Luca Marciani

Differential Effects of FODMAPs (Fermentable Oligo-, Di-, Mono-Saccharides and Polyols) on Small and Large Intestinal Contents in Healthy Subjects Shown by MRI

OBJECTIVES:The objective of this study was to investigate whether ingestion of fructose and fructans (such as inulin) can exacerbate irritable bowel syndrome (IBS) symptoms. The aim was to better understand the origin of these symptoms by magnetic resonance imaging (MRI) of the gut. METHODS: A total of 16 healthy volunteers participated in a four-way, randomized, single-blind, crossover study in which they consumed 500 ml of water containing 40 g of either glucose, fructose, inulin, or a 1:1 mixture of 40 g glucose and 40 g fructose. MRI scans were performed hourly for 5 h, assessing the volume of gastric contents, small bowel water content (SBWC), and colonic gas. Breath hydrogen (H2) was measured and symptoms recorded after each scan.RESULTS:Data are reported as mean (s.d.) (95% CI) when normally distributed and median (range) when not. Fructose increased area under the curve (AUC) from 0–5 h of SBWC to 71 (23) l/min, significantly greater than for glucose at 36 (11–132) l/min (P<0.001), whereas AUC SBWC after inulin, 33 (17–106) l/min, was no different from that after glucose. Adding glucose to fructose decreased AUC SBWC to 55 (28) l/min (P=0.08) vs. fructose. Inulin substantially increased AUC colonic gas to 33 (20) l/min, significantly greater than glucose and glucose+fructose (both P<0.05). Breath H2 rose more with inulin than with fructose. Glucose when combined with fructose significantly reduced breath H2 by 7,700 (3,121–12,300) p.p.m./min relative to fructose alone (P<0.01, n=13).CONCLUSIONS:Fructose but not inulin distends the small bowel with water. Adding glucose to fructose reduces the effect of fructose on SBWC and breath hydrogen. Inulin distends the colon with gas more than fructose, but causes few symptoms in healthy volunteers.

Effect of intragastric acid stability of fat emulsions on gastric emptying, plasma lipid profile and postprandial satiety

Fat is often included in common foods as an emulsion of dispersed oil droplets to enhance the organoleptic quality and stability. The intragastric acid stability of emulsified fat may impact on gastric emptying, satiety and plasma lipid absorption. The aim of the present study was to investigate whether, compared with an acid-unstable emulsion, an acid-stable fat emulsion would empty from the stomach more slowly, cause more rapid plasma lipid absorption and cause greater satiety. Eleven healthy male volunteers received on two separate occasions 500 ml of 15 % (w/w) [13C]palmitate-enriched olive oil-in-water emulsion meals which were either stable or unstable in the acid gastric environment. MRI was used to measure gastric emptying and the intragastric oil fraction of the meals. Blood sampling was used to measure plasma lipids and visual analogue scales were used to assess satiety. The acid-unstable fat emulsion broke and rapidly layered in the stomach. Gastric emptying of meal volume was slower for the acid-stable fat emulsion (P < 0.0001; two-way ANOVA). The rate of energy delivery of fat from the stomach to the duodenum was not different up to t = 110 min. The acid-stable emulsion induced increased fullness (P < 0.05), decreased hunger (P < 0.0002), decreased appetite (P < 0.0001) and increased the concentration of palmitic acid tracer in the chylomicron fraction (P < 0.04). This shows that it is possible to delay gastric emptying and increase satiety by stabilising the intragastric distribution of fat emulsions against the gastric acid environment. This could have implications for the design of novel foods.

Gastroparesis and Functional Dyspepsia: Excerpts from the AGA/ ANMS Meeting

Background  Despite the relatively high prevelance of gastroparesis and functional dyspepsia, the aetiology and pathophysiology of these disorders remain incompletely understood. Similarly, the diagnostic and treatment options for these two disorders are relatively limited despite recent advances in our understanding of both disorders.

Quantification of Gastrointestinal Liquid Volumes and Distribution Following a 240 mL Dose of Water in the Fasted State

The rate and extent of drug dissolution and absorption from solid oral dosage forms is highly dependent upon the volumes and distribution of gastric and small intestinal water. However, little is known about the time courses and distribution of water volumes in vivo in an undisturbed gut. Previous imaging studies offered a snapshot of water distribution in fasted humans and showed that water in the small intestine is distributed in small pockets. This study aimed to quantify the volume and number of water pockets in the upper gut of fasted healthy humans following ingestion of a glass of water (240 mL, as recommended for bioavailability/bioequivalence (BA/BE) studies), using recently validated noninvasive magnetic resonance imaging (MRI) methods. Twelve healthy volunteers underwent upper and lower abdominal MRI scans before drinking 240 mL (8 fluid ounces) of water. After ingesting the water, they were scanned at intervals for 2 h. The drink volume, inclusion criteria, and fasting conditions matched the international standards for BA/BE testing in healthy volunteers. The images were processed for gastric and intestinal total water volumes and for the number and volume of separate intestinal water pockets larger than 0.5 mL. The fasted stomach contained 35 ± 7 mL (mean ± SEM) of resting water. Upon drinking, the gastric fluid rose to 242 ± 9 mL. The gastric water volume declined rapidly after that with a half emptying time (T50%) of 13 ± 1 min. The mean gastric volume returned back to baseline 45 min after the drink. The fasted small bowel contained a total volume of 43 ± 14 mL of resting water. Twelve minutes after ingestion of water, small bowel water content rose to a maximum value of 94 ± 24 mL contained within 15 ± 2 pockets of 6 ± 2 mL each. At 45 min, when the glass of water had emptied completely from the stomach, total intestinal water volume was 77 ± 15 mL distributed into 16 ± 3 pockets of 5 ± 1 mL each. MRI provided unprecedented insights into the time course, number, volume, and location of water pockets in the stomach and small intestine under conditions that represent standard BA/BE studies using validated techniques. These data add to our current understanding of gastrointestinal physiology and will help improve physiological relevance of in vitro testing methods and in silico transport analyses for prediction of bioperformance of oral solid dosage forms, particularly for low solubility Biopharmaceutics Classification System (BCS) Class 2 and Class 4 compounds.

A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea

Background Irritable bowel syndrome with diarrhoea (IBS-D) is particularly debilitating due to urgency and episodic incontinence. Some 5-hydroxytryptamine 3 (5-HT3) receptor antagonists (5-HT3RAs) have proven effective but have serious side effects. Ondansetron, also a 5-HT3RA, has been widely used as an antiemetic with an excellent safety record for over two decades. Our aim was to assess its effectiveness in IBS-D. Methods 120 patients meeting Rome III criteria for IBS-D entered a randomised, double-blind, placebo-controlled crossover study of 5 weeks of ondansetron 4 mg versus placebo with dose titration allowed, up to two tablets three times daily in the first 3 weeks. Patients completed daily diaries documenting stool consistency using the Bristol Stool Form score. Gut transit was measured in the last week of each treatment. The primary endpoint was average stool consistency in the last 2 weeks of treatment. Results Ondansetron significantly improved stool consistency (mean difference in stool form between ondansetron and placebo −0.9, 95% CI −1.1 to −0.6, p<0.001). Compared with placebo, patients on ondansetron experienced fewer days with urgency (p<0.001), lower urgency scores (p<0.001), reduced frequency of defaecation (p=0.002) and less bloating (p=0.002), although pain scores did not change significantly. IBS symptom severity score fell more with ondansetron than placebo (83±9.8 vs 37±9.7, p=0.001). 65% reported adequate relief with ondansetron but not placebo compared with 14% reporting relief with placebo but not ondansetron, relative risk 4.7, 95% CI 2.6 to 8.5, p<0.001. Conclusions Ondansetron relieves some of the most intrusive symptoms of IBS-D, namely loose stools, frequency and urgency.

Gastric emptying of three liquid oral preoperative metabolic preconditioning regimens measured by magnetic resonance imaging in healthy adult volunteers: a randomised double-blind, crossover study.

BACKGROUND & AIMS Preoperative starvation has many undesirable effects but the minimum length of fasting is limited by gastric emptying, which may be dependent on nutrient content, viscosity and osmolarity of the feed. We compared the gastric emptying of two types of preoperative metabolic preconditioning drinks [Oral Nutritional Supplement (ONS) (Fresenius Kabi, Germany) and preOp (Nutricia Clinical Care, UK)] in healthy volunteers. METHODS Twenty (10 male, 10 female) healthy adult volunteers were studied on 3 separate occasions in a randomised crossover manner. Volunteers ingested 400 ml preOp, which is a clear carbohydrate drink (CCD) (50 g carbohydrate, 0 g protein), 70 g ONS (50 g carbohydrate and 15 g glutamine) dissolved in water to a total volume of 400 ml (ONS400) and 300 ml (ONS300). Gastric emptying time was measured using magnetic resonance imaging. RESULTS Mean (95% CI) T(50) and T(100) gastric emptying times for CCD were significantly lower (p<0.001) compared with ONS400 and ONS300. T(50) was 47 (39-55), 78 (69-87) and 81 (70-92)min for CCD, ONS400 and ONS300 respectively. Correspondingly T(100) was 94 (79-110), 156 (138-173) and 162 (140-184)min. Residual gastric volumes returned to baseline 120 min after CCD and 180 min after ONS400 and ONS300. CONCLUSIONS The faster gastric emptying for CCD compared to ONS400 and ONS300 signifies that gastric emptying may be more dependent on nutrient load than volume or viscosity in healthy volunteers. While it is safe to give CCD 2h preoperatively, ONS400 and ONS300 should be given at least 3h preoperatively.

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.

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.

Improved methods for fMRI studies of combined taste and aroma stimuli.

Previous neuroimaging studies of the cortical representation of gustatory and olfactory stimuli have often delivered tastants to the mouth in very small quantities or stimulated olfaction orthonasally. In studies of retro-nasal olfaction, swallowing was generally delayed to reduce head motion artefacts. The present fMRI study aims to improve upon such methodological limitations to allow investigation of the cortical representation of flavour (taste and aroma combination) as it typically occurs during the consumption of liquid foods. For this purpose we used (1) a novel, automated, sprayed stimulus delivery system and a larger volume of liquid sample (containing sweet tastants and banana/pear aroma volatiles) to achieve more extensive stimulation of the oral cavity taste receptors, (2) a pseudo-natural delivery paradigm that included prompt swallowing after each sample delivery to obtain physiological retro-nasal olfactory stimulation, (3) fMRI acquisition with wide brain coverage and double-echo EPI to improve sensitivity. We validated our paradigm for the delivery of volatiles using atmospheric pressure chemical ionisation mass spectrometry. This showed that the main retro-nasal delivery of volatiles in the paradigm occurs immediately after the swallow. Several brain areas were found to be activated, including the insula, frontal operculum, rolandic operculum/parietal lobe, piriform, dorsolateral prefrontal cortex, anterior cingulate cortex, ventro-medial thalamus, hippocampus and medial orbitofrontal cortex.

Effects of bowel cleansing on the intestinal microbiota

Objective An adequate bowel cleansing is essential for a successful colonoscopy. Although purgative consumption is safe for the patient, there is little consensus on how the intestinal microbiota is affected by the procedure, especially regarding the potential long-term consequences. Design 23 healthy subjects were randomised into two study groups consuming a bowel preparation (Moviprep), either in two separate doses of 1 L or as a single 2-L dose. Participants donated faecal samples at the baseline, after bowel cleansing, 14 and 28 days after the treatment. The intestinal microbiota composition was determined with phylogenetic microarray as well as quantitative PCR analysis and correlated with the previously quantified faecal serine proteases. Results The lavage introduced an instant and substantial change to the intestinal microbiota. The total microbial load was decreased by 31-fold and 22% of the participants lost the subject-specificity of their microbiota. While the bacterial levels and community composition were essentially restored within 14 days, the rate of recovery was dose dependent: consumption of the purgative in a single dose had a more severe effect on the microbiota composition than that of a double dose, and notably increased the levels of Proteobacteria, Fusobacteria and bacteria related to Dorea formicigenerans. The abundance of the latter also correlated with the amount of faecal serine proteases that were increased after purging. Conclusions Our results suggest that the bowel cleansing using two separate dosages introduces fewer alterations to the intestinal microbiota than a single dose and hence may be preferred in clinical practice.