Gut 1994; supplement 1: S18-S22

Intestinal permeability

I Bjarnason

AbstractDamage to the mucosal barrier may beassessed, non-invasively by use of sugarprobes, which permeate through thetranscellular or paracellular (tight junc-tion) routes. A standardised test, withanalysis of a five hour urine collectionhas proved useful in studying thesequelae ofnon-steroid anti-inflammatorydrug (NSAID) administration, untreatedcoeliac disease, and enteric infections.Choice of probe molecule is crucial andlactulose/l-rhamnose seem to be satisfac-tory, in contrast with polyethylene glycol.Significant correlations have been seenbetween permeability and plasma IgAconcentrates in nephropathy, and betweenpermeability and the passage ofneutrophilchemotactic agents. The increased perme-ability associated with NSAID treatmentmay relate to the adverse effectsof NSAIDs on enterocyte mitochondrialmorphology and metabolism. These twofactors may predispose the mucosa topermeation of bacterial chemoattractantmolecules that elaborate a local inflam-matory response. A similar mechanismmay operate in patients with untreatedCrohn's disease, who show abnormallyhigh permeability. Remission induced bytreatment with elemental diets coincideswith a reduction in permeability. Theperiod to relapse correlated with theinability of patients to maintain lowpermeability to sugar probes. Theseresults suggest a mechanism for thebenefits of elemental enteral nutrients inthe treatment of Crohn's disease.(Gut 1994; supplement 1: S18-S22)

Departent of ClinicalBiochemistry, King'sColiege School ofMedicine andDentistry, LondonI Bjamason

Correspondence to:Dr I Bjarnason, Departmentof Clinical Medicine, King'sCollege School of Medicineand Dentistry, BessemerRoad, London SE5 9PJ.

The pathogenesis of many small intestinal dis-eases entails interaction between changedintestinal permeability, luminal aggressivefactors, and mucosal defence mechanisms.1 -3Each of these factors can be implicated pri-marily in the pathogenesis of disease. For in-stance, non-steroidal anti-inflammatory drugs(NSAIDs) seem to cause specific damage toenterocytes, which leads to increased intestinalpermeability. This in turn may increasemucosal exposure to normal luminal contents,resulting in neutrophil chemotaxis and henceinflammation (NSAID enteropathy) in about65% of patients receiving these drugs in thelong term.412 A variety of endogenous (afterbypass surgery) and exogenous microbes(Salmonella, Shigella, Campylobacter, Giardia,and Yersinia) may overwhelm the mucosaldefence with resulting low grade neutrophilchemotaxis and increased intestinal per-meability.'3-15 Similarly, reduced mucosal

defence in both hypogammaglobulinaemiaI6-19and HIV infection (unpublished data) leads toan enteropathy, which is of similar severity tothat seen in NSAID enteropathy.The study of intestinal permeability has

been confounded by technical complexities oftest marker analysis, perceived non-specificityof results, and the dilemma that a test inducedbreach in mucosal integrity may lead to patho-genesis. This is perhaps an understandablesituation as the tests have, by and large, beenadvocated primarily for the purpose of screen-

ing for small intestinal disease,2>22 and there isa hangover from the golden era of the absorp-tion tests (D-xylose, 3-o-methyl-D-glucoseetc), when the test results had no pathogenicimplications.

Testing for increased permeabilityThe test markers in common use (PEG 400,lactulose, L-rhamnose-mannitol, 51CrEDTA.99mTcDTPA) can be analysed precisely andaccurately, but apart from the radiolabelledchelates, these analyses are time consumingand tedious.23-29

Tests of intestinal permeability were specif-ically designed to test intestinal barrier func-tion. Because it seemed probable that theywould provide a more sensitive indicatorof intestinal disease than absorption,22-24methods of assessing the intactness of theintestinal barrier were designed. Initiallylactulose, which resists degradation byintestinal disaccharidases, was used by itselfto test barrier function. While less than0 5% lactulose was excreted in 5 hour urinesamples after oral administration, there was arather low discrimination between normalsubjects and patients with coeliac disease.21Fortuitously, it was found that rendering thetest solution hyperosmolar (1500 mmol/l,with a readily absorbed osmotic filler) in-creased the urine excretion of lactulose onlymarginally in normal subjects, but greatlyin patients with coeliac disease, thereby offer-ing good discrimination between the twogroups.21

Urinary excretion of a single dose of a testsubstance is dependent on a number of factorsother than mucosal integrity (Figure), whichnot only reduce the sensitivity and specificity ofthe test procedure, but also pose a problem ofinterpretation of test results. To overcomethese problems, Menzies formulated theprinciple of differential urinary excretion oforally given test substances. The Figure detailsthe intestinal process of two such test sub-stances).22 Any variation in pre or post-mucosal determinants of the sugars' overallpermeation will affect the two test probesequally, so that their urinary excretion ratio

S18 on M

arch 17, 2020 by guest. Protected by copyright.

http://gut.bmj.com

/G

ut: first published as 10.1136/gut.35.1_Suppl.S

18 on 1 January 1994. Dow

nloaded from

Intestinal permeability

Lactulose L-RhamnoseCompleteness of ingestionGastric dilutiion

u Gastric emptyingg Intestinal dilution

Intestinal transit; Bacterial degradation -

Brush border hydrolysis 0 0Permeation pathway Paracellular TranscellularBlood flow

Endogenous production 0 0o Metabolism 0 0

Tissue distribution, Mode of renal excretion

a- Completeness of urinecollection

The urine excretion of a permeability marker given orally isdependent on a variety ofpre and postmucosalfactors aswell as intestinal permeability. When two test substancesare given together, however, the emphasis is not on theabsolute amounts excreted but their ratio (lactuloselL-rhamnose) as the ratio is independent of non-permeability factors. For instance an accelerated intestinaltransit will reduce the amount of lactulose in urine. Theamount ofL-rhamnose will be equally reduced so that theirratio (% dose) will not change.

(% of the orally administered test dose)is not affected. The di monosaccharideurinary excretion ratio then becomes a specificmeasure of intestinal permeability. 5ICrEDTAcan be substituted for the disaccharide, but theurine collection should be no longer than fivehours, as intestinal degradation of the mono-saccharide by bacteria may become important.The use of PEG 400 has posed a particular

problem for intestinal permeability workerssince its introduction in 1977.30 The mainanomaly is that 20-50% of an orally given testdose is excreted in five hour urine samples,while only 0 5-1 c1/% of lactulose or 51CrEDTAis excreted during that time.28 This occursdespite similarities in their molecular size,weight, water solubility, and physiochemicalproperties.31 Probe molecular geometry doesnot seem to be important in this respect.32 Thecompleteness of the urine excretion ofPEG 400after intravenous administration is low and vari-able.28 The results obtained with PEG 400 indisease and its behaviour after hyperosmolarstress and detergent are all in keeping with atranscellular permeation pathway. It is difficultto visualise how such a readily absorbed testprobe could be a useful means of assessing abarrier function. Moreover, various polymers ofPEG all permeate by the same route, so PEGdoes not conform to the principle of the differ-ential urinary excretion of orally given testsubstances. This non-conformity leads to reser-vations about the use ofPEG and interpretationof PEG test results.33 Furthermore, the appar-ent increased intestinal permeation of PEG 400in patients with Crohn's disease and their firstdegree relatives, (the main impetus for the test'srevival) has not been substantiated.29 34 35

Consequences of increased intestinalpermeabilityThe immediate consequences of increasedintestinal permeability have not been exten-sively studied. Increased intestinal permeabilitymay permit mucosal exposure to luminal anti-gens, with implications for the pathogenesis of

both local and systemic diseases. The possi-bility that increased intestinal permeability canlead to systemic disease such as ankylosingspondylitis, by the mechanism of molecularmimicry is, in particular, controversial.36-40There are three studies that suggest that

increased intestinal permeability to these smallprobes (approximately 340 Daltons) mayreflect increased macromolecular permeation.Davin et al found a significant correlationbetween intestinal permeation of 51CrEDTAand IgA immune complex plasma concentra-tions in patients with IgA associatednephropathies.41 Ramage et al showed a signifi-cant correlation between the permeation of51CrEDTA and ovalbumin in rats infectedwith Nippostrongylus brasiliensis.42 Finally, therewas a significant correlation between thepermeation of the neutrophil chemotacticbacterial product N-formyl-methonyl-leucyl-phenyl-alanine (analogue) and 51CrEDTA inrats treated with dithiothreitol.43 While thisestablishes a link between macromolecularpermeation and the results of the test probes, itshould be remembered that macromolecularpermeation is also governed by lipid solubility(transcellular permeation), concentration(determined by rate of degradation in part),and the local and systemic immune defencemechanisms.

Intestinal permeability in diseaseA number of environmental factors or diseasestates may increase intestinal permeability. Atleast two situations - NSAID enteropathy andCrohn's disease - have contributed substan-tially to the current understanding of intestinalpathophysiology by permeability studies linkedwith other new investigational approachesassessing small intestinal function.

NSAID ENTEROPATHYNSAID enteropathy is the prototype of a smallintestinal disease caused mainly by an action ofthis drug class in disrupting the intestinalbarrier with secondary, unavoidable inflamma-tory changes brought about by an imbalancebetween luminal aggressive factors andmucosal defence.

In rats, the first sign of NSAID toxicity isevident within one hour ofNSAID administra-tion in the form of uncoupling of enterocytemitochondrial oxidative phosphorylation.10-12At five hours, before macroscopic damage isevident, there are considerable increases in theactivities of succinate dehydrogenase andcitrate synthase (TCA enzymes), which areindeed unexpected in light of possible mito-chondrial damage. Further studies, however,using activity stains on frozen tissue sectionconfirm that there is up regulation of mito-chondrial enzyme activities both in the TCAcycle and the respiratory chain. This responseto mitochondrial damage may be appropriatebut the direct consequence of uncouplingis a drop in the production of ATP with lossof regulatory control of the intracellular junc-tions. Human evince this loss as increased

S19

on March 17, 2020 by guest. P

rotected by copyright.http://gut.bm

j.com/

Gut: first published as 10.1136/gut.35.1_S

uppl.S18 on 1 January 1994. D

ownloaded from

Bjarmason

intestinal permeability to 51CrEDTA within 12hours of receiving NSAID. Increased intesti-nal permeability is not seen with pro NSAIDsand, curiously enough, is also not seen whenindomethacin is given with glucose andcitrate.44 45 The precise role of reducedmucosal prostaglandins is uncertain, but as themain action of prostaglandins is reparative(increased mucous production, increasedblood flow, and re-epithelisation), the mainconsequence of inhibiting cyclo-oxygenasemay be to prolong the permeability changescompared with causing them.Once intestinal permeability is increased for

prolonged periods of time, the sequence ofevents are predetermined. The mucosa isexposed to luminal aggressive factors (in thesmall intestine, mainly bile, pancreas secretion,bacteria, and their degradation products), ofwhich bile is particularly well reported inNSAID enteropathy.4S49 It is only when aneutrophil chemoattractant gains access to themucosa that there is macroscopic damage.5>55In humans, there is overwhelming evidencethat the main neutrophil chemoattractant is ametronidazole sensitive microbe which mayindeed be part of the normal intestinal flora.53Once the neutrophils are activated by contactwith the chemoattractant, they cause damageto their immediate surroundings by generationof oxygen reactive species and lysosomalenzyme release.54-56 When this occurs withinthe mucosa, tissue damage is unavoidable andleads to the complications of NSAID entero-pathy, namely, blood and protein loss.8 10

Thus, NSAIDs have a specific biochemicalaction on the enterocyte, resulting in increasedintestinal permeability which, in turn, leads toa non-specific tissue reaction of NSAIDenteropathy.There are other agents that may damage

the small intestine by a similar mechanism.Chemotherapeutic agents, chronic alcoholconsumption, diabetes, and radiation allincrease small intestinal permeability, but anenteropathy has not yet been sought.57-63

CROHN'S DISEASEIntestinal permeability is almost invariablyincreased in patients with Crohn's disease.6469There are, however, important difficulties relat-ing permeability changes to disease activity. Nouniversal 'method of choice' has been acceptedfor assessing disease activity, and permeabilitychanges seem related both to disease activityand severity. Clinical disease activity scoreshave probably been the single most importantfactor hindering the development of reliableobjective indices of disease activity. Wheresuch techniques exist for assessing activityscores (faecal excretion of indium- I l 1 labelledneutrophils), widespread acceptance has notbeen forthcoming, possibly because of theinvestigator effort such techniques require.

Although increased intestinal permeabilityhas long been implicated in the pathogenesis ofinflammatory bowel disease, there is no proofof this relation. There is, however, new andinteresting evidence to suggest that the clinical

relapse of Crohn's disease may be mediatedby increased intestinal permeability with anidentical sequence of events to that seen in thetissue phase ofNSAID enteropathy.3A number of studies show the effectiveness

of the treatment of acute Crohn's disease withelemental diet as the sole course of nutri-tion.7073 Of more than 100 patients treated ata single centre, 85% achieved clinicalremission, usually within a week of startingtreatment.74 The more distal the disease, thelonger the response time. Treatment withelemental diet is as effective as total parenteralnutrition and corticosteroids, but there areimportant problems with the diet's high cost,poor palatability, and post-treatment relapserates. The method of assessing the diet's effec-tiveness is, however, suspect because it useshighly subjective clinical disease activityscores, which will indeed improve simply bystarving the patient. We therefore assessedwhether treatment with elemental diet wasmore than a symptomatic form of treatment orwhether there was evidence of functionalimprovement.A large group of patients with Crohn's

disease had variable combined assessmentsincluding those of nutritional states, intestinalpermeability, and inflammation (indium-i iileucocyte faecal excretions), and soluble inter-leukin 2 receptor values (an index of T cellactivation) pretreatment and two, and four tosix weeks after treatment.75 76 Briefly, most ofthe nutritional indices did not change signifi-cantly. Intestinal permeability and inflamma-tion were significantly and drastically reduced,but interleukin 2 soluble receptor valuesremained raised and unchanged. Interestinglyand significantly, those patients with normalintestinal permeability after treatment hadconsistently long (>six months) remissionsfrom acute disease, while those with increasedintestinal permeability relapsed within sixmonths. These results equate disease activitywith increased intestinal permeability andacute inflammation. These aspects of thedisease respond to treatment with elementaldiets, whose main action is shown not to entailthe provision of adequate calories or nutrition.(Most patients initially lost weight duringtreatment, which rarely provides more than2800 kcal/day when taken orally).

Elemental diet, however, drastically changesluminal aggressive factors. Along with the factthat the causes of relapse of Crohn's disease(NSAIDs, intestinal infections, alcohol binges,stress) all increase or have the potential toincrease intestinal permeability,13 14 77-85 thesedata suggest that the intestinal permeabilitybarrier is of crucial importance for initiatingrelapse, permitting mucosal exposure of lumi-nal antigen, eliciting neutrophil chemotaxisand hence, for being unwell. These factorswould be identical to those proposedin the second stage framework for NSAIDenteropathy. Indeed, there is considerableevidence that the immune system is recognis-ing intestinal flora in Crohn's disease.Neutrophils have increased formyl-methionyl-leucyl-phenylalanine surface receptors in acute

S20

on March 17, 2020 by guest. P

rotected by copyright.http://gut.bm

j.com/

Gut: first published as 10.1136/gut.35.1_S

uppl.S18 on 1 January 1994. D

ownloaded from

Intestinal permeability S2 1

Crohn's disease:86 87 Macpherson et al (unpub-lished data) have isolated mucosal IgG frompatients with Crohn's disease, and these IgGnot only relate quantitatively to disease activitybut are predominantly directed towardsnormal intestinal flora. The neutrophil flux tothe intestine is, however, 10 times greaterthan that seen in NSAID, hypogamma-globulinaemic, and HIV enteropathy, as wellas that seen in infectious enteritis. Thus themain problem in Crohn's disease may be theunchecked neutrophil response to commonluminal substances. The main cause of thedisease will probably not include the neutro-phils themselves, but the persistent T cellactivation may be a clue showing where tolook.

1 Bjarnason I. Intestinal permeability barriers. In: Peters TJ,ed. The cell biology of inflammation in the gastrointestinaltract. Hull: Corners Publication, 1990: 127-42.

2 Bjarnason I. Non-steroidal anti-inflammatory drug inducedsmall intestinal inflammation in man. In: Pounder R, ed.Recent advances in gastroenterology-7 London: ChurchillLivingstone, 1988: 23-46.

3 Bjarnason I, Macpherson AJS, Teahon K. Nonsteroidalanti-inflammatory drugs and inflammatory bowel disease.Can J Gastroenterol 1993; 7: 160-9.

4 Bjarnason I, Williams P, So A, Zanelli G, Lev AJ, GumpelMJ, et al. Intestinal inflammation and permeabilityin rheumatoid arthritis; effects of non-steroidal anti-inflammatory drug. Lancet 1984; ii: 1171-4.

5 Bjarmason I, Zanelli G, Smith T, Prouse P, De Lacey G,Gumpel MJ, et al. Nonsteroidal anti-inflammatory druginduced inflammation in humans. Gastroenterology 1987;93: 480-9.

6 Bjarnason I, Macpherson A. The changing gastrointestinalside effect profile of non-steroidal anti-inflammatorydrugs. A new approach for the prevention of a newproblem. Scand JT Gastroenterol 1989; 24 (suppl 163):56-64.

7 Bjarnason I, Smethurst P, Hayllar J, Levi AJ. NSAIDenteropathy; the main site of chronic blood loss in patientson NSAIDs. Gut 1900; 91: A1203.

8 Morris J, Madhok R, Sturrock RD, Capell HA, MackenzieJF. Enteroscopic diagnosis of smal bowel ulceration inpatients receiving non steroidal anti-inflammatory drugs.Lancet 1991; 337: 520.

9 Bjarnason I, Zanelli G, Prouse P, Smethurst P, Smith T,Levi S, et al. Blood and protein loss via small intestinalinflammation induced by non-steroidal anti-inflammatorydrugs. Lancet 1987; ii: 711-4.

10 Lang J, Price AB, Levi AJ, Burk M, Gumpel JM, BjamasonI. Diaphragm disease: the pathology of non-steroidal anti-inflammatory drug induced small intestinal structures, .7Clin Pathol 1988; 41: 516-26.

11 Hayllar J, Somasundaram S, Sarathchandra P, Levi AJ,Bjarmason I. Early cellular events in the pathogenesis ofNSAID enteropathy in the rate. Gastroenterology 1991;100: A216.

12 Somasundaram S, Macpherson AJ, Hayllar J, SaratchandraP, Bjarnason I. Enterocyte mitochondrial damage due toNSAID in the rat. Gut 1992; 33 (suppl): S5.

13 Noone C, Menzies IS, Banatvala JE, Scopes JW. Intestinalpermeability and lactose hydrolysis in human rotaviralgastroenteritis assessed simulatneously by non-invasivedifferential sugar permeation. Eur 7 Clin Invest 1986; 6:217-25.

14 Parrili G, Cuomo R, Nardone G, Maio G, Izzo CM,Budillon G. Investigation of intestinal function duringacute viral hepatitis using combined sugar oral loads. Gut1987; 28: 1439-44.

15 Kordossis T, Joseph AEA, Gane JN, Bridges CE, GriffinGE. Fecal leukocytosis, indium-111-labelled autologouspolymorphonuclear leucocyte abdominal scanning, andquantitative fecal indium-111 excretion in acute gastro-enteritis and enteropathogen carriage. Dig Dis Sci 1988;33: 1383-90.

16 Ament ME, Ochs HD, Davis SD. Structure and function ofthe gastrointestinal tract in primary immunodeficiencysyndromes. A study of 39 patients. Medicine 1973; 52:227-48.

17 Johnson RL, Van-Arsdel PP, Tobe AD, Ching Y. Adulthypogammaglobulinaemia with malabsorption and irondeficiency anaemia. Am J Med 1967; 43: 935-43.

18 Diaz-Buxo JA, Hermans PE, Huizenga KA.Gastrointestinal dysfunction in immunoglobulin defi-ciency. Effects of corticosteroid and tetracyclin. JAMA1975; 233: 1189-91.

19 Teahon K, Webster D, Price AB, Bjarnason I. Studies ofgastrointestinal structure and function in patients withprimary hypogammaglobulinaemia. Gut (in press).

20 Menzies IS. Medical importance of sugars in the alimentarytract. In: Grenby TH, Parker KJ, Lindley MJ, eds.Developments in sweeteners-2 London: Applied Science,1983: 89-117.

21 Menzies IS. Absorption of intact oligosaccharide in healthand disease. Bioche?n Soc Trans 1974; 2: 1042-7.

22 Menzies IS. Transmucosal passage of inert molecules inhealth and disease. Skadhauge E, Heintze K, eds.Intestinal absorption and secretion. Falk Symposium 36,Lancaster: MTP Press, 1984: 527-43.

23 Cooper BT. The small intestinal barrier. In: Losowsky Hm,Heatley RV, eds. Gut defences in clinical practice.Edinburgh: Churchill Livingstone, 1986: 117-32.

24 Hamilton I. Small intestinal permeability. In: Pounder REed. Recent advances in gastroenterology-6. Edinburgh:Churchill Livingstone, 1986: 73-91.

25 Menzies IS. Quantitative estimation of sugars in blood andurine by paper chromatography using direct densitometry.JtChromatogr 1973; 81: 109-27.

26 Menzies IS, Mount NJ, Wheeler MJ. Quantitative estima-tion of clinically important monosaccharides in plasma byrapid thin layer chromatography. Ann Clin Bioche?n 1978;15: 65-76.

27 Menzies IS, Seakins JWT. Sugars. In: Smith I, JenkinsJWT, eds. Chromatographis and electrophorectic techniques.vol 1. London: Wm Heineman 1976: 183-217.

28 Maxton DG, Bjamason I, Reynolds AP, et al. Lactulose, 51Cr labelled ethylenediaminetetraacetate, L-rhamnose andpolyethylene glycol 400 as probe markers for assessmentin vivo of human intestinal permeability. Clin Sci 1986;71: 71080.

29 Teahon K, Smethurst P, Levi AJ, Menzies IS, Bjamason I.Intestinal permeability in patients Crohn's disease andtheir first degree relatives. Gut 1992; 33: 320-3.

30 Chadwick VS, Phillips SF, Hoffman AF. Measurementof intestinal permeability using low molecular weightpolyethylene glycols. Gastroenterology 1977; 73: 241-51.

31 Hollander D, Ricketts D, Boyd CAR. Importance of probemolecular geometry in determining intestinal permeabil-ity. Can J Gastroenterol 1988; 2 (supl A): 35-8A.

32 Teahon K, Menzies IS, Bjarnason I. Importance ofmolecular geometry on permeation rates of in vivo perme-ability markers. Gut 1992; 33 (suppl): S57.

33 Peters TJ, Bjarnason I. Uses and abuses of intestinal perme-ability measurements. Can 7 Gastroenterol 1988; 2:127-32.

34 Hollander D. Crohn's disease - a permeability disorder oftight junctions. Gut 1988; 29: 1621-4.

35 Hollander D, Vadheim CM, Breththotz E, Peterson GM,Delahunty TJ, Rutter J. Increased intestinal permeabilityin Crohn's disease patients and their first degree relatives:an etiologic factor? Ann Intemr Med 1986; 105: 883-5.

36 Zaphiropoulos GC. Rheumatoid arthritis and the gut. Br JRheumatol 1986; 15: 138-9.

37 Bjamason I, Peters TJ. Helping the mucosa make sense ofmacromolecules. Gut 1987; 28: 1057-61.

38 Prendergast JH, Sullivan JS, Csczy A, Upfold LI, EdmundsJP, Bashir HV, et al. Possible role of enteric organismsin the pathogenesis of ankylosing spondylities and otherseronegative arthropathies. Infect Itnunun 1983; 41:935-41.

39 Ebringer A. The cross tolerance hypothesis, HLA-B27 andankylosing spondylitis. BrJ Rheunnatol 1983; 22 (suppl 2):53-6.

40 Keat A. Reiters syndrome and reactive arthritis in perspec-tive. NEngl7Med 1983; 309: 1605-15.

41 Davin JC, Forget P, Mahieu PR. Increased intestinalpermeability to (51Cr) EDTA is correlated with IgAcomplex-plasma levels in children with IgA-associatednephropathies. Acta Paediatr Scand 1988; 77: 118-24.

42 Ramage JK, Stanisz A, Scicchitano R, Hunt RH, PerdueMH. Effects of immunologic reaction on rat intestinalepithelium. Correlation of increased intestinal perme-ability to chromium 51 labelled ethylenediaminetetra-acetic acid and ovalbumin during acute inflammation andanaphylaxis. Gastroenterology 1988; 94: 1368-75.

43 Ferry DM, Butt TJ, Broom MF, Hunter J, Chadwick VS.Bacterial chemotactic oligopeptides and the intestinalmucosal barrier. Gastroenterology 1989; 97: 61-7.

44 Bjamason I, Fehily B, Smethurst P, Menzies IS, Levi AJ.The importance of local versus systemic effects ofNSAIDto increase small intestinal permeability in man. Gut 1991;32: 275-7.

45 Bjarnason I, Smethurst P, Walker F, Macpherson A,McElnay SC, Pearson P, et al. Glucose and citrate reducethe permeability changes caused by indomethacin.Gastroenterology 1992; 102: 1546-50.

46 Robert A, Asano T. Resistance of germ free rats toindomethacin-induced intestinal lesions. Prostaglandins1977; 14: 331-41.

47 Satoh H, Guth PH, Grossman MI. Role of bacteria ingastric ulceration produced by indomethacin in the rat:cytoprotective action of antibiotics. Gastroeneterology1983; 84: 483-9.

48 Del Soldato P, Foschi D, Benoni G, Velo GP. Early and latephases in the formation by anti-inflammatory drugs ofintestinal lesions in the rat. In: Rainsford KD, Velo GP,eds. Side effects of antiinflainmatory drugs. Lancaster: MTPPress, 1987: 67-81.

49 Brodie DA, Cook PG, Bauer BJ, Dagleg E. Indomethacin-induced intestinal lesions in the rat. Toxicol AppiPharmacol 1970; 17: 615-24.

50 Wallace JL, Keenan CM, Granger DN. Gastric ulcerationinduced by nonsteroidal antiinflammatory drugs is aneutrophil dependent process. Am J Physiol 1990; 259:G462-7.

51 Wallace JL, Arfors KB, McKnight GW. A monoclonal anti-body against the CD 18 leucocyte adhesion molecule

on March 17, 2020 by guest. P

rotected by copyright.http://gut.bm

j.com/

Gut: first published as 10.1136/gut.35.1_S

uppl.S18 on 1 January 1994. D

ownloaded from

S22 Bjarnason

prevents indomethacin-induced gastric damage in therabbit. Gastroenterology 1991; 100: 878-83.

52 Granger DN, Benoit JN, Suzuki M, Grisham MB.Leucocyte adherence to venular endothelium duringischemia perfusion. Am_7Physiol 1985; 257: G683-8.

53 Bjarnason I, Hayllar J, Smethurst P, Price AB, GrumpelMJ. Metronidazole reduces intestinal inflammation andblood loss in non-steroidal anti-inflammatory druginduced enteropathy. Gut 1990; 31: 777-80.

54 Malech MI, Callin JI. Neutrophils in human disease. N EnglJ7Med 1987; 317: 687-94.

55 Weiss SJ. Tissue destruction by neutrophils. N Engl J Med1989; 320: 365-76.

56 Segall AW. The electron transport chain of the microbicidaloxidase of phagocytic cells and its involvement in themolecular pathology of chronic granulomatous disease.In: Peters TJ, ed. The cell biology of infla?nlnation in thegastrointestinal tract. Hull: Corners Publication, 1990:51-73.

57 Bjarnason I, Ward K, Peters TJ. The leaky gut ofalcoholism; a route of entry of toxic compounds. Lancet1984; i: 179-82.

58 Cooper BT, Ukabam SO, O'Brian IA, Hare JP, Corrall RJ.Intestinal permeability in diabetic diarrhoea. Diabetic Med1987; 4: 49-52.

59 Sieber GR, Mayer RJ, Levin MJ. Increased gastrointestinalabsorption of large molecules in patients after 5-fluorouracil therapy for metastatic colon carcinoma.Cancer Res 1980; 40: 3430-6.

60 Selby P, McElwain TJ, Crofts M, Lopes N, Mundy J.51EDTA test for intestinal permeability. Lancet 1984; ii:31.

61 Pearson ADJ, Craft AW, Pledger JV, Eastham EJ, LakerMF, Pearson CS. Small bowel function in acutelymphoblastic leukaemia. Arch Dis Child 1984; 59:460-5.

62 Pledger JV, Pearson ADJ, Craft AW, Laker MF, EasthamEJ. Intestinal permeability during chemotherapy forchildhood tumors. Eur3tPediatr 1988; 147: 123-7.

63 Selby PJ, Lopes N, Mundy J, Crofts M, Millar JL, McElvainTJ. Cyclophosphamide priming reduces intestinal damagein man following high dose melphalan chemotherapy. BrJ'Cancer 1987; 55: 531-3.

64 Bjamason I, O'Morain C, Levi AJ, Peters TJ. Absorption of51 chromium-labelled ethylenediaminetetraacetate ininflammatory bowel disease. J Lab Clin Med 1986; 108:430-5.

65 O'Morain C, Abelow CA, Cheru LR, Fleischner GM, DasKM. 51 -CrEDTA test: a useful test in the assessment ofinflammatory bowel disease. J Lab Clin Med 1986; 108:430-5.

66 Casellas F, Aguade S, Soriano B, Accarino A, Molero J,Guamer L. Intestinal permeability to 99mTC-diethyl-enetetriaminopentaacetic acid in inflammatory boweldisease. Clin Invest Med 1988; 81: 767-70.

67 Pironi L, Migliolti M, Ruggeri E, Levorato M, Dallasta MA,Corbelli C, et al. Relationship between intestinal perme-ability to 51 CrEDTA and inflammatory activity inasymptomatic patients with Crohn's disease. Dig Dis Sci1990; 35: 582-8.

68 Jenkins RT, Ramage JK, Jones DB, Collins SM, Hunt RH.Small bowel and colonic permeability to 51Cr EDTA inpatients with active inflammatory bowel disease. ClinInvest Med 1988; 11: 151-5.

69 Resnik RH, Royal H, Marshall W, Barron R, Werth T.Intestinal permeability in gastrointestinal disorders. Useof 99mTc DTPA. Dig Dis Sci 1990; 35: 205-11.

70 Workman EM, Alun-Jones V, Wilson AJ, Hunter JO. Dietin the management of Crohn's disease. Hum Nutr ApplNutr 1984; 38: 469-73.

71 Alun-Jones V, Workman EM, Freeman AH, Dickinson RJ,Wilson AJ, Hunter JO. Crohn's disease: maintenance ofremission by diet. Lancet 1985; i: 177-80.

72 O'Morain C, Segal AW, Levi AJ. Elemental diet as aprimary treatment of acute Crohn's disease: a controlledtrial. BMJ 1984; 288: 1859-62.

73 Alun-Jones V. Comparison of total parenteral nutrition andelemental diet in induction of remission of Crohn'sdisease. Dig Dis Sci 1987; 32S: 100-7.

74 Teahon K, Smethurst P, Levi AJ, Bjarnason I. Ten yearsexperience with elemental diets in the management ofCrohn's disease. Gut 1990; 31: 1133-7.

75 Teahon K, Smethurst P, Levi AJ, Bjamson I. The effect ofelemental diet on intestinal inflammation and perme-ability in Crohn's disease. Gastroenterology 1991; 101:84-9.

76 Duane PD, Teahon K, Crabtree JE, Levi AJ, Heatley RV,Bjamason I. The relationship between nutritional statusand serum soluble interleukin 2 receptor concentrationsin patients with Crohn's disease treated with elementaldiet. Clin Nutr 1991; 10: 222-7.

77 Bjamason I, Williams P, Smethurst P, Peters TJ, Levi AJ.The effects of NSAID and prostaglandins on thepermeability of the human small bowel. Gut 1986; 27:1292-7.

78 Bjamason I, Smethurst P, Clarke P, Menzies IS, Levi AJ,Peters TJ. Effect of prostaglandins on indomethacininduced increased intestinal permeability in man. Scand3Gastroenterol 1989; 29 (suppl 164): 97-103.

79 Bjamason I, Smethurst P, Fenn CG, Lee CF, Menzies IS,Levi AJ. Misoprostol reduces indomethacin inducedchanges in human small intestinal permeability. Dig DisSci 1989; 34: 407-11.

80 Jenkins RT, Rooney PJ, Jones DB, Bienenstock GoodacreRC. Increased intestinal permeability in patients withrheumatoid arthritis: a side effect of oral NSAID therapy?Br3rRheumatol 1987; 26: 103-7.

81 Auer IO, Habscheid W, Hiller S, Gerhards W, Eilles C.Nicht-steroidale antiphlogistika erohen die darmperme-abilitat. Dtsch Med Wochensch 1987; 112: 1032-7.

82 Aabakken C, Osnes M. 51-Cr ethylenediaminetetraaceticacid absorption test. Effects of naproxen, a NSAID. ScandJ Gastroenterol 1990; 25: 917-24.

83 MacQueen G, Marshall J, Perdue M, Siegel S, BienenstockJ. Pavlovian conditioning of rat mucosal mast cellsto secrete rat mast cell protease II. Science 1989; 243:83-5.

84 D'Inca R, Ramage J, Hunt RH, Perdue MH. Antigen-induced mucosal damage and restitution in the smallintestine of the immunised rat. Int Arch Allergy ApplImmunol 1990; 91: 270-7.

85 Crowe SE, Sestini P, Perdue MH. Allergenic reactions ofrat jejunal mucosa. Gastroenterology 1990; 99: 74-82.

86 Sartor RB. The role of intestinal bacteria in initiation andperpetuation of inflammatory bowel disease. In: WilliamsCN, ed. Treands in inflammnatory bowel disease. FalkSymposium 56. Dordrecht: Kluwer Academic Publishers,1991: 17-27.

87 Anton PA, Targan SR, Shanahan F. Increased neutrophilreceptors for and response to the proinflammatorybacterial peptide formyl-methionyl-leucyl-phenylalaninein Crohn's disease. Gastroenterology 1989; 97: 20-8.

on March 17, 2020 by guest. P

rotected by copyright.http://gut.bm

j.com/

Gut: first published as 10.1136/gut.35.1_S

uppl.S18 on 1 January 1994. D

ownloaded from