Our aim was to understand the information from differential two-sugar excretion (2-SE) in measuring intestinal permeability. In a crossover study in 12 healthy volunteers, we compared urinary excretion ratios of lactulose (L) to mannitol [(M) LMR] after ingestion in liquid formulation (LF) or in delayed-release, methacrylate-coated capsules (CAP). Both formulations were radiolabeled. Urine was collected every 2 hours from 0-8h, and from 8-24h. Two hours after LF, gastric residual was 15.9 ± 6.2 % (SEM), and the percentage in colon was 49.6 ± 7.8 %; in 11/12 participants, liquid had entered colon within 2h. Average CAP arrival time in colon was 5.16 ± 0.46h (mode 6 h). After LF, mannitol was extensively absorbed in the first 8h; lactulose absorption was low thoughout the 24h. After the LF, the LMR (geometric mean, 95% CI/hour) in NIH Public Access Author ManuscriptNeurogastroenterol Motil. Author manuscript; available in PMC 2011 January 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript the 0-2h urine was 0.08 [0.05, 0.11]), which was lower than in 8-24h urine (0.32,[0.16, 0.46]; p<0.05). Urine LMRs at 8-24h were similar after LF or CAP. We concluded that, after LF, sugar excretion in 0-2h urine may reflect both SI and colon permeability. Colonic permeability is reflected by urine sugar excretion between 6 and 24h. CAP delivery reduces mannitol excreted at 0-6h, compared to LF. The 0 to 5 or 6h 2-SE urine likely reflects both SI and colon permeability; the higher LMR in the 8-24h urine relative to 0-2h urine should be interpreted with caution and does not mean that colon is more permeable than SI. Keywordsbarrier; irritable bowel; inflammation; LMR Differential absorption and excretion of molecular probes provide evidence of altered permeability of the intestine in gastrointestinal diseases including celiac disease, Crohn's disease and irritable bowel syndrome (IBS). Greater paracellular permeability could facilitate passage of luminal antigens, leading to local mucosal immune responses and resulting in inflammation (1) or stimulation of bowel dysfunction or visceral pain.Some highly sensitive methods for measuring intestinal permeability are too invasive to be used routinely. Ussing chamber techniques, requiring multiple intestinal mucosal biopsies at different levels of the gut, are too invasive to be used in large scale research on humans or for clinical diagnosis (2). Measurements using a single molecule (such as 51 Cr EDTA) are potentially affected by interindividual differences not related to permeability (e.g. transit or urinary excretion). Thus, human intestinal permeability has been measured by urinary excretion of two probes of different sizes but similar transit and uptake processes, and calculating the excretion ratio of a monosaccharide and a disaccharide such as mannitol and lactulose respectively (3). The amounts of lactulose and mannitol in the normal diet are negligible to trace. Other molecules are used, including sucralose. This is an artificial sweetener, ...

SUMMARY BackgroundThe consensus statements for eosinophilic oesophagitis recommend that ambulatory pH monitoring is one means of determining if gastro-oesophageal reflux is the cause of oesophageal eosinophilia and should guide pharmacological therapy.

Objectives:Rifaximin relieves irritable bowel syndrome (IBS) symptoms, bloating, abdominal pain, and loose or watery stools. Our objective was to investigate digestive functions in rifaximin-treated IBS patients.Methods:In a randomized, double-blind, placebo-controlled, parallel-group study, we compared the effects of rifaximin, 550 mg t.i.d., and placebo for 14 days in nonconstipated IBS and no evidence of small intestinal bacterial overgrowth (SIBO). All subjects completed baseline and on-treatment evaluation of colonic transit by scintigraphy, mucosal permeability by lactulose–mannitol excretion, and fecal microbiome, bile acids, and short chain fatty acids measured on random stool sample. Overall comparison of primary response measures between treatment groups was assessed using intention-to-treat analysis of covariance (ANCOVA, with baseline value as covariate).Results:There were no significant effects of treatment on bowel symptoms, small bowel or colonic permeability, or colonic transit at 24 h. Rifaximin was associated with acceleration of ascending colon emptying (14.9±2.6 h placebo; 6.9±0.9 h rifaximin; P=0.033) and overall colonic transit at 48 h (geometric center 4.0±0.3 h placebo; 4.7±0.2 h rifaximin; P=0.046); however, rifaximin did not significantly alter total fecal bile acids per g of stool or proportion of individual bile acids or acetate, propionate, or butyrate in stool. Microbiome studies showed strong associations within subjects, modest associations with time across subjects, and a small but significant association of microbial richness with treatment arm (rifaximin vs. treatment).Conclusions:In nonconstipated IBS without documented SIBO, rifaximin treatment is associated with acceleration of colonic transit and changes in microbial richness; the mechanism for reported symptomatic benefit requires further investigation.

Background: In primary bile acid diarrhoea (PBAD), feedback by farnesoid X receptor (FXR) and fibroblast growth hormone 19 (FGF19) on hepatic bile acid production is impaired. Aims:To evaluate the safety, mechanisms and efficacy of tropifexor, a non-bile acid FXR agonist, in patients with PBAD. Methods:In this double-blind, multicentre, randomised, crossover study, patients received tropifexor 60 µg or placebo once daily for 14 days in each of 2 treatment periods. Primary objectives included the effect of tropifexor on safety and tolerability, stool frequency and form. Other assessments included pharmacokinetic and pharmacodynamic measures, biochemical markers and gastrointestinal transit.Results: A total of 20 patients (tropifexor 60 µg/placebo [N=10]; placebo/tropifexor 60 µg [N=10]) were enrolled. Adverse event rates were similar with tropifexor and placebo (52.9% vs 73.7%). No patient had pruritus during tropifexor intake. Differences in stool frequency, stool form or loperamide use between two treatments were not appreciably large.Tropifexor increased FGF19 and decreased 7α-hydroxy-4-cholesten-3-one (C4) levels for up to 8 h. Plasma concentrations of tropifexor peaked at 5 hours post-dose on days 1 and 12. At Day 12, reduction in peak total bile acid concentration (33%, P=0.032) and exposure (36%, P=0.005) was noted with tropifexor. A significant increase in ascending colonic halfemptying time was observed with tropifexor (P=0.036). Conclusions:Tropifexor 60 µg once daily had an acceptable safety and tolerability profile.

NGM282 significantly impacts GE and colonic transit, consistent with the observed clinical symptoms. The specific mechanism of prokinetic activity requires further research.