scans, completed symptom questionnaires, and provided stool samples. Outcomes included small bowel water content, ascending colon motility index, and regional colonic volumes. KEY RESULTS: Small bowel water content increased fourfold from baseline after ingesting both split (p = 0.0010) and single dose (p = 0.0005). The total colonic volume increase from baseline was smaller for the split dose at 35 ± 8% than for the single dose at 102 ± 27%, p = 0.0332. The ascending colon motility index after treatment was twofold higher for the single dose group (p = 0.0103). CONCLUSIONS & INFERENCES: Ingestion of 1 and 2 L PEG electrolyte solution caused a rapid increase in the small bowel and colonic volumes and a robust rise in colonic motility. The increase in both volumes and motility was dose dependent. Such a challenge, being well-tolerated, could be a useful way of assessing colonic motility in future studies.

Novel MRI tests of orocecal transit time and whole gut transit time: studies in normal subjects.

BACKGROUND: Colonic transit tests are used to manage patients with Functional Gastrointestinal Disorders. Some tests used expose patients to ionizing radiation. The aim of this study was to compare novel magnetic resonance imaging (MRI) tests for measuring orocecal transit time (OCTT) and whole gut transit time (WGT), which also provide data on colonic volumes. METHODS: 21 healthy volunteers participated. Study 1: OCTT was determined from the arrival of the head of a meal into the cecum using MRI and the Lactose Ureide breath test (LUBT), performed concurrently. Study 2: WGT was assessed using novel MRI marker capsules and radio-opaque markers (ROMs), taken on the same morning. Studies were repeated 1 week later. KEY RESULTS: OCTT measured using MRI and LUBT was 225 min (IQR 180-270) and 225 min (IQR 165-278), respectively, correlation r(s) = 0.28 (ns). WGT measured using MRI marker capsules and ROMs was 28 h (IQR 4-50) and 31 h ± 3 (SEM), respectively, correlation r(s) = 0.85 (p < 0.0001). Repeatability assessed using the intraclass correlation coefficient (ICC) was 0.45 (p = 0.017) and 0.35 (p = 0.058) for MRI and LUBT OCTT tests. Better repeatability was observed for the WGT tests, ICC being 0.61 for the MRI marker capsules (p = 0.001) and 0.69 for the ROM method (p < 0.001) respectively. CONCLUSIONS & INFERENCES: The MRI WGT method is simple, convenient, does not use X-ray and compares well with the widely used ROM method. Both OCTT measurements showed modest reproducibility and the MRI method showed modest inter-observer agreement.

Fasting and postprandial volumes of the undisturbed colon: normal values and changes in diarrhea-predominant irritable bowel syndrome measured using serial MRI.

BACKGROUND: Previous assessments of colon morphology have relied on tests which were either invasive or used ionizing radiation. We aimed to measure regional volumes of the undisturbed colon in healthy volunteers (HV) and patients with diarrhea-predominant irritable bowel syndrome (IBS-D). METHODS: 3D regional (ascending, transverse, and descending) colon volumes were measured in fasting abdominal magnetic resonance (MR) images of 75 HVs and 25 IBS-D patients. Thirty-five of the HV and all 25 IBS-D subjects were fed a standard meal and postprandial MRI data obtained over 225 min. KEY RESULTS: Colonic regions were identified and 3D maps from cecum to sigmoid flexure were defined. Fasted regional volumes showed wide variation in both HVs being (mean ± SD) ascending colon (AC) 203 ± 75 mL, transverse (TC) 198 ± 79 mL, and descending (DC) 160 ± 86 mL with no difference from IBS-D subjects (AC 205 ± 69 mL, TC 232 ± 100 mL, and DC 151 ± 71 mL, respectively). The AC volume expanded by 10% after feeding (p = 0.007) in the 35 HV possibly due to increased ileo-colonic inflow. A later rise in AC volume occurred from t = 90 to t = 240 min as the meal residue entered the cecum. In contrast, IBS-D subjects showed a much reduced postprandial response of the AC (p < 0.0001) and a greater increase in TC volume after 90 min (p = 0.0244) compared to HV. CONCLUSIONS & INFERENCES: We have defined a normal range of the regional volumes of the undisturbed colon in fasted and fed states. The AC in IBS-D appeared less able to accommodate postprandial inflow which may account for faster colonic transit.

Effects of various food ingredients on gall bladder emptying.

BACKGROUND/OBJECTIVES: The emptying of the gall bladder in response to feeding is pivotal for the digestion of fat, but the role of various food ingredients in contracting the gall bladder postprandially is not well understood. We hypothesized that different food ingredients, when consumed, will have a different effect on stimulating gall bladder emptying. To investigate this we designed two randomized, investigator-blind, cross-over studies in healthy subjects using magnetic resonance imaging (MRI) to measure gall bladder volumes serially and non-invasively. SUBJECTS/METHODS: Study 1: exploratory study evaluating the effects of 10 different food ingredients on gall bladder emptying in eight healthy subjects. The choice of ingredients varied from common items like coffee, tea and milk to actives like curcumin and potato protease inhibitor. Study 2: mechanistic study investigating the cholecystokinin (CCK) dose response to the best performer ingredient from Study 1 in 21 healthy subjects four ways. RESULTS: The largest gall bladder volume change in Study 1 was observed with fat, which therefore became the dose-response ingredient in Study 2, where the maximum % gall bladder volume change correlated well with CCK. CONCLUSIONS: These serial test-retest studies showed that the fasted gall bladder volume varied remarkably between individuals and that individual day-to-day variability had wide coefficients of variation. Improved knowledge of how to stimulate bile release using food ingredients will be useful to improve in vitro-in vivo correlation of bioavailability testing of hydrophobic drugs. It could improve performance of cholesterol-lowering plant stanol and sterol products and possibly aid understanding of some cholesterol gallstone disease.

Delayed gastric emptying and reduced postprandial small bowel water content of equicaloric whole meal bread versus rice meals in healthy subjects: novel MRI insights.

BACKGROUND/OBJECTIVES: Postprandial bloating is a common symptom in patients with functional gastrointestinal (GI) diseases. Whole meal bread (WMB) often aggravates such symptoms though the mechanisms are unclear. We used magnetic resonance imaging (MRI) to monitor the intragastric fate of a WMB meal (11% bran) compared with a rice pudding (RP) meal. SUBJECTS/METHODS: Twelve healthy volunteers completed this randomised crossover study. They fasted overnight and after an initial MRI scan consumed a glass of orange juice with a 2267 kJ WMB or an equicaloric RP meal. Subjects underwent serial MRI scans every 45 min up to 270 min to assess gastric volumes and small bowel water content, and completed a GI symptom questionnaire. RESULTS: The MRI intragastric appearance of the two meals was markedly different. The WMB meal formed a homogeneous dark bolus with brighter liquid signal surrounding it. The RP meal separated into an upper liquid layer and a lower particulate layer allowing more rapid emptying of the liquid compared with solid phase (sieving). The WMB meal had longer gastric half-emptying times (132±8 min) compared with the RP meal (104±7 min), P<0.008. The WMB meal was associated with markedly reduced MRI-visible small bowel free mobile water content compared with the RP meal, P<0.0001. CONCLUSIONS: WMB bread forms a homogeneous bolus in the stomach, which inhibits gastric sieving and hence empties slower than the equicaloric rice meal. These properties may explain why wheat causes postprandial bloating and could be exploited to design foods that prolong satiation.

The effects of loperamide, or loperamide plus simethicone, on the distribution of gut water as assessed by MRI in a mannitol model of secretory diarrhoea.

BACKGROUND: Loperamide (LOP) is an anti-diarrhoeal agent which is thought to act largely by slowing transit with an uncertain effect on the fluid content of the small and large bowel in humans. Adding simethicone (SIM) to LOP improves its efficacy, but the mechanism of interaction is unclear. Novel MRI techniques to assess small bowel water content (SBWC) have shown that mannitol solutions markedly increase SBWC and can be used as a model of diarrhoea. AIM: We aimed to use quantitative MRI techniques to compare the actions in the gut of LOP and LOP + SIM in a model of secretory diarrhoea using mannitol. METHODS: A total of 18 healthy volunteers ingested capsules containing placebo (PLA) or 12 mg LOP or 12 mg LOP + 125 mg SIM. After 100 min they were given a drink containing 5% mannitol in 350 mL of water. They underwent baseline fasting and postprandial serial MRI scans at 45 min intervals for 4.5 h after ingesting the drink. A range of MRI sequences was acquired to image the gut. RESULTS: LOP and LOP + SIM significantly accelerated gastric emptying (P < 0.03) and reduced SBWC during the late phase (135-270 min after mannitol ingestion), P < 0.009, while delaying arrival of fluid in the ascending colon (AC). The relaxation time T2 of the contents of the AC was reduced by both drugs (P < 0.0001). CONCLUSIONS: LOP and LOP + SIM accelerate gastric emptying, but reduce small bowel water content which may contribute to the delay in oral-caecal transit and overall anti-diarrhoeal effect.

Effects of a 5-HT(3) antagonist, ondansetron, on fasting and postprandial small bowel water content assessed by magnetic resonance imaging.

BACKGROUND: 5-HT(3) antagonists have been shown to be effective in relieving the symptoms of irritable bowel syndrome with diarrhoea (IBS-D). Using a recently validated magnetic resonance imaging (MRI) method, we have demonstrated reduced fasting small bowel water content (SBWC) in IBS-D associated with accelerated small bowel transit. We hypothesized that slowing of transit with ondansetron would lead to an increase in SBWC by inhibiting fasting motility. AIM: To assess the effects of ondansetron compared with placebo in healthy volunteers on SBWC and motility in two different groups of subjects, one studied using MRI and another using manometry. METHODS: Healthy volunteers were given either a placebo or ondansetron on the day prior to and on the study day. Sixteen volunteers underwent baseline fasting and postprandial MRI scans for 270 min. In a second study, a separate group of n = 18 volunteers were intubated and overnight migrating motor complex (MMC) recorded. Baseline MRI scans were carried out after the tube was removed. RESULTS: Fasting SBWC was markedly increased by ondansetron (P < 0.0007). Ondansetron reduced the overall antroduodenal Motility Index (P < 0.04). The subjects who were intubated had significantly lower fasting SBWC (P < 0.0002) compared with the group of subjects who were not intubated. CONCLUSIONS: The 5-HT(3) receptor antagonism increased fasting small bowel water. This was associated with reduced fasting antroduodenal Motility Index which may explain the clinical benefit of such drugs.

Characterization of the time course of the superior mesenteric, abdominal aorta, internal carotid and vertebral arteries blood flow response to the oral glucose challenge test using magnetic resonance imaging.

Blood flow to the splanchnic circulation increases postprandially which may cause a reduction in systemic and cerebral perfusion leading to postprandial syncope in the elderly who lack adequate cardiovascular reserve. We used multi-station 2D phase contrast cine magnetic resonance imaging (PC-MRI) with the aim of characterizing the time course of the haemodynamic response to an oral glucose challenge test (OGCT) in the large arteries perfusing the splanchnic, systemic and cerebral circulations (superior mesenteric artery SMA, abdominal aorta AA, internal carotid arteries, ICA and vertebral arteries VA). In this study nine fasted healthy volunteers were studied. Separate cine PC-MRI scans were acquired in the neck and in the abdomen every 88 s, these two measurements being interleaved for ten baseline scans at each station with the scanner automatically moving the subject between the two stations. After ingestion of the OGCT, a further 30 cine PC-MRI scans were acquired at each station. Using this technique we were able to characterize with frequent sampling of volumetric blood flow the time course of blood flow response to the OGCT of the SMA, AA and both VA and ICA. We found a substantial variation between individuals in the amplitude and the time to the peak of the SMA blood flow response to the OGCT which correlated positively with body mass index. MRI provides a robust, non-invasive method of studying normal physiology that could be valuable in studies of diseases such as postprandial hypotension.