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Abstract defence in both hypogammaglobulinaemiaI6-19 Damage to the mucosal barrier may be and HIV infection (unpublished data) leads to assessed, non-invasively by use of sugar an enteropathy, which is of similar severity to probes, which permeate through the that seen in NSAID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 test tory changes brought about by an imbalance probe could be a useful means of assessing a between luminal aggressive factors and barrier function. Moreover, various polymers of mucosal defence. PEG all permeate by the same route, so PEG In rats, the first sign of NSAID toxicity is does not conform to the principle of the differ- evident within one hour ofNSAID administra- ential urinary excretion of orally given test tion in the form of uncoupling of enterocyte substances. This non-conformity leads to reser- mitochondrial oxidative phosphorylation.10-12 vations about the use of PEG and interpretation At five hours, before macroscopic damage is of PEG test results.33 Furthermore, the appar- evident, there are considerable increases in the ent increased intestinal permeation of PEG 400 activities of succinate dehydrogenase and in patients with Crohn's disease and their first citrate synthase (TCA enzymes), which are degree relatives, (the main impetus for the test's indeed unexpected in light of possible mito- revival) has not been substantiated.29 34 35 chondrial damage. Further studies, however, using activity stains on frozen tissue section confirm that there is up regulation of mito- Consequences of increased intestinal chondrial enzyme activities both in the TCA permeability cycle and the respiratory chain. This response The immediate consequences of increased to mitochondrial damage may be appropriate intestinal permeability have not been exten- but the direct consequence of uncoupling sively studied. Increased intestinal permeability is a drop in the production of ATP with loss may permit mucosal exposure to luminal anti- of regulatory control of the intracellular junc- gens, with implications for the pathogenesis of tions. Human evince this loss as increased S20 Bjarmason

intestinal permeability to 51CrEDTA within 12 relapse of Crohn's disease may be mediated hours of receiving NSAID. Increased intesti- by increased intestinal permeability with an nal permeability is not seen with pro NSAIDs identical sequence of events to that seen in the and, curiously enough, is also not seen when tissue phase of NSAID enteropathy.3

indomethacin is given with glucose and A number of studies show the effectiveness Gut: first published as 10.1136/gut.35.1_Suppl.S18 on 1 January 1994. Downloaded from citrate.44 45 The precise role of reduced of the treatment of acute Crohn's disease with mucosal prostaglandins is uncertain, but as the elemental diet as the sole course of nutri- main action of prostaglandins is reparative tion.7073 Of more than 100 patients treated at (increased mucous production, increased a single centre, 85% achieved clinical blood flow, and re-epithelisation), the main remission, usually within a week of starting consequence of inhibiting cyclo-oxygenase treatment.74 The more distal the disease, the may be to prolong the permeability changes longer the response time. Treatment with compared with causing them. elemental diet is as effective as total parenteral Once intestinal permeability is increased for nutrition and corticosteroids, but there are prolonged periods of time, the sequence of important problems with the diet's high cost, events are predetermined. The mucosa is poor palatability, and post-treatment relapse exposed to luminal aggressive factors (in the rates. The method of assessing the diet's effec- small intestine, mainly bile, pancreas secretion, tiveness is, however, suspect because it uses bacteria, and their degradation products), of highly subjective clinical disease activity which bile is particularly well reported in scores, which will indeed improve simply by NSAID enteropathy.4S49 It is only when a starving the patient. We therefore assessed neutrophil chemoattractant gains access to the whether treatment with elemental diet was mucosa that there is macroscopic damage.5>55 more than a symptomatic form of treatment or In humans, there is overwhelming evidence whether there was evidence of functional that the main neutrophil chemoattractant is a improvement. metronidazole sensitive microbe which may A large group of patients with Crohn's indeed be part of the normal intestinal flora.53 disease had variable combined assessments Once the neutrophils are activated by contact including those of nutritional states, intestinal with the chemoattractant, they cause damage permeability, and inflammation (indium-i ii to their immediate surroundings by generation leucocyte faecal excretions), and soluble inter- of oxygen reactive species and lysosomal leukin 2 receptor values (an index of T cell enzyme release.54-56 When this occurs within activation) pretreatment and two, and four to the mucosa, tissue damage is unavoidable and six weeks after treatment.75 76 Briefly, most of leads to the complications of NSAID entero- the nutritional indices did not change signifi- pathy, namely, blood and protein loss.8 10 cantly. Intestinal permeability and inflamma- Thus, NSAIDs have a specific biochemical tion were significantly and drastically reduced, action on the enterocyte, resulting in increased but interleukin 2 soluble receptor values intestinal permeability which, in turn, leads to remained raised and unchanged. Interestingly a non-specific tissue reaction of NSAID and significantly, those patients with normal http://gut.bmj.com/ enteropathy. intestinal permeability after treatment had There are other agents that may damage consistently long (>six months) remissions the small intestine by a similar mechanism. from acute disease, while those with increased Chemotherapeutic agents, chronic alcohol intestinal permeability relapsed within six consumption, diabetes, and radiation all months. These results equate disease activity increase small intestinal permeability, but an with increased intestinal permeability and enteropathy has not yet been sought.57-63 acute inflammation. These aspects of the on October 1, 2021 by guest. Protected copyright. disease respond to treatment with elemental diets, whose main action is shown not to entail CROHN'S DISEASE the provision of adequate calories or nutrition. Intestinal permeability is almost invariably (Most patients initially lost weight during increased in patients with Crohn's disease.6469 treatment, which rarely provides more than There are, however, important difficulties relat- 2800 kcal/day when taken orally). ing permeability changes to disease activity. No Elemental diet, however, drastically changes universal 'method of choice' has been accepted luminal aggressive factors. Along with the fact for assessing disease activity, and permeability that the causes of relapse of Crohn's disease changes seem related both to disease activity (NSAIDs, intestinal infections, alcohol binges, and severity. Clinical disease activity scores stress) all increase or have the potential to have probably been the single most important increase intestinal permeability,13 14 77-85 these factor hindering the development of reliable data suggest that the intestinal permeability objective indices of disease activity. Where barrier is of crucial importance for initiating such techniques exist for assessing activity relapse, permitting mucosal exposure of lumi- scores (faecal excretion of indium- I l1 labelled nal antigen, eliciting neutrophil chemotaxis neutrophils), widespread acceptance has not and hence, for being unwell. These factors been forthcoming, possibly because of the would be identical to those proposed investigator effort such techniques require. in the second stage framework for NSAID Although increased intestinal permeability enteropathy. Indeed, there is considerable has long been implicated in the pathogenesis of evidence that the immune system is recognis- inflammatory bowel disease, there is no proof ing intestinal flora in Crohn's disease. of this relation. There is, however, new and Neutrophils have increased formyl-methionyl- interesting evidence to suggest that the clinical leucyl-phenylalanine surface receptors in acute Intestinal permeability S2 1

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