A comparative, randomised MRI study of the physiological and appetitive responses to gelling (alginate) and non-gelling nasogastric tube feeds in healthy men.

Inclusion in nasogastric tube feeds (NGTF) of acid-sensitive, seaweed-derived alginate, expected to form a reversible gel in the stomach, may create a more normal intragastric state and modified gastrointestinal responses. This may ameliorate NGTF-associated risk of diarrhoea, upper gastrointestinal symptoms and appetite suppression. In a randomised, crossover, comparison study, undertaken in twelve healthy males, an alginate-containing feed (F + ALG) or one that was alginate-free (F-ALG) (300 ml) was given over 1 h with a 7-14-d washout period between treatments. Baseline and for 4-h post-feed initiation, MRI measurements were made to establish small bowel water content (SBWC), gastric contents volume (GCV) and appearance, and superior mesenteric artery blood flux. Blood glucose and gut peptides were measured. Subjective appetite and upper gastrointestinal symptoms scores were obtained. Ad libitum pasta consumption 3-h post-feeding was measured. F + ALG exhibited a gastric appearance consistent with gelling surrounded by a freely mobile water halo. Significant main effects of feed were seen for SBWC (P = 0·03) and peptide YY (PYY) (P = 0·004) which were attributed to generally higher values for SBWC with F + ALG (max difference between adjusted means 72 ml at 210 min) and generally lower values for PYY with F + ALG. GCV showed a faster reduction with F + ALG, less between-participant variation and a feed-by-time interaction (P = 0·04). Feed-by-time interactions were also seen with glucagon-like-peptide 1 (GLP-1) (P = 0·02) and glucose-dependent insulinotropic polypeptide (GIP) (P = 0·002), both showing a blunted response with F + ALG. Apparent intragastric gelling with F + ALG and subsequent differences in gastrointestinal and endocrine responses have been demonstrated between an alginate-containing and alginate-free feed.

MR Measures of Small Bowel Wall T2 Are Associated With Increased Permeability.

BACKGROUND: Increased small bowel permeability leads to bacterial translocation, associated with significant morbidity and mortality. Biomarkers are needed to evaluate these changes in vivo, stratify an individual's risk, and evaluate the efficacy of interventions. MRI is an established biomarker of small bowel inflammation. PURPOSE: To characterize changes in the small bowel with quantitative MRI measures associated with increased permeability induced by indomethacin. STUDY TYPE: Prospective single-center, double-blind, two-way crossover provocation study. SUBJECTS: A provocation cohort (22 healthy volunteers) and intrasubject reproducibility cohort (8 healthy volunteers). FIELD STRENGTH/SEQUENCE: 2D balanced turbo field echo sequences to measure small bowel wall thickness, T2 , and motility acquired at 3T. ASSESSMENT: Participants were randomized to receive indomethacin or placebo prior to assessment. After a minimum 2-week washout, measures were repeated with the alternative allocation. MR measures (wall thickness, T2 , motility) at each study visit were compared to the reference standard 2-hour lactulose/mannitol urinary excretion ratio (LMR) test performed by a lab technician. All analyses were performed blind. STATISTICAL TESTS: Normality was tested (Shapiro-Wilk's test). Paired testing (Student's t-test or Wilcoxon) determined the significance of paired differences with indomethacin provocation. Pearson's correlation coefficient compared significant measures with indomethacin provocation to LMR. Intrasubject (intraclass correlation) and interrater variability (Bland-Altman) were assessed. RESULTS: Indomethacin provocation induced a significant increase in LMR compared to placebo (P < 0.05) and a significant increase in small bowel T2 (0.12 seconds compared to placebo 0.07 seconds, P < 0.05). Small bowel wall thickness (P = 0.17) and motility (P = 0.149) showed no significant change. T2 and LMR were positively correlated (r = 0.68, P < 0.05). T2 measurements were robust to interobserver (intraclass correlation 0.89) and intrasubject variability (Bland-Altman bias of 0.005 seconds, 95% confidence interval [CI] -0.04 to +0.05 seconds, and 0.0006 seconds, 95% CI -0.05 to +0.06 seconds). DATA CONCLUSION: MR measures of small bowel wall T2 were significantly increased following indomethacin provocation and correlated with 2-hour LMR test results. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

Test-retest assessment of non-contrast MRI sequences to characterise and quantify the small bowel wall in healthy participants.

OBJECTIVE: Quantitative Magnetic Resonance Imaging sequences have been investigated as objective imaging biomarkers of fibrosis and inflammation in Crohn's disease. AIM: To determine the repeatability and inter- and intra-observer agreement of these measures in the prepared small bowel wall. METHODS: Ten healthy participants were scanned at 3 T on 2 separate occasions using T1 and T2 relaxometry, IVIM-DWI and MT sequences. Test-retest repeatability was assessed using the coefficient of variation (CoV) and intra-class correlation coefficients (ICCs) were used to evaluate the intra- and inter-observer agreement RESULTS: Test-retest repeatability in the bowel wall was excellent for apparent diffusion coefficient (ADC), magnetisation transfer ratio (MTR), T1, and diffusion coefficient D (CoV 5%, 7%, 8%, and 10%, respectively), good for perfusion fraction (PF) (CoV 20%) and acceptable for T2 (CoV 21%). Inter-observer agreement was good for the T2, D and ADC (ICC = 0.89, 0.86, 0.76, respectively) and moderate for T1 (ICC = 0.55). Intra-observer agreement was similar to inter-observer agreement. DISCUSSION: This study showed variable results between the different parameters measured. Test-retest repeatability was at least acceptable for all parameters except pseudo-diffusion coefficient D*. Good inter- and intra-observer agreement was obtained for T2, ADC and D, with these parameters performing best in this technical validation study.

Design and testing of microbubble-based MRI contrast agents for gastric pressure measurement.

PURPOSE: This work demonstrates specifically tailored microbubble-based preparations and their suitability as MRI contrast agents for ingestion and measuring temporal and spatial pressure variation in the human stomach. METHODS: Enhanced alginate spheres were prepared by incorporating gas-filled microbubbles into sodium alginate solution followed by the polymerization of the mixture in an aqueous calcium lactate solution. The microbubbles were prepared with a phospholipid shell and perfluorocarbon gas filling, using a mechanical cavitational agitation regime. The NMR signal changes to externally applied pressure and coming from the enhanced alginate spheres were acquired and compared with that of alginate spheres without microbubbles. In vivo investigations were also carried out on healthy volunteers to measure the pressure variation in the stomach. RESULTS: The MR signal changes in the contrast agent exhibits a linear sensitivity of approximately 40% per bar, as opposed to no measurable signal change seen in the control gas-free spheres. This novel contrast agent also demonstrates an excellent stability in simulated gastric conditions, including at body temperature. In vivo studies showed that the signal change exhibited in the meal within the antrum region is between 5% and 10%, but appears to come from both pressure changes and partial volume artifacts. CONCLUSION: This study demonstrates that alginate spheres with microbubbles can be used as an MRI contrast agent to measure pressure changes. The peristaltic movement within the stomach is seen to substantially alter the overall signal intensity of the contrast agent meal. Future work must focus on improving the contrast agent's sensitivity to pressure changes.

Feasibility Study of a New Magnetic Resonance Imaging Mini-capsule Device to Measure Whole Gut Transit Time in Paediatric Constipation.

OBJECTIVE: In England, 27,500 children are referred annually to hospital with constipation. An objective measure of whole gut transit time (WGTT) could aid management. The current standard WGTT assessment, the x-ray radiopaque marker (ROM) test, gives poor definition of colonic anatomy and the radiation dose required is undesirable in children. Our objective was to develop an alternative magnetic resonance imaging (MRI) WGTT measure to the x-ray ROM test and to demonstrate its initial feasibility in paediatric constipation. METHODS: With the Nottingham Young Person's Advisory Group we developed a small (8 × 4 mm), inert polypropylene capsule shell filled with MRI-visible fat emulsion. The capsule can be imaged using MRI fat and water in-phase and out-of-phase imaging. Sixteen patients with constipation and 19 healthy participants aged 7 to 18 years old were recruited. Following a common ROM protocol, the participants swallowed 24 mini-capsules each day for 3 days and were imaged on days 4 and 7 using MRI. The number of successful studies (feasibility) and WGTT were assessed. Participants' EuroQoL Visual Analogue Scale were also collected and compared between the day before the taking the first set of mini-capsules to the day after the last MRI study day. RESULTS: The mini-capsules were imaged successfully in the colon of all participants. The WGTT was 78 ±â€Š35 hours (mean ±â€Šstandard deviation) for patients, and 36 ±â€Š16 hours, P < 0.0001 for healthy controls. Carrying out the procedures did not change the EuroQoL Visual Analogue Scale scores before and after the procedures. CONCLUSIONS: Magnetic Resonance Imaging in Paediatric Constipation was a first-in-child feasibility study of a new medical device to measure WGTT in paediatric constipation using MRI. The study showed that the new method is feasible and is well tolerated.

Glycaemic, gastrointestinal, hormonal and appetitive responses to pearl millet or oats porridge breakfasts: a randomised, crossover trial in healthy humans.

Whole-grain cereal breakfast consumption has been associated with beneficial effects on glucose and insulin metabolism as well as satiety. Pearl millet is a popular ancient grain variety that can be grown in hot, dry regions. However, little is known about its health effects. The present study investigated the effect of a pearl millet porridge (PMP) compared with a well-known Scottish oats porridge (SOP) on glycaemic, gastrointestinal, hormonal and appetitive responses. In a randomised, two-way crossover trial, twenty-six healthy participants consumed two isoenergetic/isovolumetric PMP or SOP breakfast meals, served with a drink of water. Blood samples for glucose, insulin, glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide (GIP), peptide YY, gastric volumes and appetite ratings were collected 2 h postprandially, followed by an ad libitum meal and food intake records for the remainder of the day. The incremental AUC (iAUC2h) for blood glucose was not significantly different between the porridges (P > 0·05). The iAUC2h for gastric volume was larger for PMP compared with SOP (P = 0·045). The iAUC2h for GIP concentration was significantly lower for PMP compared with SOP (P = 0·001). Other hormones and appetite responses were similar between meals. In conclusion, the present study reports, for the first time, data on glycaemic and physiological responses to a pearl millet breakfast, showing that this ancient grain could represent a sustainable alternative with health-promoting characteristics comparable with oats. GIP is an incretin hormone linked to TAG absorption in adipose tissue; therefore, the lower GIP response for PMP may be an added health benefit.

Colon Hypersensitivity to Distension, Rather Than Excessive Gas Production, Produces Carbohydrate-Related Symptoms in Individuals With Irritable Bowel Syndrome.

BACKGROUND & AIMS: Poorly digested, fermentable carbohydrates may induce symptoms of irritable bowel syndrome (IBS) via unclear mechanisms. We performed a randomized trial with magnetic resonance imaging (MRI) analysis to investigate correlations between symptoms and changes in small- and large-bowel contents after oral challenge. METHODS: We performed a 3-period, cross-over study of 29 adult patients with IBS (based on Rome III criteria, with symptoms of abdominal pain or discomfort for at least 2 days/wk) and reported bloating. In parallel, we performed the same study of 29 healthy individuals (controls). Studies were performed in the United Kingdom from January 2013 through February 2015. On 3 separate occasions (at least 7 days apart), subjects were given a 500-mL drink containing 40 g of carbohydrate (glucose in the first period, fructose in the second, and inulin in the third, in a random order). Levels of breath hydrogen were measured and intestinal content was assessed by MRI before and at various time points after consumption of each drink. Symptoms were determined based on subjects' responses to the Hospital Anxiety and Depression Scale questionnaire and the Patient Health Questionnaire-15. The primary end point was whether participants had a clinically important symptom response during the 300 minutes after consumption of the drink. RESULTS: More patients with IBS reached the predefined symptom threshold after intake of inulin (13 of 29) or fructose (11 of 29) than glucose (6 of 29). Symptoms peaked sooner after intake of fructose than inulin. Fructose increased small-bowel water content in both patients and controls whereas inulin increased colonic volume and gas in both. Fructose and inulin increased breath hydrogen levels in both groups, compared with glucose; fructose produced an earlier increase than inulin. Controls had lower symptom scores during the period after drink consumption than patients with IBS, despite similar MRI parameters and breath hydrogen responses. In patients who reached the symptom threshold after inulin intake, peak symptom intensity correlated with peak colonic gas (r = 0.57; P < .05). Changes in MRI features and peak breath hydrogen levels were similar in patients who did and did not reach the symptom threshold. CONCLUSIONS: Patients with IBS and healthy individuals without IBS (controls) have similar physiological responses after intake of fructose or inulin; patients reported symptoms more frequently after inulin than controls. In patients with a response to inulin, symptoms related to levels of intraluminal gas, but peak gas levels did not differ significantly between responders, nonresponders, or controls. This indicates that colonic hypersensitivity to distension, rather than excessive gas production, produces carbohydrate-related symptoms in patients with IBS. Clinicaltrials.gov no: NCT01776853.

Magnetic Resonance Imaging Quantification of Fasted State Colonic Liquid Pockets in Healthy Humans.

The rate and extent of drug dissolution and absorption from solid oral dosage forms is highly dependent on the volume of liquid in the gastrointestinal tract (GIT). However, little is known about the time course of GIT liquid volumes after drinking a glass of water (8 oz), particularly in the colon, which is a targeted site for both locally and systemically acting drug products. Previous magnetic resonance imaging (MRI) studies offered novel insights on GIT liquid distribution in fasted humans in the stomach and small intestine, and showed that freely mobile liquid in the intestine collects in fairly distinct regions or "pockets". Based on this previous pilot data, we hypothesized that (1) it is possible to quantify the time course of the volume and number of liquid pockets in the undisturbed colon of fasted healthy humans following ingestion of 240 mL, using noninvasive MRI methods; (2) the amount of freely mobile water in the fasted human colon is of the order of only a few milliliters. Twelve healthy volunteers fasted overnight and underwent fasted abdominal MRI scans before drinking 240 mL (∼8 fluid ounces) of water. After ingesting the water they were scanned at frequent intervals for 2 h. The images were processed to quantify freely mobile water in the total and regional colon: ascending, transverse, and descending. The fasted colon contained (mean ± SEM) 11 ± 5 pockets of resting liquid with a total volume of 2 ± 1 mL (average). The colonic fluid peaked at 7 ± 4 mL 30 min after the water drink. This peak fluid was distributed in 17 ± 7 separate liquid pockets in the colon. The regional analysis showed that pockets of free fluid were found primarily in the ascending colon. The interindividual variability was very high; the subjects showed a range of number of colonic fluid pockets from 0 to 89 and total colonic freely mobile fluid volume from 0 to 49 mL. This is the first study measuring the time course of the number, regional location, and volume of pockets of freely mobile liquid in the undisturbed colon of fasted humans after ingestion of a glass of water. Novel insights into the colonic fluid environment will be particularly relevant to improve our understanding and design of the in vivo performance of controlled release formulations targeted to the colon. The in vivo quantitative information presented here can be input into physiologically based mechanistic models of dissolution and absorption, and can be used in the design and set up of novel in vitro performance tools predictive of the in vivo environment.

Visual morphometry and three non-invasive markers in the evaluation of liver fibrosis in chronic liver disease.

OBJECTIVE: Liver fibrosis is traditionally graded into categorical stages with cirrhosis as the highest stage. However, cirrhosis stage may vary between individuals widely in terms of the amount of fibrosis which is not assessed by traditional staging systems. We aimed to utilise visual morphometry to quantify the amount of fibrosis in liver biopsy and compare how non-invasive methods of quantifying liver fibrosis correlated with histological measures. MATERIALS AND METHODS: Liver biopsy specimens from 115 consecutive chronic liver disease patients were assessed by a single pathologist for fibrosis stage by the Clinical Research Network and METAVIR systems as well as percentage fibrosis by visual morphometry. Liver T1 relaxation times, liver stiffness measurement (LSM) by transient elastography and enhanced liver fibrosis (ELF) score were compared between fibrosis stages. In addition, these parameters were correlated with pathologist's visual estimate of percentage fibrosis and their predictive ability for advanced fibrosis and cirrhosis assessed by area under receiver operating curve (AUROC). RESULTS: All four parameters increased sequentially from fibrosis stage F0 to F4 (p<.001 for each). AUROCs for advanced fibrosis and cirrhosis were 0.931 and 1.000 respectively for pathologist's estimate of fibrosis, 0.707 and 0.926 for ELF score, 0.763 and 0.972 for T1 and 0.881 and 0.989 for LSM. LSM, ELF score and T1 correlated significantly with pathologist's estimate of percentage fibrosis. CONCLUSION: Non-invasive markers of fibrosis LSM, ELF and T1 relaxation time provide continuous surrogates for categorical histopathological staging of fibrosis which can be useful as markers of progression and regression of fibrosis on follow-up.

Patients with chronic kidney disease have abnormal upper gastro-intestinal tract digestive function: A study of uremic enteropathy.

BACKGROUND AND AIM: Chronic kidney disease (CKD) affects gastrointestinal (GI) function and results in numerous adaptive and maladaptive responses. Disruption of the colonic microbiome and its attendant consequences-the loss of gut barrier integrity and increased generation of uremic toxins-has become well-recognized. However, less attention has been paid to characterizing the mechanisms behind dysfunction of the upper GI tract, largely owing to the difficulty of studying small bowel function in vivo. This present study was designed to comprehensively describe upper GI function in those with advanced renal impairment. METHODS: Thirty-five non-diabetic subjects (12 CKD stage 4/5 patients, 23 healthy controls) underwent detailed GI magnetic resonance imaging (MRI) in both fasted and fed states. Upper GI function was assessed by quantification of gastric emptying and intra-luminal small bowel water. Characterization of hydration and cardiovascular status was performed at baseline. Gut barrier integrity was assessed using serum endotoxin level. RESULTS: Chronic kidney disease was associated with dysmotility (gastric half-emptying time 96 ± 32 vs 74 ± 27 min, P = 0.04) and reduced fasting and post-prandial small bowel water (36 ± 22 mL vs 78 ± 42 mL, P < 0.001), reflecting abnormal digestive secretion, and absorption. This was related to the degree of endotoxemia (r = -0.60, P = 0.04) and poorer symptom scores, but not to disease severity, arterial stiffness or hydration status. CONCLUSION: Chronic kidney disease adversely affects digestive function. Abnormalities in digestive secretion and absorption may potentially have a broad impact in the prevention and treatment of both CKD and its complications. Further study is required to assess the factors that contribute to this dysfunction in a wider CKD population.

Effects of Bolus and Continuous Nasogastric Feeding on Gastric Emptying, Small Bowel Water Content, Superior Mesenteric Artery Blood Flow, and Plasma Hormone Concentrations in Healthy Adults: A Randomized Crossover Study.

OBJECTIVE: We aimed to demonstrate the effect of continuous or bolus nasogastric feeding on gastric emptying, small bowel water content, and splanchnic blood flow measured by magnetic resonance imaging (MRI) in the context of changes in plasma gastrointestinal hormone secretion. BACKGROUND: Nasogastric/nasoenteral tube feeding is often complicated by diarrhea but the contribution of feeding strategy to the etiology is unclear. METHODS: Twelve healthy adult male participants who underwent nasogastric intubation before a baseline MRI scan, received 400  mL of Resource Energy (Nestle) as a bolus over 5 minutes or continuously over 4  hours via pump in this randomized crossover study. Changes in gastric volume, small bowel water content, and superior mesenteric artery blood flow and velocity were measured over 4  hours using MRI and blood glucose and plasma concentrations of insulin, peptide YY, and ghrelin were assayed every 30 minutes. RESULTS: Bolus nasogastric feeding led to significant elevations in gastric volume (P < 0.0001), superior mesenteric artery blood flow (P < 0.0001), and velocity (P = 0.0011) compared with continuous feeding. Both types of feeding reduced small bowel water content, although there was an increase in small bowel water content with bolus feeding after 90 minutes (P < 0.0068). Similarly, both types of feeding led to a fall in plasma ghrelin concentration although this fall was greater with bolus feeding (P < 0.0001). Bolus feeding also led to an increase in concentrations of insulin (P = 0.0024) and peptide YY (P < 0.0001), not seen with continuous feeding. CONCLUSION: Continuous nasogastric feeding does not increase small bowel water content, thus fluid flux within the small bowel is not a major contributor to the etiology of tube feeding-related diarrhea.

Effect of bread gluten content on gastrointestinal function: a crossover MRI study on healthy humans.

Gluten is a crucial functional component of bread, but the effect of increasing gluten content on gastrointestinal (GI) function remains uncertain. Our aim was to investigate the effect of increasing gluten content on GI function and symptoms in healthy participants using the unique capabilities of MRI. A total of twelve healthy participants completed this randomised, mechanistic, open-label, three-way crossover study. On days 1 and 2 they consumed either gluten-free bread (GFB), or normal gluten content bread (NGCB) or added gluten content bread (AGCB). The same bread was consumed on day 3, and MRI scans were performed every 60 min from fasting baseline up to 360 min after eating. The appearance of the gastric chime in the images was assessed using a visual heterogeneity score. Gastric volumes, the small bowel water content (SBWC), colonic volumes and colonic gas content and GI symptoms were measured. Fasting transverse colonic volume after the 2-d preload was significantly higher after GFB compared with NGCB and AGCB with a dose-dependent response (289 (SEM 96) v. 212 (SEM 74) v. 179 (SEM 87) ml, respectively; P=0·02). The intragastric chyme heterogeneity score was higher for the bread with increased gluten (AGCB 6 (interquartile range (IQR) 0·5) compared with GFB 3 (IQR 0·5); P=0·003). However, gastric half-emptying time was not different between breads nor were study day GI symptoms, postprandial SBWC, colonic volume and gas content. This MRI study showed novel mechanistic insights in the GI responses to different breads, which are poorly understood notwithstanding the importance of this staple food.

A study of T1 relaxation time as a measure of liver fibrosis and the influence of confounding histological factors.

Liver biopsy is the standard test for the assessment of fibrosis in liver tissue of patients with chronic liver disease. Recent studies have used a non-invasive measure of T1 relaxation time to estimate the degree of fibrosis in a single slice of the liver. Here, we extend this work to measure T1 of the whole liver and investigate the effects of additional histological factors such as steatosis, inflammation and iron accumulation on the relationship between liver T1 and fibrosis. We prospectively enrolled patients who had previously undergone liver biopsy to have MR scans. A non-breath-holding, fast scanning protocol was used to acquire MR relaxation time data (T1 and T2*), and blood serum was used to determine the enhanced liver fibrosis (ELF) score. Areas under the receiver operator curves (AUROCs) for T1 to detect advanced fibrosis and cirrhosis were derived in a training cohort and then validated in a second cohort. Combining the cohorts, the influence of various histology factors on liver T1 relaxation time was investigated. The AUROCs (95% confidence interval (CI)) for detecting advanced fibrosis (F ≥ 3) and cirrhosis (F = 4) for the training cohort were 0.81 (0.65-0.96) and 0.92 (0.81-1.0) respectively (p < 0.01). Inflammation and iron accumulation were shown to significantly alter T1 in opposing directions in the absence of advanced fibrosis; inflammation increasing T1 and iron decreasing T1. A decision tree model was developed to allow the assessment of early liver disease based on relaxation times and ELF, and to screen for the need for biopsy. T1 relaxation time increases with advanced fibrosis in liver patients, but is also influenced by iron accumulation and inflammation. Together with ELF, relaxation time measures provide a marker to stratify patients with suspected liver disease for biopsy.

Fat emulsion intragastric stability and droplet size modulate gastrointestinal responses and subsequent food intake in young adults.

BACKGROUND: Intragastric creaming and droplet size of fat emulsions may affect intragastric behavior and gastrointestinal and satiety responses. OBJECTIVES: We tested the hypotheses that gastrointestinal physiologic responses and satiety will be increased by an increase in intragastric stability and by a decrease in fat droplet size of a fat emulsion. METHODS: This was a double-blind, randomized crossover study in 11 healthy persons [8 men and 3 women, aged 24 ± 1 y; body mass index (in kg/m(2)): 24.4 ± 0.9] who consumed meals containing 300-g 20% oil and water emulsion (2220 kJ) with 1) larger, 6-µm mean droplet size (Coarse treatment) expected to cream in the stomach; 2) larger, 6-µm mean droplet size with 0.5% locust bean gum (LBG; Coarse+LBG treatment) to prevent creaming; or 3) smaller, 0.4-µm mean droplet size with LBG (Fine+LBG treatment). The participants were imaged hourly by using MRI and food intake was assessed by using a meal that participants consumed ad libitum. RESULTS: The Coarse+LBG treatment (preventing creaming in the stomach) slowed gastric emptying, resulting in 12% higher gastric volume over time (P < 0.001), increased small bowel water content (SBWC) by 11% (P < 0.01), slowed appearance of the (13)C label in the breath by 17% (P < 0.01), and reduced food intake by 9% (P < 0.05) compared with the Coarse treatment. The Fine+LBG treatment (smaller droplet size) slowed gastric emptying, resulting in 18% higher gastric volume (P < 0.001), increased SBWC content by 15% (P < 0.01), and significantly reduced food intake by 11% (P < 0.05, equivalent to an average of 411 kJ less energy consumed) compared with the Coarse+LBG treatment. These high-fat meals stimulated substantial increases in SBWC, which increased to a peak at 4 h at 568 mL (range: 150-854 mL; P < 0.01) for the Fine+LBG treatment. CONCLUSION: Manipulating intragastric stability and fat emulsion droplet size can influence human gastrointestinal physiology and food intake.

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.

Impact of extended Elexacaftor/Tezacaftor/Ivacaftor therapy on the gut microbiome in cystic fibrosis.

BACKGROUND: There is a paucity of knowledge on the longer-term effects of CF transmembrane conductance regulator (CFTR) modulator therapies upon the gut microbiome and associated outcomes. In a pilot study, we investigated longitudinal Elexacaftor/Tezacaftor/Ivacaftor (ETI) therapy on the gut microbiota, metabolomic functioning, and clinical outcomes in people with CF (pwCF). STUDY DESIGN: Faecal samples from 20 pwCF were acquired before and then following 3, 6, and 17+ months of ETI therapy. Samples were subjected to microbiota sequencing and targeted metabolomics to profile and quantify short-chain fatty acid composition. Ten healthy matched controls were included for comparison. Clinical data, including markers of intestinal function were integrated to investigate relationships. RESULTS: Extended ETI therapy increased core microbiota diversity and composition, which translated to gradual shifts in whole microbiota composition towards that observed in healthy controls. Despite becoming more similar over time, CF microbiota and functional metabolite compositions remained significantly different to healthy controls. Antibiotic treatment for pulmonary infection significantly explained a relatively large degree of variation within the whole microbiota and rarer satellite taxa. Clinical outcomes were not significantly different following ETI. CONCLUSIONS: Whilst differences persisted, a positive trajectory towards the microbiota observed in healthy controls was found. We posit that progression was predominately impeded by pulmonary antibiotics administration. We recommend future studies use integrated omics approaches within a combination of long-term longitudinal patient studies and model experimental systems. This will deepen our understanding of the impacts of CFTR modulator therapy and respiratory antibiotic interventions upon the gut microbiome and gastrointestinal pathophysiology in CF.

Colon length in pediatric health and constipation measured using magnetic resonance imaging and three dimensional skeletonization.

Recent magnetic resonance imaging (MRI) studies showed that colonic volumes in children are different between health and functional constipation. The length of the colon has however been rarely measured and principally using unphysiological colon preparations or cadaver studies. The main objective of this study was to measure the length of the undisturbed colon in children with functional constipation (FC) and healthy controls. Here, the colon of 19 healthy controls (10-18 years old) and 16 children with FC (7-18 years old) was imaged using MRI. Different regions of the colon (ascending, transverse, descending, and sigmoid-rectum) were first segmented manually on the MRI images. Three-dimensional skeletonization image analysis methods were then used to reduce the regions of interest to a central, measurable line. Total colon length (corrected for body surface area) in healthy controls was 56±2 cm/m2 (mean±SEM). Total colon length was significantly longer in children with FC 69±3 cm/m2 compared to controls (p = 0.0037). The colon regions showing the largest differences between groups were the ascending colon (p = 0.0479) and the sigmoid-rectum (p = 0.0003). In a linear regression model, there was a positive significant correlation between total colon length and age (R = 0.45, p = 0.0064), height (R = 0.49, p = 0.0031), weight (R = 0.46, p = 0.0059) and colon volume (R = 0.4543, p = 0.0061). Our findings showed significant differences in colon lengths between healthy controls and children with constipation. A new objective diagnostic imaging endpoint such as colon length may help to improve knowledge of colon morphology and function and, in turn, understanding of colon functional pathology.

The impact of heat treatment of bovine milk on gastric emptying and nutrient appearance in peripheral circulation in healthy females: a randomized controlled trial comparing pasteurized and ultra-high temperature milk.

BACKGROUND: Heat treatments of dairy, including pasteurization and ultra-high temperature (UHT) processing, alter milk macromolecular structures, and ultimately affect digestion. In vitro, animal, and human studies show faster nutrient release or circulating appearance after consuming UHT milk (UHT-M) compared with pasteurized milk (PAST-M), with a faster gastric emptying (GE) rate proposed as a possible mechanism. OBJECTIVES: To investigate the impact of milk heat treatment on GE as a mechanism of faster nutrient appearance in blood. We hypothesized that GE and circulating nutrient delivery following consumption would be faster for UHT-M than PAST-M. METHODS: In this double-blind randomized controlled cross-over trial, healthy female (n = 20; 27.3 ± 1.4 y, mean ± SD) habitual dairy consumers, consumed 500 mL of either homogenized bovine UHT-M or PAST-M (1340 compared with 1320 kJ). Gastric content volume (GCV) emptying half-time (T50) was assessed over 3 h by magnetic resonance imaging subjective digestive symptoms, plasma amino acid, lipid and B vitamin concentrations, and gastric myoelectrical activity were measured over 5 h. RESULTS: Although GCV T50 did not differ (102 ± 7 min compared with 89 ± 8 min, mean ± SEM, UHT-M and PAST-M, respectively; P = 0.051), GCV time to emptying 25% of the volume was 31% longer following UHT-M compared with PAST-M (42 ± 2 compared with 32 ± 4 min, P = 0.004). Although GCV remained larger for a longer duration following UHT-M (treatment × time interaction, P = 0.002), plasma essential amino acid AUC was greater following UHT-M than PAST-M (55,324 ± 3809 compared with 36,598 ± 5673 µmol·min·L-1, P = 0.006). Heat treatment did not impact gastric myoelectrical activity, plasma appetite hormone markers or subjective appetite scores. CONCLUSIONS: Contrary to expectations, GE was slower with UHT-M, yet, as anticipated, aminoacidemia was greater. The larger GCV following UHT-M suggests that gastric volume may poorly predict circulating nutrient appearance from complex food matrices. Dairy heat treatment may be an effective tool to modify nutrient release by impacting digestion kinetics. CLINICAL TRIAL REGISTRY: www.anzctr.org.au (ACTRN12620000172909).

MRI tagging of colonic chyme mixing in healthy subjects: Inter-observer variability and reliability of the measurement with time.

BACKGROUND: Magnetic resonance imaging (MRI) tagging techniques have been applied to the GI tract to assess bowel contractions and content mixing. We aimed to evaluate the dependence of a tagging measurement (for assessing chyme mixing) on inter-observer variability in both the ascending colon (AC) and descending colon (DC) and to investigate the temporal variation and hence reliability of the colonic tagging technique by acquiring multiple measurements over time on healthy participants. METHODS: Two independent datasets of healthy adults were used for the retrospective inter-observer variability (Study 1: 13 datasets and Study 2: 31 datasets), and ten participants were scanned for the prospective temporal variation study following a 1 L mannitol oral preparation. All colonic tagging data were acquired on 3 T MRI scanners. The mean and the standard deviation (SD) maps were generated pixel-by-pixel using custom-written software in MATLAB. The colonic regions of interest were defined using MIPAV software. Bland-Altman plots and scatter plots were used for the inter-observer variability. The mean and SD of all repeated measures for each subject were calculated along with a one-way ANOVA to test for variations with time. RESULTS: Scatter plots and Bland-Altman plots showed a large range of data with low variation and small limits of agreements (<5% CoV). The intraclass correlation coefficient of inter-rater reliability was excellent and 0.97 or above for the AC and DC measurements for both datasets. The temporal variation study shows that there was no significant difference found between the multiple measures with time (p = 0.53, one-way repeated measures ANOVA test). CONCLUSIONS: MRI tagging technique can provide an assessment of colonic chyme mixing. The inter-observer study data showed high inter-rater agreement. The temporal variation study showed some individual variations with time suggesting multiple measurements may be needed to increase accuracy.

Preventing gastric sieving by blending a solid/water meal enhances satiation in healthy humans.

Separation of solids and liquids within the stomach allows faster gastric emptying of liquids compared with solids, a phenomenon known as sieving. We tested the hypothesis that blending a solid and water meal would abolish sieving, preventing the early rapid decrease in gastric volume and thereby enhancing satiety. We carried out 2 separate studies. Study 1 was a 2-way, crossover, satiety study of 22 healthy volunteers who consumed roasted chicken and vegetables with a glass of water (1008 kJ) or the same blended to a soup. They completed satiety visual analogue scales at intervals for 3 h. Study 2 was a 2-way, crossover, mechanistic study of 18 volunteers who consumed the same meals and underwent an MRI to assess gastric emptying, gallbladder contraction, and small bowel water content (SBWC) at intervals for 3 h. In Study 1, the soup meal was associated with reduced hunger (P = 0.02). In Study 2, the volume of the gastric contents after the soup meal decreased more slowly than after the solid/liquid meal (P = 0.0003). The soup meal caused greater gallbladder contraction (P < 0.04). SBWC showed a biphasic response with an initial "gastric" phase during which SBWC was greater when the solid/liquid meal was consumed (P < 0.001) and a later "small bowel" phase when SBWC was greater when the soup meal was consumed (P < 0.01). Blending the solid/liquid meal to a soup delayed gastric emptying and increased the hormonal response to feeding, which may contribute to enhanced postprandial satiety.