Understanding measurements of intestinal permeability in healthy humans with urine lactulose and mannitol excretion

Abstract

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, ...

Novel analytical approach to a multi-sugar whole gut permeability assay

“…This approach allowed quantification of all sugar probes of interest in both urine and plasma in one run, with a detection limit of 0.05 mol/L for disaccharides and 0.10 mol/L for monosaccharides. These lower limits of detection are significantly lower than previously reported [17,18], including a recent report of Camilleri et al who found detection limits of 4.98 mol/L (1.7 g/mL) for disaccharide lactulose and 1.92 mol/L (0.035 g/mL) for monosaccharide mannitol using normal phase LC-MS for permeability analysis in urine [18]. In our study, the increased analytic sensitivity allowed a 5-fold reduction of the oral lactulose dose.…”

“…The disaccharide sucralose and the sugar alcohol erythritol are not degraded by human colonic bacteria [20,21], allowing their use as markers of colonic and total GI permeability. Alternatively, assessment of samples (either urine or plasma) collected more frequently than the classical 0-5 h urinary collection, might reflect permeability of specific parts of the gastrointestinal tract [18]. Considering that sugar probes first appear in plasma after permeation through the mucosal epithelium, we aimed to perform plasma-based permeability analysis next to the classical urinary approach.…”

Crosstalk at the mucosal border: importance of the gut microenvironment in IBS

“…Apart from this last line of defence, the mucus layer covering the intestinal mucosa as well as the gut microbiota and products from the immune system (such as defensins and secreted antibodies) have important roles in maintaining gut integrity. 135 Between 12% and 50% of patients with IBS have been reported to have altered intestinal permeability in research studies 136 using various methods to reflect gut permeability at different parts of the gastrointestinal tract, [137][138][139] and both postinfectious IBS as well as nonselected groups of patients with IBS have been investigated. An acute bacterial infection results in a transient increase in intestinal permeability.…”

Comparison of an enzymatic assay with liquid chromatography-pulsed amperometric detection for the determination of lactulose and mannitol in urine of healthy subjects and patients with active celiac disease

“…The importance of %LMR as marker of IP in different GI diseases has already been highlighted by different studies utilizing different procedures [9]. In this framework, to our knowledge, this is the first study comparing the HPAEC-PAD with ESAT.…”