S18 Gut 1994; supplement 1: S18-S22 Intestinal permeability I Bjarnason Gut: first published as 10.1136/gut.35.1_Suppl.S18 on 1 January 1994. Downloaded from Abstract defence in both hypogammaglobulinaemiaI6-19 Damage to the mucosal barrier may be and HIV infection (unpublished data) leads to assessed, non-invasively by use of sugar an enteropathy, which is of similar severity to probes, which permeate through the that seen in NSAID enteropathy. transcellular or paracellular (tight junc- The study of intestinal permeability has tion) routes. A standardised test, with been confounded by technical complexities of analysis of a five hour urine collection test marker analysis, perceived non-specificity has proved useful in studying the of results, and the dilemma that a test induced sequelae ofnon-steroid anti-inflammatory breach in mucosal integrity may lead to patho- drug (NSAID) administration, untreated genesis. This is perhaps an understandable coeliac disease, and enteric infections. situation as the tests have, by and large, been Choice of probe molecule is crucial and advocated primarily for the purpose of screen- lactulose/l-rhamnose seem to be satisfac- ing for small intestinal disease,2>22 and there is tory, in contrast with polyethylene glycol. a hangover from the golden era of the absorp- Significant correlations have been seen tion tests (D-xylose, 3-o-methyl-D-glucose between permeability and plasma IgA etc), when the test results had no pathogenic concentrates in nephropathy, and between implications. permeability and the passage ofneutrophil chemotactic agents. The increased perme- ability associated with NSAID treatment Testing for increased permeability may relate to the adverse effects The test markers in common use (PEG 400, of NSAIDs on enterocyte mitochondrial lactulose, L-rhamnose-mannitol, 51CrEDTA. morphology and metabolism. These two 99mTcDTPA) can be analysed precisely and factors may predispose the mucosa to accurately, but apart from the radiolabelled permeation of bacterial chemoattractant chelates, these analyses are time consuming molecules that elaborate a local inflam- and tedious.23-29 matory response. A similar mechanism Tests of intestinal permeability were specif- may operate in patients with untreated ically designed to test intestinal barrier func- Crohn's disease, who show abnormally tion. Because it seemed probable that they high permeability. Remission induced by would provide a more sensitive indicator treatment with elemental diets coincides of intestinal disease than absorption,22-24 http://gut.bmj.com/ with a reduction in permeability. The methods of assessing the intactness of the period to relapse correlated with the intestinal barrier were designed. Initially inability of patients to maintain low lactulose, which resists degradation by permeability to sugar probes. These intestinal disaccharidases, was used by itself results suggest a mechanism for the to test barrier function. While less than benefits of elemental enteral nutrients in 0 5% lactulose was excreted in 5 hour urine the treatment of Crohn's disease. samples after oral administration, there was a on October 1, 2021 by guest. Protected copyright. (Gut 1994; supplement 1: S18-S22) rather low discrimination between normal subjects and patients with coeliac disease.21 Fortuitously, it was found that rendering the The pathogenesis of many small intestinal dis- test solution hyperosmolar (1500 mmol/l, eases entails interaction between changed with a readily absorbed osmotic filler) in- intestinal permeability, luminal aggressive creased the urine excretion of lactulose only factors, and mucosal defence mechanisms.1-3 marginally in normal subjects, but greatly Each of these factors can be implicated pri- in patients with coeliac disease, thereby offer- marily in the pathogenesis of disease. For in- ing good discrimination between the two stance, non-steroidal anti-inflammatory drugs groups.21 (NSAIDs) seem to cause specific damage to Urinary excretion of a single dose of a test enterocytes, which leads to increased intestinal substance is dependent on a number of factors permeability. This in turn may increase other than mucosal integrity (Figure), which mucosal exposure to normal luminal contents, not only reduce the sensitivity and specificity of resulting in neutrophil chemotaxis and Departent of Clinical hence the test procedure, but also pose a problem of Biochemistry, King's inflammation (NSAID enteropathy) in about interpretation of test results. To overcome Coliege School of 65% of patients receiving these drugs in the these problems, Menzies formulated the Medicine and long term.412 A variety of endogenous (after of Dentistry, London principle differential urinary excretion of I Bjamason bypass surgery) and exogenous microbes orally given test substances. The Figure details (Salmonella, Shigella, Campylobacter, Giardia, the intestinal process of two such test sub- Correspondence to: Dr I Bjarnason, Department and Yersinia) may overwhelm the mucosal stances).22 Any variation in pre or post- of Clinical Medicine, King's defence with resulting low grade neutrophil mucosal determinants of the sugars' overall College School of Medicine and Dentistry, Bessemer chemotaxis and increased intestinal per- permeation will affect the two test probes Road, London SE5 9PJ. meability.'3-15 Similarly, reduced mucosal equally, so that their urinary excretion ratio Intestinal permeability S19 Lactulose L-Rhamnose Completeness of ingestion both local and systemic diseases. The possi- Gastric dilutiion bility that increased intestinal permeability can u Gastric emptying lead to systemic disease such as ankylosing g Intestinal dilution by the mechanism of molecular Intestinal transit spondylitis, Gut: first published as 10.1136/gut.35.1_Suppl.S18 on 1 January 1994. Downloaded from ; Bacterial degradation - mimicry is, in particular, controversial.36-40 There are three studies that suggest that Brush border hydrolysis 0 0 increased intestinal permeability to these small Permeation pathway Paracellular Transcellular Blood flow probes (approximately 340 Daltons) may reflect increased macromolecular permeation. Endogenous production 0 0 Davin et al found a significant correlation o Metabolism 0 0 Tissue distribution between intestinal permeation of 51CrEDTA , Mode of renal excretion and IgA immune complex plasma concentra- a- Completeness of urine tions in patients with IgA associated collection nephropathies.41 Ramage et al showed a signifi- The urine excretion ofa permeability marker given orally is cant correlation between the permeation of dependent on a variety ofpre and postmucosalfactors as well as intestinal permeability. When two test substances 51CrEDTA and ovalbumin in rats infected are given together, however, the emphasis is not on the with Nippostrongylus brasiliensis.42 Finally, there absolute amounts excreted but their ratio (lactulosel was a significant correlation between the L-rhamnose) as the ratio is independent of non- permeabilityfactors. For instance an accelerated intestinal permeation of the neutrophil chemotactic transit will reduce the amount oflactulose in urine. The bacterial product N-formyl-methonyl-leucyl- amount ofL-rhamnose will be equally reduced so that their phenyl-alanine (analogue) and 51CrEDTA in ratio (% dose) will not change. rats treated with dithiothreitol.43 While this establishes a link between macromolecular (% of the orally administered test dose) permeation and the results of the test probes, it is not affected. The di monosaccharide should be remembered that macromolecular urinary excretion ratio then becomes a specific permeation is also governed by lipid solubility measure of intestinal permeability. 5ICrEDTA (transcellular permeation), concentration can be substituted for the disaccharide, but the (determined by rate of degradation in part), urine collection should be no longer than five and the local and systemic immune defence hours, as intestinal degradation of the mono- mechanisms. saccharide by bacteria may become important. The use of PEG 400 has posed a particular problem for intestinal permeability workers Intestinal permeability in disease since its introduction in 1977.30 The main A number of environmental factors or disease anomaly is that 20-50% of an orally given test states may increase intestinal permeability. At dose is excreted in five hour urine samples, least two situations - NSAID enteropathy and while only 0 5-1 c1/% of lactulose or 51CrEDTA Crohn's disease - have contributed substan- is excreted during that time.28 This occurs tially to the current understanding of intestinal despite similarities in their molecular size, pathophysiology by permeability studies linked http://gut.bmj.com/ weight, water solubility, and physiochemical with other new investigational approaches properties.31 Probe molecular geometry does assessing small intestinal function. not seem to be important in this respect.32 The completeness ofthe urine excretion ofPEG 400 after intravenous administration is low and vari- NSAID ENTEROPATHY able.28 The results obtained with PEG 400 in NSAID enteropathy is the prototype of a small disease and its behaviour after hyperosmolar intestinal disease caused mainly by an action of on October 1, 2021 by guest. Protected copyright. stress and detergent are all in keeping with a this drug class in disrupting the intestinal transcellular permeation pathway. It is difficult barrier with secondary, unavoidable inflamma- to visualise how such a readily absorbed