Irritable bowel syndrome (IBS) is a heterogeneous condition and defined according to symptoms. Low-grade inflammation has been associated with IBS, particularly that following infection, but whether ...altered intestinal permeability profiles relate to irritable bowel subtype or onset is uncertain. Our aim was to compare small and large intestinal permeability in various subtypes of IBS to healthy controls.
Intestinal permeability was measured using 1.8 MBq of 51Cr-EDTA and collecting urine over 24 h; Study 1: patients with diarrhea-predominant postinfectious IBS (N=15), constipation-predominant IBS (N=15), and healthy controls (N=15); Study 2: two groups of diarrhea-predominant IBS (D-IBS), one with a history of onset after acute gastroenteritis (postinfectious) (N=15) and the other without such a history (nonpostinfectious) (N=15) both compared with healthy controls (N=12).
Permeability expressed as percentage of total dose excreted in urine (median inter-quartile range). Study 1: Proximal small intestinal permeability was increased in postinfectious IBS (0.19 0.12-0.23) in contrast to constipated IBS (0.085 0.043-0.13) and controls (0.07 0.035-0.19) (p=0.02). IBS patients with eczema, asthma, or hayfever had increased proximal small intestinal permeability compared with IBS patients without atopy (p=0.02). Study 2: Small intestinal permeability was greater in nonpostinfectious diarrhea-predominant IBS (0.84 0.69-1.49) compared with postinfectious IBS (0.43 0.29-0.63, p=0.028) or controls (0.27 0.2-0.39), p=0.001).
Small intestinal permeability is frequently abnormal in diarrhea-predominant IBS. Those without a history of infectious onset appear to have a more severe defect.
The gastrointestinal environment in which drug products need to disintegrate before the drug can dissolve and be absorbed has not been studied in detail due to limitations, especially invasiveness of ...existing techniques. Minimal in vivo data is available on undisturbed gastrointestinal motility to improve relevance of predictive dissolution models and in silico tools such as physiologically-based pharmacokinetic models. Recent advances in magnetic resonance imaging methods could provide novel data and insights that can be used as a reference to validate and, if necessary, optimize these models. The conventional method for measuring gastrointestinal motility is via a manometric technique involving intubation. Nevertheless, it is feasible to measure gastrointestinal motility with magnetic resonance imaging. The aim of this study was is to develop and validate a magnetic resonance imaging method using the most recent semi-automated analysis method against concomitant perfused manometry method.
Eighteen healthy fasted participants were recruited for this study. The participants were intubated with a water-perfused manometry catheter. Subsequently, stomach motility was assessed by cine-MRI acquired at intervals, of 3.5min sets, at coronal oblique planes through the abdomen and by simultaneous water perfused manometry, before and after administration of a standard bioavailability / bioequivalence 8 ounces (~240mL) drink of water. The magnetic resonance imaging motility images were analysed using Spatio-Temporal Motility analysis STMM techniques. The area under the curve of the gastric motility contractions was calculated for each set and compared between techniques. The study visit was then repeated one week later.
Data from 15 participants was analysed. There was a good correlation between the MRI antral motility plots area under the curve and corresponding perfused manometry motility area under the curve (r = 0.860) during both antral contractions and quiescence.
Non-invasive dynamic magnetic resonance imaging of gastric antral motility coupled with recently developed, semi-automated magnetic resonance imaging data processing techniques correlated well with simultaneous, 'gold standard' water perfused manometry. This will be particularly helpful for research purposes related to oral absorption where the absorption of a drug is highly depending on the underlying gastrointestinal processes such as gastric emptying, gastrointestinal motility and availability of residual fluid volumes.
This trial was registered at ClinicalTrials.gov as NCT03191045.
Health-promoting dietary fibre including inulin often triggers gastrointestinal symptoms in patients with IBS, limiting their intake. Our aim was to test if coadministering psyllium with inulin would ...reduce gas production.
A randomised, four-period, four-treatment, placebo-controlled, crossover trial in 19 patients with IBS. Subjects ingested a 500 mL test drink containing either inulin 20 g, psyllium 20 g, inulin 20 g+ psyllium 20 g or dextrose 20 g (placebo). Breath hydrogen was measured every 30 min with MRI scans hourly for 6 hours. Faecal samples from a subset of the patients with IBS were tested using an
fermentation model. Primary endpoint was colonic gas assessed by MRI.
Colonic gas rose steadily from 0 to 6 hours, with inulin causing the greatest rise, median (IQR) AUC
3145 (848-6502) mL·min. This was significantly reduced with inulin and psyllium coadministration to 618 (62-2345) mL·min (p=0.02), not significantly different from placebo. Colonic volumes AUC
were significantly larger than placebo for both inulin (p=0.002) and inulin and psyllium coadministration (p=0.005). Breath hydrogen rose significantly from 120 min after inulin but not psyllium; coadministration of psyllium with inulin delayed and reduced the maximum increase, AUC
from 7230 (3255-17910) ppm·hour to 1035 (360-4320) ppm·hour, p=0.007.Fermentation
produced more gas with inulin than psyllium. Combining psyllium with inulin did not reduce gas production.
Psyllium reduced inulin-related gas production in patients with IBS but does not directly inhibit fermentation. Whether coadministration with psyllium increases the tolerability of prebiotics in IBS warrants further study.
NCT03265002.
Summary
Background
Chronic constipation affects approximately 17% of the population worldwide and remains an important unmet need since patients are often dissatisfied with treatment. Kiwifruit may ...offer an alternative to traditional laxatives and have been shown to increase stool volume, frequency and improve consistency.
Aims
Using non‐invasive MRI techniques, we assessed the effect of ingestion of kiwifruit on fluid distribution in the intestines and bowel function.
Methods
Two period crossover trial of kiwifruit vs control in healthy adults. Intervention: two kiwifruits twice daily vs isocaloric control (maltodextrin) twice daily, consumed for a total of 3 days. Subjects underwent MRI scanning fasted and at hourly intervals for 7 hours on the third day. Primary outcome: T1 relaxation time of ascending colon (T1AC) using MRI. Secondary outcomes: Small bowel water content (SBWC), colonic volume, gut transit time, T1 of descending colon, stool frequency and form.
Results
Fourteen volunteers completed the study. T1AC was higher after kiwifruit ingestion (P = 0.029) during the second half of the day (when meal residue would be expected to reach the AC, AUC T1 T240‐420 minutes; mean (SD) 137 (39) s*minute with kiwifruit versus 108 (40) s*minute with control. SBWC (P < 0.001), colon volumes (P = 0.004), as well as stool frequency (1.46 ± 0.66 with kiwifruit vs 1.14 ± 0.46 stools per day with control; P = 0.034) and stool form score (Bristol Stool Chart score 4.1 (0.9) with kiwifruit versus 3.4 (0.7) with control; P = 0.011) were markedly increased in participants consuming kiwifruit compared to control.
Conclusion
Consumption of kiwifruit in healthy volunteers increases water retention in the small bowel and ascending colon and increases total colonic volume. The data may explain the observed increase in stool frequency and looser stool consistencies, suggesting that kiwifruit could be used as a dietary alternative to laxatives in mild constipation.
The postinfectious irritable bowel syndrome (PI-IBS) suggests that impaired resolution of inflammation could cause IBS symptoms. The authors hypothesised that polymorphisms in genes whose expression ...were altered by gastroenteritis might be linked to IBS with diarrhoea (IBS-D) which closely resembles PI-IBS.
Part 1: 25 healthy volunteers (HVs), 21 patients 6 months after Campylobacter jejuni infection, 37 IBS-D and 19 IBS with constipation (IBS-C) underwent rectal biopsy for gene expression analysis and peripheral blood mononuclear cell cytokine production assessment. Part 2: Polymorphisms in genes whose expression was altered in Part 1 were assessed in 179 HV, 179 IBS-D, 122 IBS-C and 41 PI-IBS.
Part 1: Mucosal expression of seven genes was altered in IBS: CCL11, CCL13, Calpain 8 and TNFSF15 increased while NR1D1, GPR161 and GABRE decreased with similar patterns after infection with C jejuni. Part 2: The authors assessed 21 known single nucleotide polymorphisms (SNPs) in these seven genes and one SNP in each of the TNFα and IL-10 genes. Three out of five TNFSF15 SNPs (rs6478108, rs6478109 and rs7848647) showed reduced minor allele frequency (MAF) (0.28, 0.27 and 0.27) in subjects with IBS-D compared with HV (0.38, 0.36 and 0.37; p=0.007, 0.015 and 0.007, respectively) confirming others recent findings. The authors also replicated the previously reported association of the TNFα SNP rs1800629 with PI-IBS which showed an increase in the MAF at 0.30 versus 0.19 for HV (p=0.04).
IBS-D and PI-IBS patients are associated with TNFSF15 and TNFα genetic polymorphisms which also predispose to Crohn's disease suggesting possible common underlying pathogenesis.
Background & Aims Postprandial symptoms are common in patients with irritable bowel syndrome with diarrhea (IBS-D) and could be diet related. We studied postprandial changes in distribution of water ...in the upper gastrointestinal tract of healthy volunteers (HVs) and patients with IBS-D after contrasting meals. Methods In study 1, 11 HVs consumed 350-mL test meals with 5% mannitol (unabsorbable) or 5% glucose (readily absorbed). In study 2, 17 HVs consumed a 331-kcal meal, with or without 15 g bran. In study 3, 26 patients with IBS-D consumed the study 2 diet with bran meal. All subjects underwent serial magnetic resonance imaging analysis. Results In study 1, subjects' small bowel water content (SBWC) increased after the mannitol but not glucose meals, reaching 381 mL (interquartile range, 343–491 mL) and 47 mL (18–78 mL), respectively, 40 minutes after eating ( P < .001). In study 2, SBWC initially decreased after both meal types and then increased, plateauing at 180–405 minutes and was greater after the bran meal ( P = .02). In study 3, fasting and postprandial SBWC was lower in IBS-D than in HVs ( P < .05 and P < .0001, respectively). Patients with IBS-D had faster orocecal transit times (135 minutes; 90–180 minutes) compared with HVs (225 minutes; 203–293 minutes; P < .0001) and reduced terminal ileum diameter ( P < .003). Conclusions Postprandial SBWC initially decreases, because of rapid, nutrient-driven fluid absorption, and then increases after a mixed liquid/solid meal. Patients with IBS-D have reduced fasting and postprandial SBWC with faster transit, possibly indicating increased small intestinal tone.
Irritable bowel syndrome after gastroenteritis is well recognized. Our aim was to determine whether postinfective IBS (PI-IBS) has histological or clinical features that are distinct from those of ...IBS patients with no history of preceding infection.
A total of 75 consecutive IBS outpatients and 36 healthy control subjects completed a questionnaire detailing symptoms, mode of onset, and previous psychiatric history. All underwent a full diagnostic workup including rectal biopsy, which included immunostaining and quantification for lamina propria or intraepithelial T lymphocytes, serotonin-containing enterochromaffin (EC), and mast cells. Patients were divided according to onset of symptoms into PI-IBS (n = 23) or non-PI-IBS (n = 52) patients.
Diarrhea predominance occurred more frequently in PI-IBS (70%) than in non-PI-IBS (42%) patients (p = 0.03). A history of previous treatment for anxiety or depression was present in 26% of PI-IBS patients compared to 54% of non-PI-IBS (p = 0.02). Biopsy results for all patients were normal using conventional criteria; however, quantification revealed that PI-IBS showed increased EC cells compared to those of non-PI-IBS patients (p = 0.017) and controls (p = 0.02). Lamina propria T lymphocytes were increased in PI-IBS (p = 0.026) and non-PI-IBS (p = 0.011) patients compared to controls. Mast cells were increased in non-PI-IBS patients (p = 0.054) compared to controls.
Individuals with PI-IBS are a clinically distinct subgroup characterized by diarrheal symptoms, less psychiatric illness, and increased serotonin-containing EC cells compared to those with non-PI-IBS.
Serotonin is widely distributed throughout the gut within both the enteric nerves and enterochromaffin (EC) cells. EC cells are located in the gut mucosa with maximal numbers in the duodenum and ...rectum where they act as signal transducers, responding to pressure and luminal substances both bacterial and dietary. Activation leads to serotonin release which acts on a range of receptors on mucosal afferent and myenteric interneurones to initiate secretomotor reflexes. These cause nausea and vomiting as well as intestinal secretion, propulsion and if pronounced, diarrhoea. Inflammation in animal models acts via T lymphocytes to increase EC cell numbers and mucosal serotonin (5-HT) content while inflammatory cytokines decrease serotonin transporter (SERT) function. Inflammation due to coeliac disease and following gastrointestinal infection increases mucosal 5-HT availability by a combination of increased EC cells and depressed SERT. Irritable bowel syndrome (IBS) developing after gastrointestinal infection and IBS with diarrhoea is associated with excess 5-HT. The associated diarrhoeal symptoms respond well to 5-HT
3 receptor antagonists. These drugs also inhibit the nausea and vomiting occurring in patients undergoing chemotherapy which cause a marked increase in release of 5-HT as well as other mediators. Other conditions including IBS-C and constipation may have inadequate 5-HT release and benefit from both 5-HT
3 and 5-HT
4 receptor agonists.
Oral specially coated formulations have the potential to improve treatment outcomes of a range of diseases in distal intestinal tract whilst limiting systemic drug absorption and adverse effects. ...Their development is challenging, partly because of limited knowledge of the physiological and pathological distal gastrointestinal factors, including colonic chyme fluid distribution and motor function. Recently, non-invasive techniques such as magnetic resonance imaging (MRI) have started to provide novel important insights. In this feasibility study, we formulated a coated capsule consisting of a hydroxypropyl methylcellulose (HPMC) shell, coated with a synthetic polymer based on polymethacrylate-based copolymer (Eudragit
) that can withstand the upper gastrointestinal tract conditions. The capsule was filled with olive oil as MRI-visible marker fluid. This allowed us to test the ability of MRI to track such a coated capsule in the gastrointestinal tract and to assess whether it is possible to image its loss of integrity by exploiting the ability of MRI to image fat and water separately and in combination. Ten healthy participants were administered capsules with varying amounts of coating and underwent MRI imaging of the gastrointestinal tract at 45 min intervals. The results indicate that it is feasible to track the capsules present in the gastrointestinal tract at different locations, as they were detected in all 10 participants. By the 360 min endpoint of the study, in nine participants the capsules were imaged in the small bowel, in eight participants in the terminal ileum, and in four in the colon. Loss of capsule integrity was observed in eight participants, occurring predominantly in distal intestinal regions. The data indicate that the described approach could be applied to assess performance of oral formulations in undisturbed distal gastrointestinal regions, without the need for ionizing radiation or contrast agents.
•Gastrointestinal symptoms are experienced by the majority of CF patients.•Oro-caecal transit time was 2 h longer in CF than controls.•Absent postprandial drop in small bowel water suggests partial ...ileal obstruction.•Using MRI as an endpoint may facilitate future gut research in CF.
Cystic fibrosis (CF) is a multi-system genetic disorder affecting >72,000 people worldwide. Most CF patients experience gastrointestinal symptoms and can develop complications. However, the mechanisms of CF gut disease are not well understood. We evaluated gut function and transit in CF using magnetic resonance imaging (MRI). We hypothesised oro-caecal transit time (OCTT) is longer in CF; with lower small bowel water content (SBWC).
Twelve CF patients aged 12–40 years and 12 age and sex-matched controls underwent serial MRIs over 1 day with standardised meals. The primary endpoint was OCTT, assessed by the appearance of a food bolus in the caecum. Other measures included corrected SBWC and corrected colonic volume (both area under the curve, AUC), gastric half-emptying time and gastrointestinal symptoms.
OCTT was longer in CF (CF 330 mins 270, >360 vs. controls 210 mins 173, 315, p = 0.04), with no difference in gastric half-emptying times. Corrected SBWC was higher in CF (CF 62 L.min/m2 36, 80 vs. controls 34 L.min/m2 28, 41, p = 0.021); minimal postprandial decrease between T240 and T300 (CF 13 mL/m2 -13, 57 vs. controls 102 mL/m2 67, 108, p = 0.002) suggests impaired ileal emptying. Corrected colonic volumes were higher in CF (CF 186 L.min/m2 167, 206 vs. controls 123 L.min/m2 89, 146, p = 0.012). There were no differences in gastrointestinal symptoms.
MRI provides novel insights into CF pathophysiology. Sub-clinical ileal obstruction may be more prevalent than previously thought. Gastrointestinal MRI shows promise as an investigational tool in CF.
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