Chapter 23 Intestinal barrier function

23

Intestinal barrier function I. Bjarnason", A. Cederberg', A. Akvistb and S. Smale"

"Professor of Digestive Diseases, Honorary Consultant Physician and Gastroenterologist, Department of Medicine, Guy's, King's, St Thomas' School, Bessemer Road, London SE5 9PJ bResearch Fellow, Department of Gastroenterology, Sahlgrenska University Hospital, S-413 45 Goteborg, Sweden "Research Fellow, Department of Medicine, Guy's, King's, St Thomas' School, Bessemer Road, London SE5 9PJ

The interest in assessing intestinal permeability non-invasively in man stems from the fact that such tests can be used for assessing intestinal function, pathogenesis and prognosis of intestinal disease and as a diagnostic screening test for small bowel disease. There are a number of intestinal permeability tests available. They may differ in their sensitivity depending on test dose composition and simple modifications of established methods can be used to specifically assess regional permeability in the stomach and colon. Increased intestinal permeability is found in at least 40 different conditions. The clinical implications are uncertain. One suggestion is that increased intestinal permeability may play a pathogenic role in some systemic (autoimmune) diseases. There is however better evidence that the consequences are a local inflammatory reaction within the intestine. This has led to the description of the so-called "new enteropathies" that seem to have a common final pathogenesis. This inflammation is usually asymptomatic, but the complications of blood and protein loss may lead to iron deficiency anaemia and hypoalbuminaemia, respectively. Some patients may develop intestinal strictures that are sometimes confused with Crohn's disease. Intestinal damage as a consequence of increased intestinal

657

Biology of the Intestine in Growing Animals R. Zabielski, P.c. Gregory and B. Westrom (Eds.) 2002 Elsevier Science. B.V. All rights reserved.

658

1. Bjarnason, A. Cederborg, A. Akvist and S. Smale

permeability needs to be differentiated from spondylarthropathic ileitis and classical inflammatory bowel disease.

1.

INTRODUCTION

The intestine has the role of facilitating the absorption of electrolytes, water, nutrients and specific (essential) compounds whilst maintaining an effective barrier to the permeation of potentially harmful macromolecules. Absorption, above what would occur by non-mediated passive diffusion, is achieved by expression of specific brush border carriers (for amino acids, monosaccharides, etc.) and, in the case of lipids, by solubilising intestinal contents. The intestinal barrier function is somewhat more complex. There is a general consensus that it encompasses active (cellular and humoral immunity) and passive (mucous, brush border membrane, intercellular junctions) components. It is the latter that have become clinically important. Thirty years ago it was demonstrated that recovery of non-metabolized oligo saccharides in the urine following oral administration could provide a reliable noninvasive measure of intestinal permeability in man (Menzies, 1974). Acceptance of the method was initially slow, the reasons being that the reliability of the method depends upon detailed control of the test procedure (the osmotic aspects of dose composition), uncertainties about the interpretation and clinical significance of the test results as well as the introduction of polyethylene glycol (PEG 400) (Chadwick et al., I977a; Chadwick et aI., 1977b) which suggested permeability changes that were often the reverse of those indicated by oligosaccharide probes. Subsequent development led to the introduction of tests of" differential permeability" employing combinations of non-metabolizable probes that cross the absorptive surface by different pathways (Menzies et aI., 1979; Menzies, 1984). This development allowed the specific and reproducible assessment of intestinal permeability which was relatively unaffected by non-mucosal factors (Bjamason et aI., 1995). Subsequently it was appreciated that intestinal permeability, as measured with the oligosaccharide and other suitable test probes, reflected the state of the intestinal barrier function to water-soluble macromolecules. This suggested that measurement of intestinal permeability might provide insight into the aetiology and pathogenesis of various intestinal diseases. The last 10 years have seen a proliferation of studies from different sources with over 3000 publications addressing the importance of the intestinal barrier function in various circumstances. With respect to non-invasive intestinal permeability testing in man the main purpose of these tests have been to: I. Assess intestinal physiology. 2. Detect intestinal disease as clinical screening tests.

Intestinal barrier function

659

3. Monitor response to therapy and confirm a diagnosis (e.g. gluten withdrawal and challenge in coeliac disease) as well as to provide prognostic information, 4. Investigate the impact of non-intestinal factors on intestinal function. These may be exogenous, related to radiotherapy, drugs, alcohol, dietary or environmental factors; or endogenous due to malnutrition, reduced blood flow, anaemia and other systemic conditions. 5. Assess the importance of the intestinal barrier function in the aetiology, pathophysiology and pathogenesis of intestinal and systemic disease. Not only has an impaired intestinal barrier been suggested as a source of antigens in autoimmune diseases, but there is also the suggestion that "delayed gut closure" postpartum may be an important mechanism in oral tolerance, which if unduly prolonged can result in disease. Unfortunately there has been a tendency to underestimate the complexity of factors affecting the outcome of the non-invasive intestinal permeability test procedures. The essential aspects of these techniques will therefore be discussed, together with modifications that allow different functions and regions of the gut to be assessed. Clinical applications, with special reference to the characterization of reaction to food constituents, drugs and other causes of intestinal dysfunction will then be described.

2.

NON-INVASIVE USE OF PROBES TO ASSESS INTESTINAL FUNCTION AND INTEGRITY

The use of single test substances, which enjoyed considerable popularity 20-30 years ago, provided results that were open to a number of variables (intestinal dilution, transit times, renal function, etc.) and the techniques therefore lacked somewhat in specificity, reproducibility and reliability. The differential urinary excretion technique overcame many of these shortcomings. The principle is outlined in fig. I and in effect has allowed the specific and quantitative measure of intestinal permeability, absorptive capacity and even intestinal disaccharidase activities. The differential urinary excretion ratio of probes that differ with respect to the permeation pathways they have access to, provides a more specific way of expressing the state of intestinal permeability than the behaviour of a single probe. It is important to appreciate that the biological implications of increased intestinal permeability need to be viewed in global context. If transit time is rapid and mucosal contact time minimal the consequences of increased intestinal permeability may be negligible. Similarly, if contact time between a macromolecule and the mucosa is protracted then increased permeation may be evident without a concomitant increase in intestinal permeability.

660

1. Bjarnason, A. Cederborg, A. Akvist and S. Smale

51CrEDTA NonFactors affecting the urinary excretion or of orally administered test substances Monosaccharide hydrolysed disaccharide 99mTcDTPA Completeness of ingestion

;::

;::

;::

Gastric dilution

;::

;::

;::

Pre-

Gastric emptying

;::

;::

;:;:

mucosal

Intestinal dilution Intestinal transit

;:;:

;:;:

;:;:

;:;:

;:;:

;:;:

Bacterial degradation

;:;:

;:;:

;:;:

Unstirred water layer

;:;:

;::

;:;:

Digestion-hydrolysis

0

0

Route of permeation

A

B

0 B

Intestinal blood flow

;:;:

;:;:

;::

Metabolism

0 0

0

Endogenous production" Tissue distribution

C

0 0 D

Mucosal

Post-

0 D

=

=

=

Timing and completeness of urinary collectiorr"

;:;:

;:;:

;:;:

Bacterial degradation

§

§

0

Analytical performance

=

=

mucosal Renal function

Fig. I Factors affecting the urinary excretion of orally administered test substances. The principal of the differential urinary excretion of ingested test substances. When a single test substance is ingested the amount recovered in urine is dependent on all the pre- and postmucosal factors as well as the state of the intestine. Increased or decreased urinary recovery could therefore be due to a change in any of these factors. However when two test substances (i.e. di-ymcno-saccharides) are administered together a change in pre- or post-mucosal factors will affect the probes equally so that their urinary excretion ratio (% dose) is not affected. = : Idential or affects all the test substances equally. §: Occurs mainly when the test solution enters the caecum. 0: Does not take place. A & B: Indicates different routes of permeation. C & D: Mono- and disaccharides have a slightly different volume of distribution following intravenous administration and hence there is a slight difference in the speed and completeness of their urinary excretions. This is for practical purposes not of major importance. *: There may be a minimal endogenous production of mannitol. **: Roughly equal for the mono- and disaccharides, but see C & D above.

The choice of test substances for the differential urinary excretion tests need careful attention to, but essentially the probes must fulfil a set of desired properties. This involves being non-toxic, non-metabolized, nondegraded, water-soluble, lipid-insoluble, of certain size (and possibly shape), lack of affinity for mediated transport systems and the need to be effectively excreted in urine (Menzies, 1984; Hamilton, 1986; Travis and

Intestinal barrier function

661

Menzies, 1992; Bjamason et al., 1995).Of particular note is that urinary excretion will be delayed if there is a degree of lipid solubility. Having set these stringent criteria for marker selection it can be argued that increased intestinal permeability, so assessed, only applies to substances with similar physicochemical properties. Sugars such as lactulose and other non-metabolized disaccharides (melibiose), trisaccharide (raffinose) or polysaccharides (dextran and polysuerose) (Menzies, 1974; Laker and Menzies, 1977; Wheeler et al., 1978; Oman et al., 1992; Oman et al., 1995) in addition to isotopically-labelled slCrEDTA (Bjamason et al., 1983a; Bjamason et aI., I983b) or 99mTcDTPA (Casellas et al., 1986) were all initially employed as single markers. Figure 2

D·glucose

D-xylose

\

L-l

L-

P

ATP~

~

~

ADP

f\

,

,

,

,

Ir

, ,

-

\/ Fig. 2. Absorption-permeability pathways within the intestine. The choice of test markers for assessing absorptive capacity and intestinal permeability are decided on by virtue of their physicochemical properties and mode of permeation across the gastrointestinal tract. The markers in common use are: 3-0-methyl-D-glucose: which is transported by an active carrier mediated transport system; D-xylose: which is transported by passive carrier mediated transport system; L-rhamnose: which passes the brush border by non-mediated diffusion via aqueous pores; Lactulose: which permeates selectively across the intercellular junctions; PEG 400: permeation pathway uncertain, but the bulk of evidence suggests that it is lipid soluble and hence capable of crossing the lipophilic domains of the brush border membrane.

662

I. Bjarnason, A. Cederborg, A. Akvist and S. Smale

outlines the permeation pathways that some of the more clinically useful test markers use. Characterisation of these probes are as follows: • Large-pore probes (~ 0.5 nm molecular radius) Di-, tri- and poly-saccharides are frequently used for assessing "large pore" permeation (Menzies, 1974; Laker and Menzies, 1977; Wheeler et al., 1978; Oman et al., 1992; Oman et al., 1995). Lactulose is the most widely used "non-absorbed" disaccharide. Melibiose has similar characteristics, but the use of cellobiose (Cobden et al., 1978; Cobden et al., 1980a; Cobden et al., 1980b; Hamilton et al., 1982; Hamilton et al., 1985) should be discouraged as this disaccharide is susceptible to hydrolysis by human intestinal lactase (Dahlqvist, 1962). Raffinose, stachyose and f1uoresceinlabelled dextran also resist the action of human intestinal disaccharidases. More recently polysucrose (Oman et al., 1992; Oman et al., 1995; Oman et al., 1996; Soderholm et al., 1998) has been introduced as a suitable test probe. All of these sugars are susceptible to rapid degradation by colonic bacteria. 51 CrEDTA was introduced for the non-invasive estimation of human intestinal permeability (Rask-Madsen and Schwartz, 1979; Bjarnason et al., 1983a; Bjarnason et al., 1983b), having been extensively validated in experimental animals (Lokken, 1970), and being a reference substance for measurement of glomerular filtration rates in man (Chantler et al., 1969). It has a physiological disposition almost identical to that of lactulose and melibiose. 99mTcDTPA is equally suitable as 51CrEDTA for use as a probe and is associated with a further decrease in the already low radiation that occurs during the procedure (Case lias et al., 1986). Resistance to bacterial degradation, while allowing 51 CrEDTA to be used for assessing colonic permeability (Jenkins et al., 1991; Jenkins et al., 1992), poses potential problems when the marker is used with a monosaccharide, in accordance with the differential urinary excretion principle, unless the urinary collection times are short (certainly not more than 5 h (Bjarnason et al., 1994; Sigthorsson et al., 2000) . • Small-pore probes (::S; 0.4 nm molecular radius) Uptake of mannitol from human intestine is relatively slow suggesting lack of affinity for biochemically mediated mucosal transport. Distribution following absorption is extracellular, and recovery in urine is complete following intravenous instillation (Laker, and Mount, 1980; Laker et al., 1982). Trace amounts may be present in normal urine, but in insufficient quantities to cause concern. L-rhamnose is also widely used as a small-pore probe, but recovery in urine after intravenous instillation is somewhat less rapid and complete than that for mannitol (Maxton, 1986).

Intestinal barrier function

663

• Permeation pathway undetermined PEG 400, which comprises a mixture of at least eight polymers (MW 194-502 Dalton), has been widely used as a probe for estimating human intestinal permeability (Chadwick et aI., 1977a; Chadwick et aI., 1977b; Sundquist et al., 1980; Sundqvist et aI., 1981; Magnusson et aI., 1983; Serrander et aI., 1984; Sundquist et aI., 1984; Faith-Magnusson et aI., 1985; Hollander et al., 1986; Stintzing et aI., 1986; Hollander et aI., 1988; FalthMagnusson et aI., 1989; Johansen et aI., 1989; Krugilak et aI., 1989; Serrander et aI., 1989; Stenhammar et aI., 1989; Magnusson et aI., 1990; Magnusson et aI., 1992; Munkholm et aI., 1994). PEG 400 has some worrying features. Its permeation rates are at least 20 fold higher than that of monosaccharides that permeate the intestine by non-mediated diffusion and recovery in urine following intravenous administration is only in the range of 26-72% in 5 h depending on polymer size (Maxton et aI., 1986). Alterations in the permeation of PEG 400 recorded in various diseases does not accord in a logical fashion with the behaviour of other "large-pore" probes such as 51CrEDTA. For these reasons the use of PEG 400 for assessing intestinal permeability is not recommended. However the reason for the behaviour of PEG is of considerable interest and controversy. At present it is most likely, but controversial, that the polymers of PEG 400 have a degree of lipid solubility (Menzies, 1984; Krugilak et aI., 1989; Ma et al., 1990; Iqbal et aI., 1993; Cox et aI., 1997) which would both explain the high permeation rates and low . . unnary recovenes,

2.1. Mediated transport Intestinal diseases may also affect carrier mediated transport systems and test probes with an affinity for these have been widely used for investigation of intestinal disease. In general the use of such probes for diagnostic screening has proved disappointing because of a lack in sensitivity as there is so much reserve capacity within the intestine. The main use of these tests is to assess the potential contribution of malabsorption to malnutrition and the test probes are sometimes employed in physiological studies. For the purpose of this review the important probes are: 1. 3-0-methyl-D-glucose (MW 194), which is a synthetic monosaccharide with affinity for the active intestinal Na-linked D-glucose transport system. It is resistant to metabolism and to bacterial degradation and renal clearance in the human is complete after intravenous administration (Fordtran, 1962; Menzies, 1984). It is absorbed predominantly from the proximal jejunum.

664

1. Bjarnason, A. Cederborg, A. Akvist and S. Smale

2. D-xylose (MW 150 Dalton), which is a pentose of plant origin. In the human absorption is by a passive carrier-mediated system, distinct from that utilised by 3-0-methyl-D-glucose. It is purportedly metabolized by the liver after reaching the circulation" with perhaps no more than 50% being recovered in urine following intravenous administration (Fordtran et al., 1962; Menzies, 1984). If correct this is difficult to reconcile with the fact that increased D-xylose urinary excretion has not been documented in patients with severely impaired liver function (Budillon et al., 1985; Romiti et al., 1990; Wicks et al., 1993). 3. Vitamin B 12 (with intrinsic factor) is selectively absorbed by an active carrier-mediated process confined to the last few centimetres of the ileum. The use of radiolabelled vitamin B 12 for investigation of vitamin B 12 deficiency is routine in most hospitals (Schiling test), but as demonstrated below it can be used to assess when an ingested test solution reaches the ileum.

3.

EVALVAnON OF GASTROINTESTINAL PERMEABILITY

There are various ways to assess regional intestinal permeability. The precise choice of probe markers, the ideal test dose composition, timing of the test and analytical matters are all issues that deserve particular attention, but in some cases these issues have been neglected or simply ignored. The ideal intestinal permeability test conforms to the differential urinary principle although as yet this has not always been possible.

3.1.

Assessment of intestinal permeability

The straightforward assessment of small intestinal permeability was the starting point that fuelled further investigations and it remains the most widely used test procedure. In accordance with the differential excretion principle a distinction is made between small (accommodate probes of <0.4 mm such as L-rhamnose and mannitol) and large (which accommodate lactulose, 51 CrEDT A, etc.) aqueous channels with a high and low mucosal prevalence, respectively. The prevalence of intestinal large/small aqueous channels (in reality large/large + small channels) in normal UK residents, expressed as the differential urinary excretion of Iactulose/Lvrhamnose, is about 1/40 (0.025) and characteristically rises in the presence of mucosal damage due to a variety of causes. Normal ranges may vary from country to country which may be due to racial or environmental factors (Ukabam et al., 1986; Behrens et al., 1987; Jenkins et al., 1989; Sullivan et al., 1992).

Intestinal barrier function

665

The test procedure itself is simple. The test solution incorporates a combination of a large and small permeability probes, characteristically lactulose and L-rhamnose or mannitol. There should be a defined fasting period before ingestion of the test solution, to optimise comparable test conditions, as the presence of food in the stomach may exert an osmotic influence, see below. One to two hours after ingestion food and fluids are encouraged. Complete urinary collections are made into a container containing a preservative for the sugars and which also serves to destroy potential pathogens. There are now a number of techniques for sugar separation and analysis; the precise method will depend on local expertise and experience. The results are expressed as a ratio of the % excretion of the large/small probe in the urine. If 51CrEDTA is used as a "large pore" probe along with a monosaccharide the timing of urinary collection is crucial and should not exceed 5 h (Maxton et al., 1986; Bjarnason et al., 1994). The expression of intestinal permeability as a 24 h urinary excretion ratio of say 51 CrEDT A/ mannitol, which has in fact been carried out (Jorgensen et al., 2001), is in absolute contravention of the principles outlined above (Menzies, 1984; Travis and Menzies 1992; Bjarnason et al., 1995) and will predictably yield inaccurate and non-representative data. Alternatively, 51CrEDTA can be used by itself, without any monosaccharide, in which case the 24 h urinary excretion provides a very sensitive index of intestinal permeability at the cost of loss of specificity for small bowel permeability (Bjarnason et al., 1983a; Bjarnason et al., 1983b; Bjarnason et al., 1984a; Bjarnason et al., 1984b; Bjarnason et al., 1985; Bjarnason et al., 1986a).

3.2.

Assessment of gastric permeability

Sutherland et al., 1994 presented a method in which sucrose is employed for assessing gastric as opposed to small intestinal permeability. The validity of the test rests on the assumption that small intestine hydrolysis of sucrose is so rapid and complete that uptake of sucrose following ingestion can be regarded as a specific feature of gastric permeability (Meddings et al., 1993; Smecuol et aI., 1997). Theoretically this is at best a somewhat crude approximation because increased urinary excretion of sucrose from the small intestine as sucrosuria is found in a variety of small bowel diseases (Santini et aI., 1957; Gryboski et al., 1963; Maxton et al., 1989; Maxton et al., 1990; Bjarnason et al., 1996; Cox et al., 1998; Taylor et al., 2000). Curiously, some studies have administered the test solution before the subjects went to sleep. Nevertheless the method detects many patients with NSAID-induced gastric ulcers (Sutherland et al., 1994), gastric ulcers and cancers (Kawabata et al., 1998). Gastric permeability may

666

I. Bjarnason, A. Cederborg, A. Akvist and S. Smale

be increased in subjects taking aspirin (Rabassa et al., 1996), indomethacin (Gotteland et al., 2001) and ibuprofen (Smetonika et al., 1999). Gastric permeability is increased in Helicobacter pylori positive subjects (Borch et al., 1998; Fakuda et al., 2001), while it decreases within the normal range after successful treatment (Goodgame et al., 1997). Those with Falciparum malaria (Wilairatana et al., 1997), misusing alcohol (Keshavarzian et al., 1999) or receiving corticosteroids (Kiziltas et al., 1998) also have increased permeability. Sucrose permeation is predictably increased in coeliac disease (Vogelsang et al., 1996; Smecuol, 1997). Thus sucrose permeation may be useful for diagnostic screening but its main use may be in research.

3.3.

Colonic permeability

A characteristic test solution for assessing colonic permeability involves the combined administration of 51CrEDTA with lactulose followed by a 0-24 h urine collection for marker analyses (Jenkins et al., 1991; Jenkins et al., 1992; Qvist et al., 1994). The two probes permeate the small bowel at equal rates (Jenkins et al., 1994). However, when the test solution enters the colon lactulose is rapidly degraded whilst 51 CrEDTA is not. The difference between the 24 h recovery of 51CrEDTA and lactulose therefore represent colonic permeation. The test shows increased colonic permeability in severe colonic disease (Jenkins et al., 1991; Jenkins et al., 1992; Qvist et al., 1994). For those who want to avoid the radiation of 51 CrEDTA it is reasonable to use sucralose which resists bacterial degradation and which has been well validated as a marker of colonic permeability. In ulcerative proctitis the uptake of 51 CrEDTA from colon, estimated by measuring recovery in urine following a test enema, is markedly increased and provides an alternative way of assessing colonic permeability.

3.4.

The ideal test?

There is at present no ideal test, but for research purposes it would be easy to simultaneously assess gastric, intestinal and colonic permeability. Such a test would involve an overnight fast and ingestion of a disaccharide (lactulose or melibiose), monosaccharide (mannitol or L-rhamnose), sucrose and a non-degraded marker CICrEDTA or sucralose). A 5 h urinary collection would yield data on gastric (sucrose) and small intestinal (di-yrnonosaccharide) permeability while the complete 0-24 h collection would is misspelled as woulod provide data on colonic permeability (urinary

Intestinal barrier function

667

excretion of the non-degraded marker and disaccharide should read: marker minus the disaccharide). The more adventurous worker might add 3-0methyl-D-glucose and D-xylose to the test as this would additionally allow assessment of intestinal absorptive capacity.

4.

LOCALISING INTESTINAL PERMEABILITY CHANGES

It is possible to define further the levels at which intestinal permeation and absorption occur. This can be done by comparison of the plasma concentration/time profile of the constituent being investigated with those derived from simultaneously ingested markers, the uptake of which are known to be related to defined regions of the intestine (Teahon et al., 1996). In the case of intestinal permeability, comparison of the uptake of 51CrEDTA with that of simultaneously administered reference markers allows the site of increased intestinal permeability to be verified. One such test employed: i) 3-0-methyl-D-glucose rapidly absorbed by the D-glucose carrier mechanism on entering the small bowel. ii) 57CoVitamin B1rintrinsic factor complex absorbed by specific carriers from the terminal ileum. iii) Sulphasalazine passes unchanged into the caecum where it is cleaved by azo-reductase containing bacteria into 5-aminosalicylic acid and sulphapyridine. The appearance of sulphapyridine in serum therefore indicates when the test solution enters the caecum. Figure 3 shows representative time profile results obtained with this test from patients with untreated coeliac disease (shows increased serum levels of 51CrEDTA which correspond to the 3-0-methyl-D-glucose absorption curve), Crohn's disease (where the peak serum levels of 51CrEDTA correspond to appearance of the ileal and colonic markers) and ulcerative colitis (increased serum levels of 51CrEDTA appear some time following the appearances of Vit B I2 and sulphapyridine). This method shows that the site of increased intestinal permeability in patients with coeliac and inflammatory bowel disease is indeed the diseased intestinal mucosa itself. Further analysis of the test results allows interesting information on transit times to be deduced. The time from ingestion of the test solution to the time of appearance of 3-0-methyl-D-glucose reflects the gastric emptying time of liquids. The time to the appearance of sulphapyridine indicates oro-caecal transit time and the time of appearance of sulphapyridine less that of 3-0-methyl-D-glucose then becomes a specific measure of jejuno to caecal transit.

668

1. Bjarnason, A. Cederborg, A. Akvist and S. Smale 3-0-melhyl-D-glucose

10

Sulpha pyridine

CONTROLS

0.1

2

4

8

6

10

12

14

16

18

20

22

24

Time (h)

10

COELIAC DISEASE

2

4

6

8

10

12

14

16

18

10

22

24

22

24

20 Time (h)

CROHN'S ILEITIS

~

s
0.01

0

2

4

6

8

10

12

14

16

18

20

Time (h)

10

ULCERATIVE

-~~ c

~ 0.1

0.01

0

2

4

6

8

10

12

14

16

18

20

22

Time (h)

Fig. 3.

Localisation of intestinal permeability changes.

24

Intestinal barrier function

5.

669

FORMULATION OF INTESTINAL PERMEABILITY TEST SOLUTIONS

Apart from the precise choice of probes, the effects of osmotic fillers (glycerol, glucose, sodium chloride, sucrose, lactose, etc.) on the sensitivity and reliability of the intestinal permeability test procedure also need careful consideration. 5.1.

"Hyperosmolar stress" and osmotic fillers

Ingestion of hyperosmolar solutions (above 1500 mosm/L) cause significant temporary increase of intestinal permeability to the large probes in normal human subjects. Initially, when a single "permeability" test probe was used (for instance lactulose), this allowed a better discrimination between normal subjects and patients with coeliac disease (Menzies, 1974; Laker and Menzies, 1977; Wheeler et al., 1978; Menzies et al., 1990). This information was then extrapolated over to the differential tests (Menzies et al., 1979). After glycerol was found to be the most suitable "osmotic filler" other workers tried to "individualise" their own test by adding other substances to the test solution, not realising that there is individual variation both in susceptibility to the stress and the efficiency with which osmotic fillers are absorbed. There is now ample evidence to show that the use of "osmotic fillers" is of very questionable value (Maxton et al., 1986; Menzies et al., 1990; Bjamason et al., 1994). 5.2.

Osmotic effect of poorly absorbed solute in test solutions

The solute content of test solutions, especially of lactulose, mannitol and rhamnose, which are relatively poorly absorbed, also needs to be carefully controlled. These substances withhold fluid within the intestine and accelerate transit (Menzies et al., 1990; Jenkins et al., 1994). This unavoidably affects the sensitivity of the test procedure. To minimise such distortions it is desirable to keep the dose of poorly absorbed probes (and other solutes in the test solution) as low as reliable analysis of the urinary and plasma concentrations will allow. 6.

ANALYSES OF TEST MARKERS

Reliable separation and quantitation of these sugar markers in urine requires great care and experience (Menzies, and Crane, 1998). Quantitative thinlayer chromatography, enzyme analyses, radioisotopic counting, GLC and

670

I. Bjamason, A. Cederborg, A. Akvist and S. Smale

HPLC all have their proponents and pitfalls, but detailed discussion of the techniques is outside the scope of this communication.

7.

CONDITIONS ASSOCIATED WITH INCREASED INTESTINAL PERMEABILITY

Investigation of intestinal permeability can be used clinically for diagnostic screening and assessing response to therapy. Increased intestinal permeability has been found in a number of conditions and a brief summary is presented to outline the main clinical uses of the tests.

7.1.

Coeliac disease

Intestinal permeability tests were initially designed to allow non-invasive diagnostic screen for coeliac disease. All the more reliable studies show that untreated coeliac disease (or gluten sensitive enteropathy) is associated with a high prevalence of increased small intestinal permeability (95% of patients are abnormal) (Cobden et al., 1978; Cobden et al., 1980a; Hamilton et al., 1982; Bjarnason et al., 1983b; Andre et al., 1984; Bjarnason et al., 1986; Dawson et al., 1988; Fotherby et al., 1988; Juby et al., 1989a; Juby et al., 1989b; Lobley et al., 1990; Cummins et al., 1991; Catassi et al., 1993; Bjarnason et al., 1994; Cummins et al., 2001; ViI et al., 2001). Intestinal permeability improves and often returns to normal, depending on the sensitivity of the test, when response to a gluten-free diet is satisfactory. Exposure to gluten fractions present in wheat and certain other cereals is an essential predisposing factor: presumably these produce the characteristic reaction after penetrating the intestinal mucosa of susceptible individuals. Measurement of intestinal permeability as a screening procedure for coeliac disease is now largely obsolete, as the presence of serum antibodies to transglutaminase is equally sensitive and of greater specificity (Baldas et al., 2000). In a problematic patient, in whom it is difficult to assess the compliance to the diet, a persistent increase in intestinal permeability usually indicates dietary indiscretions.

7.2.

Inflammatory bowel disease

Tests of intestinal permeability are exceptionally sensitive (over 90%) for the detection of active small bowel Crohn's disease and half of those with colonic disease are also abnormal (Ukabam et al., 1982; Bjarnason et al., 1983a; Casellas et al., 1986; O'Morain et al., 1986; Andre et al., 1988;

Intestinal barrier function

671

Resnick et al., 1990; Howden et al., 1991; Teahon et al., 1993) and can therefore be used for diagnostic screen. Quantitatively, the permeability changes relate to the extent and activity of disease. Following surgical resection the intestinal permeability test yields unreliable results. Patients with ulcerative colitis usually have normal small intestinal permeability, but colonic permeability is increased (Jenkins, 1992). Permeability tests can be used to assess response to therapy in patients with Crohn's disease (Sanderson et al., 1987; Teahon et al., 1991). More importantly, increased intestinal permeability in patients with clinically quiescent disease may predict a clinical relapse of disease while those with normal results often maintain clinical remission (Teahon et al., 1993; Wyatt et al., 1993; D'Inca et al., 1999; Hilsden et al., 1999; Amott et al., 2000; Tibble, 2000). This might suggest that defective intestinal barrier function could play a central role in the relapse of inflammatory bowel disease by allowing mucosal exposure of luminal antigens (Bjarnason et al., 1993a; Bjarnason et al., 1993b; Bjarnason et al., 1995). However, increased permeability could equally be regarded as providing a sensitive indication of the presence and progress of an established inflammatory lesion (Tibble et al., 2000). Altered intestinal permeability in the relatives of patients with Crohn's disease has been quoted as evidence for the presence of subclinical disease, if not of a genetically-determined factor of aetiological importance (Katz et al., 1989; Teahon et al., 1992; May et al., 1993; Munkholm et al., 1994; Yacyshyn and Meddings, 1995; Hilsden et al., 1996; Peeters et al., 1997; Soderholm et al., 1999). The prevalence of the increased intestinal permeability amongst these relatives is usually in the range of 10-20%. In such a complex situation as Crohri's disease unequivocal demonstration of an aetiological role for increased intestinal permeability, which must certainly be considered a result as well as a possible cause of the inflammatory lesion, is likely to be difficult unless it can be clearly shown that it precedes all other features of the pathological process. Ideas are plentiful but experimental support is as yet scarce.

7.3. Nonsteroidal anti-inflammatory drugs The effects of NSAIDs on intestinal permeability were first noticed when patients with rheumatoid arthritis were investigated to assess whether increased macromolecular permeation could be an aetiological factor (Bjarnason et al., 1984b; Bjarnason et al., 1993c). Although increased permeability was demonstrated it turned out, somewhat ironically, to be

672

l. Bjarnason, A. Cederborg, A. Akvist and S. Smale

iatrogenic! All commonly used NSAIDs are associated with increased intestinal permeability (Bjamason et al., 1991a; Bjamason et al., 1991b; Bjamason et al., 1992a; Choi et al., 1995; Sigthorsson et al., 1998a). Although the mechanism of the initial damage is speculative and only adequately studied in experimental animals (Somasundaram et al., 1995; Somasundaram et al., 1997; Somasundaram et al., 2000), it is suggested that NSAIDs uncouple mitochondrial oxidative phosphorylation by virtue of their physicochemical properties (lipid solubility and acidity) (Scarpignatio et al., 1999). The new generation of highly selective cyclooxygenase-2 inhibitors and nabumetone, both of which are non-acidic and do not uncouple oxidative phosphorylation (Mahmud et al., 1996a), do not increase intestinal permeability or cause small bowel inflammation (Bjamason et al., 1991; Sigthorsson et al., 1998b; Sigthorsson et al., 2000; Shah et al., 2001) in normal human volunteers.

7.4.

Immunological incompetence

Patients with hypogammaglobulinaemia of various aetiology and those infected by the human immunodeficiency virus with severely compromised immunity almost invariably have increased intestinal permeability (Guarino et al., 1991; Fleming et al., 1993; Lim et al., 1993; Teahon et al., 1994; Tepper et al., 1994; Keating et al., 1995; Obinna et al., 1995; Bao et al., 1996; Lima et al., 1997; Murphy et al., 1999; Pemet et al., 1999). The permeability changes relate to the severity of the immune suppression. The precise reason for the permeability changes are not known but might involve a direct effect of the human immunodeficiency virus on the intestinal mucosa or the consequences of intestinal infection. There has also been the suggestion that a leaky intestine might be the source of antigens which might playa role in autoimmune diseases (Hong and Amman, 1972), an idea that is being reactivated (Jasin et al., 1983; Albert and Inman, 1999; Smale et al., 2001).

7.5.

Intestinal permeability in food intolerance and allergy

Studies of intestinal permeability in food allergy and intolerance are of considerable interest, but suffer from a lack of agreed diagnostic criteria. Eczema is usually included in this discussion because a genetically determined impairment of immunological responsiveness to dietary antigens may underlie this condition (Kokkonen et al., 1980; Lessof et al., 1980; Atherton, 1981). Eczematous and asthmatic children, but not adults, may experience bronchospasm on challenge with specific foods and exclusion

Intestinal barrier function

673

diets may produce dramatic improvement of eczema (Atherton et aI., 1978; Juto et aI., 1978; Hill and Lynch, 1982; Goldsborough and Francis, 1983; Forget, 1985). Adult patients with severe atopic eczema, with and without food intolerance, had normal intestinal permeability (Bjamason et aI., 1985; Hamilton et aI., 1985; Barba et al., 1989) as did those with food intolerance without eczema (Scadding et aI., 1989; Paganelli et al., 1990). Two studies, however demonstrated increased intestinal permeability (Newton et al., 1984; Ukabam et al., 1984). Food allergy appears to be a prevalent condition in France and is associated with increased intestinal permeability (Andre et aI., 1984; Andre, 1986; Andre et al., 1987). Intestinal permeability mayor may not be increased in food-allergic eczematous children (Pike et aI., 1986; Dupont et aI., 1989; Pike et al., 1989; Barau and Dupont, 1990). Children with cow's milk intolerance have markedly increased intestinal permeability (Hamilton et al., 1987; Schrander et aI.,1990; Jalonen et al., 1991).

7.6.

Intestinal function in the newborn

There is some suggestion that the foetal intestine in experimental animals is "hyper-permeable" and allows absorption from amniotic fluid of macromolecules that would otherwise be excluded from absorption (Brace, 1997). Following delivery there is apparently gradual tightening of the intestinal barrier as a part of the maturing process. This "gut closure" has been extensively studied in animals and takes place after 32 h in the calf (Stott et al., 1979), 86 h in the pig (Leece and Morgan, 1962) and 21 days in the rat (Morris and Morris, 1978). However, a drawback to these studies is the fact that intestinal permeability was not assessed directly. Rather, macromolecular permeation was measured, which poses problems for interpretation as this is dependant on a variety of immunological factors as well as intestinal permeability. The subject of gut closure in humans is of considerable interest but study is hampered by various practical issues. Vukavic compared IgA levels before and after breast feeding and concluded that gut closure occurred within 30 h in infants exposed to milk within 6 h of delivery. Delay of breast feeding delayed gut closure. Weaver et al. showed that preterm infants had increased intestinal permeability (lactulose./mannitol) (Weaver et al., 1984), at a time when feeding with cow's milk is associated with significant serum levels of beta-lactoglobulin (Roberton et al., 1982), and that gut closure occurred over a week. Neonates delivered at term also had increased intestinal permeability which normalised over 4 days (Weaver et al., 1984) and there is no further decrease in intestinal

674

1. Bjarnason, A. Cederborg, A. Akvist and S. Smale

permeability during months I to 12 (Gotteland et al., 1998). Using the lactulosejmannitol intestinal permeability test Catassi et al. suggested that there is a rapid decrease in intestinal permeability in the first week of life and that this closure occurs more rapidly in breast fed infants as opposed to those on artificial formulas (Catassi et al., 1995), an observation supported from other studies (Weaver, 1988). The reason for this is not clear. One possibility is that the artificial formulations contain greater quantities of antigens that might elicit a subclinical inflammatory reaction. This is supported in studies in the rat where pups receiving cow's milk as opposed to suckling animals, had greatly delayed gut closure (Arvola et al., 1993). Gut closure could however be induced by corticosteroids in these animals (Teichberg et al., 1990). The biological importance of the early gut closure is somewhat speculative. The increased intestinal permeability might be important for the acquisition of immunoglobulins from colostrum during the first few days of life. Calves and piglets that do not receive colostrum are prone to develop septicaemia and enterocolitis and breast fed infants have less bacterial infections than those on artificial diets (Goldman et al., 1990). The importance of increased intestinal permeability in the neonate, its possible role in oral tolerance and the processes leading to gut closure are still not known in full detail, but may be of major importance in the development of the child's immunological system.

7.7.

Miscellaneous

Increased intestinal permeability has been demonstrated in a number of diverse conditions. Table 1 shows representative conditions, but is by no means complete. The obvious question arising from the demonstration of increased intestinal permeability in so many and such diverse diseases is whether the permeability changes have any serious consequences. In this context it is important to remember that the intestinal barrier function, along with immunological mechanisms, has been regarded of central importance for the protection of the intestinal mucosa from "luminal aggressive factors", which in reality represent the highest concentration of bacteria and antigens to which the organism is exposed. On balance it is unlikely that the increased intestinal permeability to small water-soluble test markers is synonymous with antigen permeation although in some cases it may be (Davin et al., 1988; Ramage et al., 1988). There is however better evidence for the idea that increased intestinal permeability leads to a local inflammatory reaction.

Intestinal barrier function

675

Table I Conditions associated with increased intestinal permeability Condition

References

Alcohol misuse

(Menzies I.S., 1974; Bjarnason I. et al., 1984; Smethurst P. et al., 1988; Keshavarzian A. et al., 1999; Parlesak A. et aI., 2000) (Pearson A.D.J. et al., 1984; Selby P.I. et al., 1987; Pledger J.V. et aI., 1988; Parrilli, G. et aI., 1989; Mahendra P. et aI., 1994; Kohout P. et al., 1999) (Maxton D.G. et al., 1989; Buchman A.L. et aI., 1995; Willumsen J.F. et al., 1997; van der Hulst R.R. et al., 1998) (Walsh D.S. et al., 1996; Doig C.J. et al., 1998; Faries P.L. et al., 1998; Hernandez G. et aI., 1999; Kompan L. et al., 1999) (Cooper B.T. et aI., 1987; Carratu R. et aI., 1999) (Qvist H. et aI., 1994; Carratu R. et al., 1998) (Noone C. et al., 1986; Alam A.N. et aI., 1994; de Maar E.F. et aI., 1996; Raj S.M. et aI., 1996; Riordan S.M. et aI., 1997; Wilairatana P. et aI., 1997; Barboza Junior M.S. et al., 1999; Zhang Y. et al., 2000) (Leclercq-Foucart J. et al., 1986; Leclercq-Foucart J. et al., 1987; van Elburg R.M. et al., 1996) (Pape H.C. et aI., 1994; Langkamp-Henken B. et al., 1995; Pernet P. et al., 1998; Brooks A.D. et al., 1999; Iwata H. et al., 2000; Liverani E. et al., 2000) (Budillon G. et aI., 1985; Wicks C. et aI., 1993; Welsh F.K. et aI., 1998; Campillo B. et aI., 1999; Ersoz G. et al., 1999) (Iqbal T.H. et aI., 1996; Northrop-Clewes C.A. et aI., 1997; Goto K. et al., 1999; Menzies I.S. et aI., 1999) (Van Der Meer S.B. et aI., 1990; Saltzman J.R. et aI., 1995; D'Eufemia P. et aI., 1996; Davies K.N. et al., 1996; Fradkin A. et aI., 1996; Ryan A.J. et aI., 1996; Yacyshyn B. et al., 1996; Shulman R.J. et aI., 1998; Picco P. et al., 2000)

Cytotoxic drugs

Starvation-nutrition

Critically ill

Diabetes Radiation Intestinal infections

Cystic fibrosis Stress-burn-surgery-ischemia

Liver disease

Geographical variations Various

8.

INCREASED INTESTINAL PERMEABILITY AND INTESTINAL INFLAMMATION

The local intestinal consequences of increased intestinal permeability have been most extensively studied in relation to NSAID ingestion. This group of drugs is extensively used world-wide for analgesic and anti-inflammatory purposes. In general the gastrointestinal tract bears the main brunt of NSAID-related side-effects. Whilst those in the stomach and duodenum have been well studied, because biopsy is routine and the serious endpoints

676

I. Bjarnason, A. Cederborg, A. Akvist and S. Smale

of bleeding and perforation are amenable to epidemiological study (Langman, 1989; Whittle, 1992; Langman et al., 1994; Rodrigues and Jick, 1994; Scarpignatio et al., 1999), the demonstration that NSAIDs (see above) increase intestinal permeability led to systemic study of the mechanism of this increased intestinal permeability and its consequences. It is now clear that the increase in intestinal permeability due to NSAIDs is not due to their ability to inhibit cyclooxygenase, but due to their interference with mitochondrial function (Somasundaram et al., 1995). Hence all acidic NSAIDs uncouple mitochondrial oxidative phosphorylation at micromolar concentrations and inhibit electron transport (mitochondrial respiration) at slightly higher concentrations (Mahmud et al., 1996a; Mahmud et al., 1996b). Either action renders the cell deficient in ATP (Carefoli, 1987; Jacob, 1999), which in turn leads to loss of control over the integrity of the tight junctions between adjacent enterocytes and hence increased intestinal permeability. Classical uncouplers of oxidative phosphorylation, such as dinitrophenol, have the same effect on intestinal permeability (Somasundaram et al., 1997; Somasundaram et al., 2000). Based on the idea that increased intestinal permeability might lead to intestinal inflammation, studies were specifically designed to address this issue. Using the technique of III Indium labelled neutrophils it was shown that about 60% of patients on long term NSAIDs had small intestinal inflammation (Bjarnason et al., 1984b; Bjarnason et al., 1987; Sigthorsson et al., 1998a), since then confirmed by the use of faecal marker (calprotectin) (TibbIe et al., 1999), by enteroscopy (Morris et al., 1991a; Morris et al., 1991b; Morris et al., 1992; Morris et al., 1996), clinically (Langman et al., 1985) and at autopsy (Allison et al., 1992). The pathogenesis of this inflammation is complex and mostly worked out in the experimental animal (Wallace and Granger et al., 1992; Bjarnason et al., 1993a; Wallace, 1997). In short, the increased intestinal permeability allows bile acids (also uncouplers of oxidative phosphorylation), ingested antigens and bacteria and their degradation products access to the small intestinal mucosa (Bjarnason et al., 1992b; Bjarnason et al., 1993a). This elicits a neutrophil predominant inflammatory reaction, which by itself is low grade as shown from the human studies. The precise role of cyclooxygenase inhibition in this damage is uncertain although it seems likely that it predominantly interferes with regulation of intestinal blood flow. Having demonstrated the inflammatory reaction possible complications were sought. It was shown that patients with NSAID enteropathy had significant small intestinal bleeding (Bjarnason et al., 1984b; Hayllar et al., 1994) and intestinal protein loss (Bjarnason et al., 1984b). Some patients also had mildly impaired ileal function (Bjarnason et al., 1993c) and occasional patients developed small

Intestinal barrier function

677

intestinal strictures (Bjarnason et aI., 1988; Lang, 1988; Levi et aI., 1990; Huber et aI., 1992; McCune et aI., 1992). NSAID enteropathy is perceived as being an asymptomatic condition, but may of course contribute to the non-specific dyspepsia of which so many patients on NSAIDs complain. The associated bleeding may play a part in the iron deficiency anaemia which is so common in rheumatic patients and the protein loss may lead to hypoalbuminaemia seen in about 10% of patients with rheumatoid arthritis admitted to hospital. NSAID-induced small intestinal inflammation is the prototype and best documented consequence of increased intestinal permeability. A generalisation might be anticipated that all the above diseases were associated with a similar enteropathy if the pathogenic framework ofNSAID-enteropathy was correct. As it turns out this does appear to be the case. Figure 4 shows some of the conditions where increased intestinal permeability has been found and where intestinal inflammation has been sought. It is evident that by whichever mechanism the intestinal barrier function is disrupted this is associated with a low grade inflammatory response. There are some

Intestinal Condition

BARRIER BREAKERS

LUMINAL AGGRESSORS

IMPAIRED MUCOSAL DEFENCE

Permeability Inflammation

NSAIDs Alcohol Chronic renal failure Radiation Cytotoxic drugs

x2-5 x2-5 x2-3 x2-3 x2-5

3.0% 2.6% 5.2% 3.0% Unknown

Infections Salmonella Shigella Yersinia Cystic Fibrosis

x2-5

7.2%

x2-15

Unknown

Hypogammaglobulinemia HIV-AIDS

x2-7

6.9%

x2-10

2.0%

Fig. 4. Ineraction between intestinal permeability and inflammation. Intestinal permeability and inflammation has been assessed concomitantly in a number of conditions. Within the group of barrier breakers are drugs or conditions that lead directly to disruption of intestinal integrity. Consequentially to this breach in the barrier function there is the development of inflammation which is similar in its intensity. Increased luminal aggressors are best evident in intestinal infections. The primary event there is probably an inflammatory reaction followed by an increase in intestinal permeability. Nevertheless the permeability and inflammatory changes are very similar to those for the barrier breakers. Similarly, in disease associated with impared mucosal defence the permeability and inflammatory changes resemble that of the above. Collectively this suggests that the main neutrophil chemottractant within the gastrointestinal tract is the normal intestinal flora.

678

I. Bjarnason, A. Cederborg, A. Akvist and S. Smale

differences in the intensity of the inflammation in these various conditions, but despite this there is a significant conformity in the results. This is strong evidence for the idea that increased intestinal permeability almost invariably leads to a local enteropathy. The proof or refution of this hypothesis will corne from studies of intestinal inflammation in other conditions listed in I that are consistently associated with increased intestinal permeability.

9.

CONCLUSIONS AND FUTURE STUDIES

Tests of intestinal permeability are simple to use, accurate and sensitive and provide information which cannot be obtained by other non-invasive methods. The test procedures exploiting the principle of "differential: oral absorption described, in which renal excretion of several test markers are measured following oral administration, allow specific assessment of regional changes in permeability. Nevertheless there are many practical aspects of their use needing special attention, which have in part been outlined. It seems likely that a wider range of applications are yet to emerge with introduction of new permeability test probes, appropriately designed probes that have physicochemical properties resembling endotoxins and other antigens and which will therefore provide greater pathophysiological information. At this stage there are a number of pressing problems and questions to address, not least the possibility that increased intestinal permeability may be a source of antigens that play a part in autoimmune disease. The idea that increased intestinal permeability could predispose to, or modify the course of, systemic pathology is very attractive, but this difficult question remains to be resolved. Substantial interest is already evident in the role of the intestine in rheumatoid arthritis and spondylarthropathy (Leirisalo-Repo and Repo, 1992; Leirisalo-Repo et al., 1994; Smale et al., 200 I). A recent advance which involves an integrated approach to the study of intestinal permeability and inflammation in various diseases is providing insight into the existence of a common final pathway for an intestinal inflammatory response. Measurements of intestinal permeability hold the promise of making and maintaining a valuable contribution to the detection and monitoring of intestinal abnormalities in clinical medicine and research.

REFERENCES Alam, A.N., Sarker, S.A., Wahed, M.A., Khatun, M., Rahaman, M.M., 1994. Enteric protein loss and intestinal permeability changes in children during acute shigellosis and after recovery: effect of zinc supplementation. Gut 35, 1707-1711.

Intestinal barrier function

679

Albert, L.1, Inman R.D., 1999. Molecular mimicry and autoimmunity. N. Eng. 1. Med. 341, 2068-2074. Allison, M.e., Howatson A.G., Torrance C.1., Lee F.D., Russell R.I., 1992. Gastrointestinal damage associated with the use of nonsteroidal anti-inflammatory drugs. N. Engl. 1. Med. 327, 749-754. Andre, e., 1986. Diagnostic objectif et test I'efficacite therapeutique par mesure de la permeabilite intestine. Presse Med. 15, 105-108. Andre, C; Andre, F., Colin, L., Cavagna, S., 1987. Measurement of intestinal permeability to mannitol and lactulose as a means of diagnosing food allergy and evaluating therapeutic effectiveness of disodium chromoglycate. Ann. Allergy 59, 127-130. Andre, C; Collin, L., Descos, L., Daniere, S., 1984. Non-invasive evaluation of intestinal permeability in food allergy, coeliac disease and inflammatory bowel disease. Gut 25, Al I89-AI 190. Andre, F., Andre, C.. Emery, Y., 1988. Assessement of the lactulose-mannitol test in Crohri's disease. Gut 29,511-515. Amott, J.D., Kingstone, K., Ghosh, S., 2000. Abnormal intestinal permeability predicts relapse in inactive Crohn's disease. Scand. J. Gastroenterol. 35, 1163-1169. Arvola, T., lsolauri, E., Rantala, 1., Kaila, M., Majamaa, H., Virtanen, E., Arviommi, H., 1993. Increased in vitro intestinal permeability in suckling rats to cow milk during lactation. 1. Pediat. Gastroenterol. Nutr. 16, 294-300. Atherton, 0.1., 1981. Allergy and atopic eczema II. Clin. Experim. Dermatol. 6, 317325. Atherton, 0.1., Sewell, M., Soothill, 1.F., Wells, R.S., Chivers, e.D., 1978. A double blind, controlled, crossover trial of antigen avoidance diet in atopic eczema. Lancet i, 401-403. Baldas, V., Tommasini, A., Trevisiol, C., Berti, I., Fasano, A., Sblattero, D., Bradbury, A., Marzari, R., Barillari, G., Ventura, A., Not, T., 2000. Development of a novel rapid noninvasive screening test for coeliac disease. Gut 47, 628-631. Bao, Y., Silva, T.M., Guerrant, R.L., Lima, A.A., Fox, 1.W., 1996. Direct analysis of mannitol, lactulose and glucose in urine samples by high-performance anion-exchange chromatography with pulsed amperometric detection. Clinical evaluation of intestinal permeability in human immunodeficiency virus infection. 1. Chromatogr. B. Biomed. Allp. 685, 105-112. Barau, E., Dupont, C; 1990. Modifications of intestinal permeability during food provocation procedures in pediatric irritable bowel syndrome. 1. Pediat. Gastroenterol. Nutr. 11,72-77. Barba, A., Schena, D., Andreaus, M.e., Faccini, G., Pasini, F., Brocco, G., Cavallini, G., Scuro, L.A., Chieregato, G.e., 1989. Intestinal permeability in patients with atopic eczema. Brit. J. Dermatol. 120, 71-75. Barboza, Junior, M.S., Silva, T.M., Guerrant, R.L., Lima, A.A., 1999. Measurement of intestinal permeability using mannitol and lactulose in children with diarrheal diseases. Braz. 1. Med. BioI. Res. 32, 1499·-1504. Behrens, R.H., Lunn, P.G., Northrop, e.A., Hanlon, P.W., Neale, G., 1987. Factors affecting the integrity of the intestinal mucosa of Gambian children. Amer. J. Clin. Nutr. 45, 1433-1441. Bjamason, 1., Batt, R., Catt, S., Macpherson, A., Maxton, D., Menzies, I.S., 1996. Evaluation of differential disaccharide excretion in urine for non-invasive assessment of intestinal disaccharidase activity caused by a-glucosidase inhibition, primary hypolactasia and coeliac disease. Gut 39, 374-381. Bjamason, 1., Fehilly, B., Smethurst, P., Menzies, I.S., Levi, A.1., 1991a. The importance of local versus systemic effects of non-steroidal anti-inflammatory drugs to increase intestinal permeability in man. Gut. 32,275-277.

680

1. Bjarnason, A. Cederborg, A. Akvist and S. Smale

Bjamason, I., Goolamali, S.K., Levi, A.J., Peters, T.J., 1985. Intestinal permeability in patients with atopic eczema. Brit. 1. Dermatol. 112, 291-297. Bjamason, I., Hayllar, 1., Macpherson, A.J., Russell, AS., 1993c. Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine. Gastroenterology 104, 18321847. Bjarnason, I., Hayllar, 1., Smethurst, P., Price, A.B., Menzies, I.S., Gumpel, M.J., 1992b. Metronidazole reduces inflammation and blood loss in NSAID enteropathy. Gut 33, 1204-1208. Bjarnason, I., Macpherson, A, Sornasundaram, S., Teahon, K., 1993a. Nonsteroidal antiinflammatory drugs and inflammatory bowel disease. Can. 1. Gastroenterol. 7, 160--169. Bjamason, I., Macpherson, A.J.M., Hollander, D., 1995. Intestinal permeability: An overview. Gastroenterology 108, 1566--1581. Bjarnason, I., Macpherson, AJ.S., Somasundaram, S., Teahon, K., 1993b. Non-steroidal anti-inflammatory drugs and Crohn's disease. In: Scholmeric, J., Kruis, W., Goebbell, H., Hohenberger, W., Gross, V. (Eds.), Inflammatory bowel diseases: Pathophysiology as basis of treatment. Falk Symposium No 67. Kluwer Academic Publishers, Lancaster 208-222. Bjarnason, I., Marsh, M.N., Price, A., Levi, AJ., Peters, TJ., 1986. Intestinal permeability in patients with coeliac disease and dermatitis herpetiformis. Gut 26, 1214--1219. Bjamason, I., Maxton, D., Reynolds, A.P., Catt, S., Peters, TJ., Menzies, I.S., 1994. A comparison of 4 markers of intestinal permeability in control subjects and patients with coeliac disease. Scand. J. Gastroenterol. 26, 630-639. Bjamason, I., O'Morain, C., Levi, A.J., Peters, T.J., I 983a. The absorption of 51Cr EDT A in inflammatory bowel disease. Gastroenterology 85, 318-322. Bjarnason, I., Peters, T.J., Veall, N., 1983b. A persistent defect of intestinal permeability in coeliac disease as demonstrated by a 51Cr-labelled EDTA absorption test. Lancet i 323325. Bjamason, I., Smethurst, P., Macpherson, A., Walker, F., McElnay, i.c, Passmore AP., Menzies, I.S., I992a. Glucose and citrate reduce the permeability changes caused by indomethacin in humans. Gastroenterology 102, 1546--1550. Bjarnason, I., Smethurst, P., Menzies, I.S., Peters, TJ., 1991b. The effect of polyacrylic acid polymers (carbopol) on small intestinal function and permeability changes caused by indomethacin. Scand. 1. Gastroenterol. 26, 685-688. Bjamason, I., Ward, K., Peters, TJ., 1984a. The leaky gut of alcoholism: possible route of entry for toxic compounds. Lancet i 179-182. Bjarnason, I., Williams, P., Smethurst, P., Peters, T.J., Levi, A.J., 1986a. The effect of NSAIDs and prostaglandins on the permeability of the human small intestine. Gut 27, 1292-1297. Bjarnason, I., Williams, P., So, A., Zanelli, G., Levi, A.J., Gurnpel, M.J., Peters, TJ., Ansell, B., 1984b. Intestinal permeability and inflammation in rheumatoid arthritis; effects of non-steroidal anti-inflammatory drugs. Lancet ii 1171-1174. Bjarnason, I., Zanelli, G., Smethurst, P., Burke, M., Gumpel, M.J., Price, A.B., Levi, A.1., 1988. Clinico-pathological features of nonsteroidal antiinflammatory drug induced small intestinal structures. Gastroenterology 94, 1070--1074. Bjarnason, I., Zanelli, G., Smith, T., Prouse, P., Williams, P., DeLacey, G., Gumpel, M.J., Levi, A.J., 1987. Nonsteroidal antiinflammatory drug induced intestinal inflammation in humans. Gastroenterology 93, 480-489. Borch, K., Sjostedt, c., Hammestad, U., Soderholm, J.D., Franzen, L., Mardh, S., 1998. Asymptomatic Helicobacter pylori gastritis is associated with increased sucrose permeability. Dig. Dis. Sci. 43, 749-753. Brace, R.A., 1997. Physiology of amniotic fluid regulation. Clin. Obstet. Gyn. 40, 280--289.

Intestinal barrier function

681

Brooks, A.D., Hochwald, S.N., Heslin, MJ., Harrison, L.E., Burt, M., Brennan, M.F., 1999. Intestinal permeability after early postoperative enteral nutrition in patients with upper gastrointestinal malignancy. J. Parent. Enter. Nutr. 23, 75-79. Buchman, A.L., Moukarzel, A.A., Bhuta, S., Belle, M., Ament, M.E., Eckhert, C.D., Hollander, D., Gornbein, J.V., Kopple, J.D., Ijayaroghavan, S.R., 1995. Parenteral nutrition is associated with intestinal morphologic and functional changes in humans. J. Parent. Enter. Nutr. 19,453-460. Budillon, G., Parrilli, G., Pacella, M., Cuomo, R., Menzies, I.S., 1985. Investigation of intestine and liver function in cirrhosis using combined sugar oral loads. J. Hepatol. 1,513-524. Campillo, B., Pernet, P., Bories, P.N., Richardet, J.P., Devanlay, M., Aussel, c., 1999. Intestinal permeability in liver cirrhosis: relationship with severe septic complications. Eur. J. Gastroenterol. Hepatol. II, 755-759. Carefoli, E., 1987. Intra cellular calcium homeostasis. Ann. Rev. Biochem. 56, 395-433. Carratu, R., Secondulfo, M., de Magistris, L., Daniele, B., Pignata, S., D' Agostino, L., Frezza, P., Elmo, M., Silvestro, G., Sasso, F.S., 1998. Assessment of small intestinal damage in patients treated with pelvic radiotherapy. Oncol. Rep. 5, 635--639. Carratu, R., Secondulfo, M., de Magistris, L., Iafusco, D., Urio, A., Carbone, M.G., Pontoni, G., Carteni, M., Prisco, F" 1999. Altered intestinal permeability to mannitol in diabetes mellitus type I. J. Pediat. Gastroenterol. Nutr. 28, 264-269. Case lias, F., Aguade, S., Soriano, B., Accarino, A., Molero, J., Guamer, L., 1986. Intestinal permeability to 99mTc diethylene-tetraaminopentaacetic acid in inflammatory bowel disease. Amer. J. Gastroenterol. 81, 767-770. Catassi, C; Bonucci, A., Coppa, G.V., Carlucci, A., Giorgi, P.L., 1995. Intestinal permeability changes during the first month: effect of natural versus artificial feeding. J. Pediat. Gastroenterol. Nutr. 21, 383-386. Catassi, C; Rossini, M., Ratsch, I.-M., Bearzi, I., Santinelli, A., Castagnani, R., Pisani, E., Coppa, G.V., Giorgi, P.L., 1993. Dose dependent effects of protracted ingestion of small amounts of gliadin in coeliac disease children: a clinical and jejunal morphometric study. Gut 34, 1515-1519. Chadwick, V.S., Phillips, S.F., Hofman, A.F., 1977a. Measurements of intestinal permeability using low molecular weight polyethylene glycols (PEG 400). I. Chemical analysis and biological properties of PEG 400. Gastroenterology 73, 241-246. Chadwick, V.S., Phillips, S.F., Hofman, A.F., 1977b. Measurements of intestinal permeability using low molecular weight polyethylene glycols (PEG 400). II. Application to study of normal and abnormal permeability states in man and animals. Gastroenterology 73, 247-251. Chantler, c., Garnett, E.S., Parsons, V., Veall, N., 1969. Glomerular filtration rate measurement in man by the single injection method using 5ICrEDTA. CHn. Sci. 37, 169-180. Choi, V.M., Coates, J.E., Chooi, J., Thomson, A.B., Russell, A.S., 1995. Small bowel permeability-a variable effect of NSAIDS. Clin. Invest. Med. 18, 357-361. Cobden, I., Dickinson, R.J., Rothwell, J., Axon, A.T.R., 1978. Intestinal permeability assessed by excretion ratios of two molecules: Results in coeliac disease. Brit. Med. J. 2, 1060. Cobden, I., Rothwell, L, Axon, A.T.R., 1980a. Intestinal permeability abd screening tests for coeliac disease. Gut 21,512-518. Cobden, I., Rothwell, L, Axon, A.T.R., Dixon, M.F., Lintott, OJ., Rowell, N.R., 1980b. Small intestinal structure and passive permeability in systemic sclerosis. Gut 21, 293-298. Cooper, B.T., Ukabam, S.D., O'Brien, LA.D., Hara, J.P.O., Corrall, RJ.M., 1987. Intestinal permeability in diabetic diarrhoea. Diabet. Medicine 4, 49-52.

682

1. Bjarnason, A. Cederborg, A. Akvist and S. Smale

Cox, M.A., Iqbal, T.H., Lewis, K.O., Cooper, B.T., 1997. Viewpoints in intestinal permeability. Gastroenterology 112, 669--670. Cox, M.A., Lewis, K.O., Cooper, B.Y., 1998. Sucrosaemia in untreated coeliac disease: a potential screening test. Dig. Dis. Sci. 43, 1096--1101. Cummins, A.G., Penttila, I.A., Labrooy,J.T., Robb, T.A., Davidson, G.P., 1991. Recoveryofthe small intestine in coeliac diseaseonagluten-free diet: changes in intestinal permeability, small bowel morphology and T-cell activity. J. Gastroenterol. Hepatol. 6, 53-57. Cummins, A.G., Thompson, F.M., Butler, R.N., Cassidy, J.C; Gillis, D., Lorenzetti, M., Southcott, E.K., Wilson, P.C., 2001. Improvement in intestinal permeability precedes morphometric recovery of the small intestine in coeliac disease. Clin. Sci. 100, 37Cf-386. D'Eufemia, P., Celli, M., Finocchiaro, R., Pacifico, L., Viozzi, L., Zaccagnini, M., Cardi, E., Giardini, 0., 1996. Abnormal intestinal permeability in children with autism. Acta Paediat. 85, 1076--1079. D'lnca, R., Di Leo, V., Corrao, G., Martines, D., D'Odorico, A., Mestriner, c, Venturi, C., Longo, G., Stumiolo, G.C., 1999. Intestinal permeability test as a predictor of clinical course in Crohn's disease. Amer. J. Gastroenterol. 94, 2956--2960. Dahlqvist, A., 1962. Specificity of human intestinal disaccharidases and implications for hereditary disaccharide intolerance. J. Clin. Invest. 41, 463-470. Davies, K.N., King, D., Billington, D., Barrett, J.A., 1996. Intestinal permeability and orocaecal transit in elderly patients with Parkinson's disease. Postgrad. Med. J. 72, 164-167. Davin, J.C, Forget, P., Mahieu, P.R., 1988. Increased intestinal permeability to (51Cr)EDTA is correlated with IgA immune complex-plasma levels in children with IgA-associated nephropathies. Acta Pediatr. Scand. 77, 118-124. Dawson, DJ., Lobley, RW., Burrows, P.C., Notman, l.A., Mahon, M., Holmes, R., 1988. Changes in jejunal permeability and passive permeation of sugars in intestinal biopsies in coeliac disease and Crohn's disease. Clin. Sci. 74,427-431. de Maar, E.F., Kleibeuker, J.H., Boersma-van, Ek.W, The, T.H., van Son, WJ., 1996. Increased intestinal permeability during cytomegalovirus infection in renal transplant recipients. Transp!. Int. 9, 576--580. Doig, CJ., Sutherland, L.R, Sandham, J.D., Fick, G.H., Verhoef, M., Meddings, J.B., 1998. Increased intestinal permeability is associated with the development of multiple organ dysfunction syndrome in critically ill intensive care unit patients. Amer. J. Respir. Crit. Care Med. 158, 444-451. Dupont, C., Barau, E., Molkhou, P., Raynaud, F., Barbet, J.P., Dehennin, L., 1989. Foodinduced alteration in intestinal permeability in children with cow's milk-sensitive enteropathy and atopic dermatitis. J. Pediat. Gastroenterol. Nutr. 8, 459-465. Ersoz, G., Aydin, A., Erdem, S., Yuksel, D., Akarca, U., Kumanlioglu K., 1999. Intestinal permeability in liver cirrhosis. Eur. J. Gastroenterol. Hepatol. II, 409-412. Fakuda, Y., Samba, H., Okui, M., Tamura, K., Tamida, N., Satomi, M., Shimoyama, T., Hishigami, T., 200 I. Helicobacter pylori increases mucosal permeability of the stomach and small intestine. Digestion 63 (Supp!. I), 93-96. Faith-Magnusson, K., Jansson, G., Stenhammar, L., Sundquist, T., Magnusson, K.E., 1989. Intestinal permeability assessed with different-sized polyethylene glycols in children undergoing small-intestinal biopsy for suspected coeliac disease. Scand. J. Gastroentero!. 24,40-46. Falth-Magnusson, K., Kjellman, N.I.M., Sundquist, T., Magnusson, K.E., 1985. Gastrointestinal permeability in atopic and non-atopic mothers, assessed with different sized polyethylene glycols (PEG 400 and PEG 1000). Clin. Allergy 15, 565-570. Faries, P.L., Simon, RJ., Martella, A.T., Lee, M.J., Machiedo, G.W., 1998. Intestinal permeability correlates with severity of injury in trauma patients. J. Trauma. 44, 1031-1035.

Intestinal barrier function

683

Fleming, S.c., Kynaston, l.A., Laker, M.F., Pearson, AD., Kapernbwa, M.S., Griffin, G.E., 1993. Analysis of multiple sugar probes in urine and plasma by high-performance anionexchange chromatography with pulsed electrochemical detection. Application in the assessment of intestinal permeability inhuman immunedeficiency virus infection. J. Chromatogr. 640, 293-297. Fordtran, J.S., Clodi, P.H., Soergel, K.H., Ingelfinger, F.J., 1962. Sugar absorption tests, with special reference to 3-0-methyl-D-glucose and D-xylose. Ann. Int. Med. 57, 883-891. Forget, P., Sodoyez-Goffaux, F., Zapitelli, A., 1985. Permeability of the small intestine to 51CrEDTA in children with acute gastroenteritis or eczema. J. Pediat. Gastroenterol. Nutr. 4, 393-396. Fotherby, K.J., Wraight, K.J., Neale, G., 1988.51 CrEDTA/ 14C mannitol intestinal permeability test. Clinical use in screening for coeliac disease. Scand. J. Gastroenterol. 23, 171-177. Fradkin, A., Yahav, J., Diver-Haber, A, Zerner, D., Jonas, A., 1996. Colchicine enhances intestinal permeability in patients with familial Mediterranean fever. Eur. J. Clin Pharmacol. 51,241-245. Goldman, A.S., Goldblum, R.M., Schmalstieg, F.C., 1990. Protective properties of human milk. Perinatal nutrition. Part III. In: Walker, W.A., Watkins, J.S. (Eds.), Nutrition in paediatrics. Basic Science and clinical applications 2ed. BC Decker, Hamilton, Canada, 449457. Goldsborough, J., Francis, D.E.M., 1983. Dietary management. In: Coombes, R.A.A (Ed.), Proceedings of the Second Fission's Food Allergy Workshop. The Medicine Publishing Foundation, Oxford, 89-95. Goodgame, R.W., Malaty, H.M., el-Zimai, T.Y., Graham, D.Y., 1997. Decrease in gastric mucosal permeability to sucrose following cure of Helicobacter pylori infection. Helicobacter 2, 44-47. Goto, K., Chew, F., Torun, B., Peerson, J.M., Brown, K.H., 1999. Epidemiology of altered intestinal permeability to lactulose and mannitol in Guatemalan infants. J. Pediat. Gastroenterol. Nutr. 28, 282-290. Gotteland, M., Cruchet Munoz, S., Araya Quezada, M., Espinoza Madariaga, L, Brunser Tesarschu, 0., 1998. Intestinal permeability in the first year of life. The effect of diarrhea. An. Esp. Pediatr. 49, 125--128. Gotteland, M., Cruchet, S., Verbeke, J., 2001. Effect of Lactobacillus ingestion on the gastroduodenal mucosal barrier alteration induced by indomethacin. Aliment. Pharmacol. Ther. 15, 11-l7. Gryboski, J.D., Thayer, W.R., Gabrielson, I.W., Spiro, H.M., 1963. Disacchariduria in gastrointestinal disease. Gastroenterology 45, 633-637. Guarino, A., Tarallo, L., Guandalini, S., Troncone, R., Albano, F., Rubino, A, 1991. Impaired intestinal function in symptomatic HIV infection. J. Pediat. Gastroenterol. Nutr. 12,453-458. Hamilton, I., 1986. Small intestinal permeability. In: Pounder, R.E. (Ed.), Recent advances in Gastroenterology-6. Churchill Livingstone, Edinburgh, 73-91. Hamilton, I., Cobden, I., Axon, A.T.R., 1982. Intestinal permeability in coeliac disease: The response to gluten withdrawal and single dose gluten challange. Gut 23, 202-210. Hamilton, I., Fairris, G.M., Rothwell, J., Cunliffe, W.J., Dixon, M.F., Axon, A.T.R., 1985. Small intestinal permeability in dermatological disease. Quart. J. Med. 56, 559-567. Hamilton, I., Hill, A, Rose, B., Boucher, I.A.D., Forsyth, J.S., 1987. Small intestinal permeability in pediatric clinical practice. J. Pediat. Gastroenterol. Nutr. 6, 697-701. Hayllar, L, Price, A.B., Smith, T., Macpherson, A., Gumpel, M.J., Bjarnason, I., 1994. Nonsteroidal antiinflammatory drug-induced small intestinal inflammation and blood

684

1. Bjarnason, A. Cederborg, A. Akvist and S. Smale

loss: effect of sulphasalazine and other disease modifying drugs. Arthritis Rheum. 37, 1146-1150. Hernandez, G., Velasco, N., Wainstein, C, Castillo, L., Bugedo, G., Maiz, A., Lopez, F., Guzman, S., Vargas, C, 1999. Gut mucosal atrophy after a short enteral fasting period in critically ill patients. J. Crit. Care 14, 73-77. Hill, D.1., Lynch, B.C., 1982. Elemental diet in the management of severe eczema in childhood. Clin. Allergy 12,313-315. Hilsden, R.1., Meddings, lB., Hardin, r. Gall, D.G., Sutherland, L.R., 1999. Intestinal permeability and postheparin plasma diamine oxidase activity in the prediction of Crohn's disease relapse. Inflamm. Bowel. Dis. 5, 85-9\. Hilsden, R.1., Meddings, lB., Sutherland, L.R., 1996. Intestinal permeability changes in response to acetylsalicylic acid in relatives of patients with Crohn's disease. Gastroenterology 110, 1395-1403. Hollander, D., Rickets, D., Boyd, CA.R., 1988. Importance of 'probe' molecular geometry in determining intestinal permeability. Can. J. Gastroenterol. 2 (Suppl. A), 35A-38A. Hollander, D., Vadheim, C., Brettholz, E., Pattersen, G.M., Delahunty, T., Rotter, Ll., 1986. Increased intestinal permeability in patients with Crohn's disease and their relatives. Ann. Int. Med. 105, 883-885. Hong, R., Amman, Al, 1972. Selective absence ofIgA: Autoimmune phenomena and autoimmune diseases. Human. Pathol. 69,451-496. Howden, C.W., Robertson, c., Duncan, A., Morris, A.1., Russell, R.\., 1991. Comparison of different measurements of intestinal permeability in inflammatory bowel disease. Amer. l Gastroenterol. 86, 1445-1449. Huber, T., Ruchti, c., Halter, F., 1992. Nonsteroidal antiinflammatory drug-induced colonic structures: a case report. Gastroenterology 100, 1119-1122. Iqbal, T.H., Lewis, K.O., Cooper, B.T., 1993. Diffusion of polyethylene glycol-400 across lipid barriers in vitro. Clin. Sci. 85, 111-115. Iqbal, T.H., Lewis, K.O., Gearty, lC., Cooper, B.T., 1996. Small intestinal permeability to mannitol and lactulose in the three ethnic groups resident in west Birmingham. Gut 39, 199-203. Iwata, H., Matsushita, M., Nishikimi, N., Sakurai, T., Nimura, Y., 2000. Intestinal permeability is increased in patients with intermittent claudication. J. Vasco Surg. 31, 1003-1007. Jacob, M., 1999. Mechanism of nonsteroidal anti-inflammatory drug-induced damage in the small bowel. PhD Thesis, University of London. Jalonen, T., 199\. Identical intestinal permeability changes in children with different clinical manifestations of cow's milk allergy. J. Allergy Clin. Immunol. 88, 737-742. Jasin, H.E., 1983. Bacterial lipopolysaccharides induce in vitro degradation of cartilate matrix through chondrocyte activation. J. Clin. Invest. 72,2014-2019. Jenkins, A.P., Menzies, I.S., Nukajam, W.S., Creamer, B., 1994. The effect of ingested lactulose on absorption ofL-rhamnose, D-xylose and 3-O-methyl-D-glucose in subjects with ileostomies. Scand. J. Gastroenterol. 29, 820-825. Jenkins, AP., Menzies, I.S., Nukajam, W.S., Grellier, L., Mathan, V.I., Creamer, B., 1989. Geographical variation in intestinal permeability. Gut 30, AI509-151O. Jenkins, AP., Nukajam, W.S., Menzies, I.S., Creamer, B., 1992. Simultaneous administration of lactulose and 51Cr-ethylenediaminetetraacetic acid. A test to distinguish colonic from small-intestinal permeability change. Scand. J. Gastroenterol. 27, 769-773. Jenkins, A.P., Trew, D.R., Nukajam, W.S., Crump, B.1., Menzies, I.S., Creamer, B., 199\. Do nonsteroidal anti-inflammatory drugs increase colonic permeability? Gut 32, 66-69. Johansen, K., Stintzing, G., Magnusson, K.E., Sundquist, T., Jalil, F., Murtaza. A., Khan, S.R., Lindblad, B.S., Mollby, R., Orusild, E., Svensson, L., 1989. Intestinal permeability

Intestinal barrier function

685

assessed with polyethylene glycols in children with diarrhoea due to rotavirus and common bacterial pathogens in a developing country. J Pediat. Gastroenterol. Nutr. 9, 307-313. Jorgensen, J., Ranlov, PJ., Bjerrum, PJ., Diemer, H., Bisgaard, K., Elsborg, L., 2001. Is an increased intestinal permeability a valid predictor of relapse in Crohn's disease? Scand. J. Gastroenterol. 36, 521-527. Juby, L.D., Rothwell, J., Axon, A.T.R., 1989a. Cellobiose/mannitol sugar test: A sensitive tubeless test for coeliac disease. Results on 1010 unselected patients. Gut 30, 476-480. Juby, L.D., Rothwell, J., Axon, A.T.R., 1989b. Lactulose/rnannitol test. An ideal screening test for coeliac disease. Gastroenterology 96, 79-85. Juto, P., Engberg, S., Winberg, J., 1978. Treatment of infantile atopic dermatitis with a strict elimination diet. Clin. Allergy 8, 493-500. Katz, K.D., Hollander, D., Vadheim, C.M., Mceleree, c., Dalahunty, T., Dadufalza, V.D., Krugliak, P., Rotter, J.I., 1989. Intestinal permeability in patients with Crohn's disease and their healthy relatives. Gastroenterology 97, 927-931. Kawabata, H., Meddings, J.B., Uchida, Y, Matsuda, K., Sasahara, K., 1998. Sucrose penneability as a means of detecting disease of the upper gastrointestinal tract. Amer. J. Gastroenterol. 13, 1002-1006. Keating, J., Bjamason, 1., Somasundaram, S., Macpherson, A., Francis, N., Price, A.B., Sharpstone, D., Smithson, J., Menzies, LS., Gazzard, LS., 1995. Intestinal absorptive capacity, intestinal permeability and jejunal histology in HfV infected patients and their relation to diarrhoea. Gut 37, 623-629. Keshavarzian, A., Holmes, E.W., Patel, M., Iber, F., Fields, J.Z., Pethkar, S., 1999. Leaky gut in alcoholic cirrhosis: a possible mechanism for alcoholic-induced liver damage. Amer. J. Gastroenterol. 94, 200-207. Kiziltas, S., Imerynz, N., Gurcon, T., Siva, A, Saip, S., Dumankow, AL., Kalaya, C; Ulusoy, N.B., 1998. Corticosteroid therapy augments gastroduodenal permeability to sucrose. Amer. l Gastroenterol. 93, 2420-2425. Kohout, P., Cerman, J., Bratova, M., Zadak, Z., 1999. Small bowel permeability in patients with cytostatic therapy. Nutrition 15, 546-549. Kokkonen, J., Simila, S., Herva, R., 1980. Gastrointestinal findings in atopic children. Eur. J. Pediat. 134,249-252. Kompan, L., Kremzar, B., Gadzijev, E., Prosek, M., 1999. Effects of early enteral nutrition on intestinal permeability and the development of multiple organ failure after multiple injury. Intens. Care Med. 25, 157-161. Krugilak, P., Hollander, D., Ma, T.Y, Tran, D., Dadufalza, V.D., Katz, K.D., Ce, K., 1989. Mechanism of polyethylene glycol 400 permeability of perfused rat intestine. Gastroenterology 97,1164-1170. Laker, M.F., Bull, HJ., Menzies, LS., 1982. Evaluation of mannitol for use as a probe marker of gastrointestinal permeability in man. Eur. J. Clin. Invest. 12, 485-491. Laker, M.F., Menzies, LS., 1977. Increase in human intestinal permeability following ingestion of hypertonic solutions. J. Physiol. (London) 265, 881-894. Laker, M.F, Mount, IN., 1980. Mannitol estimation in biological fluids by gas liquid chromatography of trimethylsilyl derivatives. Clin. Chern. 26, 441-443. Lang, J., Price, A.B., Levi, AJ., Burk, M., Gumpel, J.M., Bjarnason, 1., 1988. Diaphragm disease: the pathology of non-steroidal anti-inflammatory drug induced small intestinal structures. J. Clin. Path. 41, 516-526. Langkamp-Henken, B., Donovan, T.B., Pate, L.M., Maull, C.D., Kudsk, K.A, 1995. Increased intestinal permeability following blunt and penetrating trauma. Crit. Care Med. 23, 660-664. Langman, MJ.S., 1989. Epidemiological evidence on the association between peptic ulceration and antiinflammatory drugs. Gastroenterology 96, 640-646.

686

I. Bjarnason, A. Cederborg, A. Akvist and S. Smale

Langman, M.1.S., Morgan, L., Worrall, A., 1985. Use of anti-inflammatory drugs by patients with small or large bowel perforation and haemorrhage. Brit. Med. J. 290, 347-349. Langman, M.1.S., Weil, J., Wainwright, P., Lawson, D.H., Rawlins, M.D., Logan, R.F.A., Murphy, M., Vessey, M.P., Colin-Jones, D.G., 1994. Risk of bleeding peptic ulcers associated with individual non-steroidal anti-inflammatory drugs, Lancet 343, 1075-1078. Leclercq-Foucart, J., Forget, P., Sodoyez-Gouffaux, F., Zappitelli, A., 1986. Intestinal permeability to 51CrEDT A in children with cystic fibrosis. 1. Pediat. Gastroenterol. Nutr. 5, 384--387. Leclercq-Foucart, J., Forget, P., Van Cutsem, 1.L., 1987. Lactulose-rhamnose intestinal permeability in children with cystic fibrosis. J. Pediat. Gastroenterol. Nutr. 6, 66-70. Leece, 1.G., Morgan, D.A., 1962. Effects of dietary regimen on cessation of intestinal absorption of large molecules (closure) in the neonatal pig and lamb. 1. Nutr. 78, 263268. Leirisalo-Repo, H., Repo, H., 1992. Gut and spondyloarthropathies. Rheum. Clin N. Amer. 18,23-35. Leirisalo-Repo, H., Turunen, U., Stenman, S., Helenius, P., Seppala, K., 1994. High frequency of silent inflammatory bowel disease in spondylarthropathy. Arthritis Rheum. 37,23-31. Lessof, M.H., Wraith, D.G., Merrett, 1., Buisseret, P.O., 1980. Food allergy and intolerance in 100 patients- Local and systemic effects. Quart. 1. Med. 195, 259-27 I. Levi, S., DeLacey, G., Price, A.B., Gumpel, M.1., Levi, A.1., Bjarnason, 1., 1990. 'Diaphragm like' structures of the small bowel in patients treated with non-steroidal antiinflammatory drugs. Brit. .I. Radiol. 63, 186-189. Lim, S.G., Menzies, 1.S., Lee, c.A., Johnson, M.A., Pounder, R.E., 1993. Intestinal permeability and function in patients infected with human immunodeficiency virus. Scand. 1. Gastroenterol. 28, 573-580. Lima, A.A., Silva, T.M., Gifoni, A.M., Barrett, L.J., McAuliffe, l.T., Bao, Y., Fox, .I.W., Fedorko, D.P., Guerrant, R.L., 1997. Mucosal injury and disruption of intestinal barrier function in HIV-infected individuals with and without diarrhoea and cryptosporiasis in northeast Brazil. Amer. 1. Gastroenterol. 92, 1861-1866. Liverani, E., Silveri, N.G., Gasbarrini, G., Mingrone, G., 2000. Intestinal permeability increases with the severity of abdominal trauma: a comparison between gas liquid chromatographic and enzymatic method. Hepatogastroenterology 47, 1037-1041. Lobley, R.W., Burrows, P.c., Warwick, R., Dawson, 0.1., Holmes, R., 1990. Simultaneous assessment of intestinal permeability and lactose tolerance with orally administered raffinose, lactose and L-arabinose. Clin. Sci. 79, 175-183. Lokken, P., 1970. Studies on 51CrEDTA and its evaluation as a reference substance in gastrointestinal disease. Norwegian Monographs in Medical Science. Universforlaget, Oslo. Ma, T.Y., Hollander, D., Krugliak, P., Katz, K., 1990. PEG 400, a hydrophyllic molecular probe for measuring intestinal permeability. Gastroenterology 98, 39-46. Magnusson, K.E., Sundquist, T., Sjodahl, R., Tageson, C; 1983. Altered intestinal permeability to low-molecular-weight polyethylene glycols (PEG 400) in patients with Crohn's disease. Acta Chir. Scand. 149, 323-327. Magnusson, M., Magnusson, K.E., Sundqvist, T., Denneberg, T., 1990. Urinary excretion of differently sized polyethylene glycols after intravenous administration in uremic and control rats: effects of low- and high-protein diets. Nephron 56, 312-6. Magnusson, M., Magnusson, K.E., Sundqvist, T., Denneberg, T., 1992. Reduced intestinal permeability measured by differently sized polyethylene glycols in acute uremic rats. Nephron 60,193--198.

Intestinal barrier function

687

Mahendra, P., Bedlow, AJ., Ager, S., Ancliff, PJ., Wraight, E.P., Marcus, R.E., 1994. Technetium (99mTc)-labelled white cell scanning, 5ICr-EDTA and 14C-mannitol-Iabelled intestinal permeability studies: non-invasive methods of diagnosing acute intestinal graft-versus-host disease. Bone Marrow. Transplant. 13, 835-837. Mahmud, T., Raft, S.S., Scott, D.L., Wrigglesworth, lM., Bjarnason, L, 1996a. Nonsteroidal antiinflammatory drugs and uncoupling of mitochondrial oxidative phosphorylation. Arthritis Rheum. 39, 1998--2003. Mahrnud, T., Scott, D., Bjarnason, l., I996b. A unifying hypothesis for the mechanism of NSAID related gastrointestinal toxicity. Ann. Rheum. Dis. 55,211-213. Maxton, D.G., Bjarnason, L, Reynolds, A.P., Catt, S.D., Peters, T.l, Menzies, r.S., 1986. Lactulose, 51CrEDT A, L-rhamnose and polyethylene glycol 400 as probe markers for in vivo assessment of human intestinal permeability. Clin. Sci. 71, 71-80. Maxton, D.G., Catt, S.D., Menzies, I.S., 1989. Intestinal disaccharidases assessed in congenital asucrasia by differential urinary disaccharide excretion. Dig. Dis. Sci. 34, 129131. Maxton, D.G., Catt, S.D., Menzies, r.S., 1990. Combined assessment of intestinal disaccharidases in congenital asucrasia by differential urinary disaccharide excretion. J. Clin. Pathol. 43, 406-9. Maxton, D.G., Menzies, I.Sc, Slavin, B., Thompson, R.P.H., 1989. Small intestinal function during enteral feeding and starvation in man. Clin. Sci. 77, 401-406. May, G.R., Sutherland, L.R., Meddings, lB., 1993. Is small intestinal permeability really increased in relatives of patients with Crohn's disease? Gastroenterology 104, 16271632. McCune, K.H., Allen, D., Cranley, B., 1992. Small bowel diaphragm disease-Strictures associated with non-steroidal anti-inflammatory drugs. Ulster Med. 1 61, 182-184. Meddings, lB., Sutherland, L.R., Byles, Nil., Wallace, Ll..; 1993. Sucrose: a novel permeability marker for gastroduodenal disease. Gastroenterology 104, 1619-1626. Menzies, l.Si, 1984. Transmucosal passage of inert molecules in health and disease. In: Skadhauge, E., Heintze, K. (Eds.), Intestinal absorption and secretion. Lancaster, Falk Symposium 36. MTP Press, 527--543. Menzies, r.S., 1974. Absorption of intact oligosaccharide in health and disease. Biochem. Soc. Transact. 2, 1042-1047. Menzies, I.S., Crane, R.C., 1998. Quantitative estimation of sugars by thin-layer chromatography and scanning densitometry. Assessing intestinal absorptive capacity and permeability in vivo. In: Preedy, V.R, Watson, R.R. (Eds.), Methods in disease: Investigating the gastrointestinal tract. Oxford University Press, Oxford. 53-63. Menzies, I.,S., Jenkins, A.P., Heduan, E., Catt, S.D., Segal, M.B., Creamer, B., 1990. The effect of poorly absorbed solute on intestinal absorption. Scand. 1 Gastroentero!' 25, 1257-1264. Menzies, I.S., Pounder, R., Heyer, S., Laker, M.F., Bull, i., Wheeler, P.G., Creamer, B., 1979. Abnormal intestinal permeability to sugars in villus atrophy. Lancet ii, 11071109. Menzies, l.S; Zuckerman, MJ., Nukajam, W.S., Somasundaram, S., Murphy, B., Jenkins, A.P., Crane, R.S., Gregory, G.G., 1999. Geography of intestinal permeability and absorption. Gut 44, 483-489. Morris, A.D., Holt, S.D., Silvoso, G.R., Hewitt, r, Tatum, W., Grandione, J., 1991a. The effect of anti-inflammatory drug administration in patients with rheumatoid arthritis. An endoscopic assessment. Scand. 1 Gastroentero!. 16 (Supp!. 67), 131-135. Morris, A.J., Lee, F.D., Capell, H.A., McKenzie, IF., Sturrock, R.D., 1996. Jejunallesins in ankylosing spondilitis are due to nonsteroidal anti-inflammatroy drug therapy. Arthritis Rheum. (Suppl, 9), S205.

688

I. Bjarnason, A. Cederborg, A. Akvist and S. Smale

Morris, AJ., Madhok, R., Sturrock, R.D., Capell, H.A, Mackenzie, J.F., 1991b. Enteroscopic diagnosis of small bowel ulceration in patients receiving non-steroidal antiinflammatory drugs. Lancet 337, 520. Morris, AJ., Wasson, L.A, Mackenzie, IF., 1992. Small bowel enteroscopy in undiagnosed gastrointestinal blood loss. Gut 33, 887~889. Morris, B., Morris, R., 1978. Macromolecular uptake and transport by the small intestine by the small intestine of suckling rat. In: Hemmings, W.A. (Ed.), Antigen absorption by the gut. Lancaster MRP Press, 23-30. Munkholm, P., Langholz, E., Hollander, D., Thornberg, K., Orholm, M., Katz, K.D., Binder, Y., 1994. Intestinal permeability in patients with Crohn's disease and ulcerative colitis and their first degree relatives. Gut 35, 68-72. Murphy, B., Taylor, C., Crane, C., Kizza, A., Bjarnason, I., 1999. A comparison between intestinal function in HIY seropositive patients in Kampala and London. Scand. J. Gastroenterol. 34, 491---495. Newton, lA., Maxton, D.G., Bjarnason, I., Reynolds, AP., Menzies, I.S., 1984. Intestinal permeability in atopic eczema. Clin. Sci. 67, MP. Noone, C., Menzies, I.S., Banatvala, lE., Scopes, J.W., 1986. Intestinal permeability and lactose hydrolysis in human rotaviral gastroenteritis assessed simultaneously by noninvasive differential sugar permeation. Em. J. Clin. Invest. 16, 217~225. Northrop-Clewes, C.A., Lunn, P.G., Downes, R.M., 1997. Lactose maldigestion in breastfeeding Gambian infants. J. Pediat. Gastroenterol. Nutr. 24, 257-263. O'Morain, c., Abelon, A.C., Chervli, L.R., Fleischner, G.M., Das, K.M., 1986. 51CrEDTA a useful test in the assessement of inflammatory bowel disease. J. Lab. Clin. Med. 108, 430---435. Obinna, F.C., Cook, G., Beale, T., Dave, S., Cunningham, D., Fleming, S.C., Claydon, E., Harris, J.W., Kapembwa, M.S., 1995. Comparative assessment of small intestinal and colonic permeability in HlY-infected homosexual men. AIDS 9, 1009-1016. Oman, H., Akerblom, E., Richter, W., Johansson, S.G.O., 1992. Chemical and physiological properties of polysucrose, a new marker of intestinal permeability to macromolecules. Int. Arch. Allergy Immunol. 98, 220-226. Oman, H., Blomquist, L., Henriksson, A.E.K., Johansson, S.G.O., 1995. Comparison of polysucrose 15000,51 Cr -labelled ethylenediaminotetraacetic acid, and 14C-mannitol as markers of intestinal permeability in man. Scand. J. Gastroenterol. 30, 1172-1177. Oman, H., Henriksson, A.E., Johansson, S.G., Blomquist, L., 1996. Detection of naproxeninduced intestinal permeability change may be facilitated by adding a standardised meal but not by forming marker ratios. Scand. J. Gastroenterol. 31, 1182-1188. Paganelli, R., Fagiolo, U., Cancian, M., Sturniolo, G.C., Scala, E., D'Offizi, G.P., 1990. Intestinal permeability in irritable bowel syndrome. Effect of diet and sodium chromoglycate administration. Ann. Allergy 64, 377-380. Pape, H.C., Dwenger, A., Regel, G., Auf'm'Kolck, M., Gollub, F., Wisner, D., Sturm, lA., Tseherne, H., 1994. Increased gut permeability after multiple trauma. Brit. J. Surg. 81, 850-852. Parlesak, A., Schafer, c., Schutz, T., Bode, J.e., Bode, C., 2000. Increased intestinal permeability to macromolecules and endotoxemia in patients with chronic alcohol abuse in different stages of alcohol-induced liver disease. J. Hepatol. 32, 742-747. Parrilli, G., Iaffaioli, R.Y., Martorano, M., Cuomo, R., Tafuto, S., Zampino, M.G., Budillon, G., Bianco, A.R., 1989. Effects of anthracycline therapy on intestinal absorption in patients with advanced breast cancer. Cancer. Res. 49, 3689-3691. Pearson, A.D.J., Craft, A.W., Pledger, lY., Eastham, E.l, Laker, M.F., Pearson, C.S., 1984. Small bowel function in acute lymphoblastic leukemia. Arch. Dis. Child 59, 460---465.

Intestinal barrier function

689

Peeters, M., Geypens, B., Claus, D., Nevens, H., Ghoos, Y., Verbeke, G., Baert, F., Vermiere, S., Vlietinck, R., Rutgeers, P., 1997. Clustering of increased intestinal permeability in families with Crohn's disease. Gastroenterology 113, 802-807. Pernet, P., Aussel, C, Le Boucher, J., Giboudeau, 1., Cynober, L., Coudray-Lucas, C., 1998. Standardization of the lactulose-mannitol test in rats: application to bum injury. Eur. Surg. Res. 30, 69-74. Pernet, P., Vittecoq, D., Kodjo, A., Randrianarisolo, M.-H., Dumitrescu, L., Blondon, H., Bergmann, J.-F., Giboudeau, J., Aussel, C., 1999. Intestinal absorption and permeability in human immunodeficiency virus-infected patients. Scand. J. Gastroenterol. 34, 29-34. Picco, P., Gattorno, M., Marchese, N., Vignola, S., Sormani, M.P., Barabino, A., Buoncompagni, A., 2000. Increased gut permeability in juvenile chronic arthritides. A multivariate analysis of the diagnostic parameters. Clin. Exp. Rheumatol. 18,773-778. Pike, M.G., Heddle, R.1., Boulton, P., Turner, M.W., Atherton, 0.1., 1986. Increased intestinal permeability in atopic eczema. J. Invest. Dermatol. 86, 101-104. Pike, M.G., Riches, P., Atherton, 0.1., 1989. Fecal ai-Antitrypsin concentration and gastrointestinal permeability to oligosaccharides in atopic dermatitis. Pediat. Dermatol. 6, 10-12. Pledger, 1.V., Pearson, A.D.l, Craft, A.W., Laker, M.F., Eastham, E.1., 1988. Intestinal permeability during chemotherapy for childhood tumors. Eur. J. Pediat. 147, 123-127. Qvist, H., Somasundaram S., Macpherson, A., Menzies, I.S., Giercksky, K., Bjarnason, 1., 1994. The effect of pelvic radiation on small and large intestinal absorption and permeability in man. Gastroenterology 106, A430. Rabassa, A.A., Goodgame, R., Sutton, F.M., Ou, C.N., Rognerud, C, Graham, D.Y., 1996. Effect of aspirin and Helicobacter pylori on the gastroduodenal mucosal permeability to sucrose. Gut 39, 159-163. Raj, S.M., Sein, K.T., Anuar, A,K., Mustaffa, B.E., 1996. Effect of intestinal helminthiasis on intestinal permeability of early primary schoolchildren. Trans. R. Soc. Trop. Med. Hyg. 90, 666-669. Ramage, 1,K., Stanisz, A., Scicchitano, R., Hunt, R.H., Perdue, M.H., 1988. Effects ofimmunologic reactions on rat intestinal epithelium. Correlation of increased intestinal permeability to chromium 51-labelled ethylenediaminetetraacetic acid and ovalbumin during acute inflammation and anaphylaxis. Gastroenterology 94, 1368-1375. Rask-Madsen, J., Schwartz, M., 1979. Absorption of 51CrEDTA in ulcerative colitis following rectal instillation. Scand. J. Gastroenterol. 5, 361-368. Resnick, R.H., Royal, H., Marshall, W., Barron, R., Werth, T., 1990. Intestinal permeability in gastrointestinal disorders. Dig. Dis. Sci. 35. 205-211. Riordan, S.M., Mciver, C.1., Thomas, D.H., Duncombe, V.M., Bolin, T.D., Thomas, M.C., 1997. Luminal bacteria and small-intestinal permeability. Scand. J. Gastroenterol. 32, 556-563. Roberton, D.M., Paganelli, R., Dinwiddil, R., Levinsky, R.1., 1982. Milk antigen in the preterm and term neonate. Arch. Dis. Child 57, 369-372. Rodrigues, L.A.G., lick, H., 1994. Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet 343, 769772. Romiti, A., Merli, M., Martorano, M., Pari IIi, G., Martino, F., Riggio, 0., Trucelli, A., Copocaccia, L., Budillion, G., 1990. Malabsorption and nutritional abnormalities in patients with liver cirrhosis. Ital. J. Gastroenterol. 22, 118-123. Ryan, A.1., Chang, R.T., Gisolfi, C.V., 1996. Gastrointestinal permeability following aspirin intake and prolonged running. Med. Sci. Sports Exerc. 28, 698-705. Saltzman, J.,R., Kowdley, K,V., Perrone, G., Russell, R.M., 1995. Changes in small-intestine permeability with aging. J. Amer. Geriatr. Soc. 43, 160-164.

690

l. Bjarnason, A. Cederborg, A. Akvist and S. Smale

Sanderson, I.R., Boulton, P., Menzies, I.S., Walker-Smith, lA., 1987. Improvement of abnormal lactulose/rhamnose permeability in active Crohn's disease of the small bowel by an elemental diet. Gut 28, 1073-1076. Santini, R., Perez-Santiago, E., Martinez-De-Jesus, J., Butterworth, e.E., 1957. Evidence of increased intestinal absorption of molecular sucrose in sprue. Amer. J. Dig. Dis. 2, 663668. Scadding, C; Bjamason, I., Brostoff, L, Levi, A.J., Peters, T.J., 1989. Intestinal permeability to 51Cr-labelled ethylenediaminetetraacetate in food-intolerant subjects. Digestion 42, 104-109. Scarpignatio, C., Bjarnason, 1., Bretagne, l-F, de Pouvourville, G., Garcia Rodriguez, L.A., Goldstein, lL., Muller, P., Simon, B., 1999. Towards a GI safer antiinflammatory therapy. Gastroenterol. Int. 12, 180-215. Schrander, r.r.r. Unsalan-Hooyen, R.W.M., Forest, P.P., Jansen, r. 1990. [51Cr]EDTA intestinal permeability in children with cow's milk intolerance. J. Pediat. Gastroenterol. Nutr. 10, 189--192. Selby, P.J., Lopes, N., Mundy, L, Crofts, M., Millar, J.L, McElwain, T.J., 1987. Cyclophosphomide priming reduces intestinal damage in man following high dose melphalan chemotherapy. Brit. J. Cancer. 55, 531-533. Serrander, R., Magnusson, K.E., Kihlstrom, E., Sundquist, T., 1989. Acute Yersinia infection in man increases intestinal permeability for low-molecular weight polyethylene glycols (PEG 400). Scand. J. Infect. Dis. 18,409--413. Serrander, R., Magnusson, K.E., Sundquist, T., 1984. Acute infection with giardia lamblia and rotavirus decrease intestinal permeability to low molecular weight polyethylene glycols (PEG 400). Scand. J. Infect. Dis. 16,339--344. Shah, A.A., Thjodleifsson, B., Murray, F.E., Sigthorsson, G., Oddson, E., Gudjonsson, H., Price, A.B., Fitzgerald, D.J., Bjarnason, 1., 2001. Selective inhibition of COX-2 in humans is associated with less gastrointestinal injury: a comparison of nimesulide and naproxen. Gut 48, 339-346. Shulman, R.J., Schanler, R.J., Lau, C., Heitkemper, M., Ou, e.N., Smith, E.O., 1998. Early feeding, antenatal glucocorticoids, and human milk decrease intestinal permeability in preterm infants. Pediat. Res. 44, 19--23. Sigthorsson, G., Crane, R., Simon, T., Hoover, M., Quan, H., Bolognese, L, Bjarnason, I., 2000. COX-2 inhibition with rofecoxib does not increase intestinal permeability in healthy subjects: a double blind crossover study comparing rofecoxib with placebo and indomethacin. Gut 47, 527-532. Sigthorsson, G., Jacob, M., Wrigglesworth, lM., Somasundaram, S., Tavares, I., Foster, R., Roseth, A., Raft, S., Mahmud, T., Simpson, R., Bjarnason, I., 1998b. A comparison of indomethacin and nimesulide, a selective cyclooxygenase-2 inhibitor, on key pathophysiological steps in the pathogenesis of nsaid enteropathy in the rat. Scand. J. Gastroenterol. 33, 728-735. Sigthorsson, G., TibbIe, r., Hayllar, i. Menzies, I., Macpherson, A., Moots, R., Scott, D., G.M.J., Bjarnason, I., 1998a. Intestinal permeability and inflammation in patients on NSAIDs. Gut 43, 506--511. Smale, S., Natt, R.S., Orchard, T.R., Russell, A.S., Bjamason, I., 200 I. Inflammatory disease and spondylarthropathy. Arthritis Rheum (in press). Smecuol, E., Bai, J.e., Vazques, H., Kogan, Z., Cabanne, A., Niveloni, S., Pedreira, S., Boerr, L., Maurino, E., Meddings, lB., 1997. Gastrointestinal permeability in coeliac disease. Gastroenterology 112, 1129--1136. Smethurst, P., Menzies, I.S., Levi, A.l, Bjarnason, 1., 1988. Is alcohol directly toxic to the small bowel mucosa? Clin. Sci. 75, 50-51 P.

Intestinal barrier function

691

Smetonika, R.D., Lambert, O.P., Murray, R., Eddy, D., Hom, M., Giosolfi, C.V., 1999. Intestinal permeability in runners in the 1996 Chicago marathon. lnt. J, Sport. Nutr. 9, 426-433. Soderholm, lD., Olaison, G., Lindberg, E., Hannestad, U., Vindels, A, Tysk, C., Janerot, G., Sjodahl, R.I., 1999. Different intestinal permeability patterns in relatives and spouses of patients with Crohn's disease: an inherited defect in mucosal defence? Gut 44,96-100. Soderholm, J.D., Oman, H., Blomquist, L., Veen, L, Lindmark, T., Olaison, G., 1998. Reversible increase in tight junction permeability to macromolecules in rat ileal mucosa in vitro by sodium caprate, a constituent of milk fat. Dig. Dis. Sci. 43, 1547-1552. Somasundaram, S., Hayllar, J., Rafi, S., Wrigglesworth, L, Macpherson, A., Bjarnason, I., 1995. The biochemical basis of NSAID-induced damage to the gastrointestinal tract: A review and a hypothesis. Scand. J. Gastroenterol. 30, 289--299. Somasundaram, S., Rafi, S., Hayllar, L, Sigthorsson, G., Jacob, M., Price, AB., Macpherson A., Mahrnod, T., Scott, D., Wrigglesworth, lM., Bjamason, I., 1997. Mitochondrial damage: A possible mechanism of the topical phase of NSAID-induced injury to the rat intestine. Gut 41,344-353. Somasundaram, S., Sigthorsson, G., Price, A.B., Tavares, LA, Rafi, S., Mahmud, T., Roseth, A., Foster, R., Macpherson, S., Wrigglesworth, lM., Bjarnason, I., 2000. The relative importance of inhibition of cyclooxygenase and uncoupling of oxidative phosphorylation in the gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs. Alim. Pharm. Therap. 14, 639--650. Stenharnmar, L., Faith-Magnusson, K., Jansson, G., Magnusson, K.E., Sundqvist, T., 1989. Intestinal permeability to inert sugars and different-sized polyethyleneglycols in children with celiac disease. J. Pediat. Gastroenterol. Nutr. 9, 281-289. Stintzing, G., Johansen, K., Magnusson, K.E., Svensson, L., Sundquist, T., 1986. Intestinal permeability in small children during and after rotavirus diarrhoea assessed with different-sized polyethylene glycols (PEG 400 and PEG 1000). Acta Pediat. Scand. 75, 1005-1009. Stott, G.H., Marx, D.B., Menefee, B.E., Nightengale, G.T., 1979. Colostra immunoglobulin transfer in calves. I. Period of absorption. J. Diary Sci. 62, 1632-1638. Sullivan, P.B., Lunn, P.G., Northrop, C.C., Crowe, P.T., Marsh, M.N., Neale, G., 1992. Persistent diarrhea and malnutrition-the impact of treatment on small bowel structure and permeability. J. Pediat, Gastroenterol. Nutr. 14,208--215. Sundquist, T., Magnusson, K.E., Larsson, L., Tageson, C., Backman, L., Nordenvall, B. 1984. Reduced intestinal permeability to low-molecular-weight polyethylene glycols (PEG400) in patients with jejunoileal bypass. Acta Chir Scand. 150, 567-571. Sundquist, T., Magnusson, K.E., Sjodahl, R., Stjernstrom, I., Tageson, C, 1980. Passage of molecules through the wall of the gastrointestinal tract. II. Application of low-molecular weight polyethyleneglycol and a deterministic mathematical model for determining intestinal permeability in man. Gut 21, 208-214. Sundqvist, T., Tageson, c., Magnusson, K.E., 1981. Simulation of a multi compartment model for the intestinal permeability to low-molecular-weight probes (polyethylene glycol 400). Mathemat. Biosci. 56, 287-309. Sutherland, L.R., Verhoef, M., Wallace, lL., Rosendaahl, G.V., Crutcher, R., Meddings, lB., 1994. A simple, non-invasive marker of gastric damage: sucrose permeability. Lancet 343, 998-1000. Taylor, C., Hodgson, K., Sharpstone, D., Sigthorsson, G., Coutts, M.I., Sherwood, R., Menzies, l.S; Gazzard, B., Bjamason, I., 2000. The prevalence and severity of intestinal disaccharidase deficiency in HIV-infected subjects. Scand. J. Gastroenterol. 35, 599--606.

692

1. Bjarnason, A. Cederborg, A. Akvist and S. Smale

Teahon, K., Smethurst, P., Levi, A.1., Bjamason, 1., 1991. The effect of elemental diet on intestinal permeability and inflammation in Crohn's disease. Gastroenterology 101, 84-89. Teahon, K., Smethurst, P., Levi, A.1., Menzies, 1.S., Bjamason, I., 1992. Intestinal permeability in patients with Crohn's disease and their first degree relatives. Gut 33, 320-323. Teahon, K., Smethurst, P., Macpherson, A.1., Levi, A.l, Menzies, 1.S., Bjamason, 1., 1993. Intestinal permeability in Crohn's disease and its relation to disease activity and relapse following treatment with elemental diet. Eur. 1 Gastroenterol. Hepatol. 5, 79-84. Teahon, K., Somasundaram, S., Smith, T., Menzies, I., Bjarnason, 1., 1996. Assessing the site of increased intestinal permeability in coeliac and inflammatory bowel disease. Gut 38, 864-869. Teahon, K., Webster, A.D., Price, A.B., Bjarnason, I., 1994. Studies of gastrointestinal structure and function in patients with primary hypogammaglobulinaemia. Gut 35, 12441249. Teichberg, S., Isolauri, E., Wapnir, R.A., Roberts, B., Lifshitz, F., 1990. Development of the neonatal rat small intestinal barrier to nonspecific macromolecular absorption: effect of early weaning to artificial diets. Pediat. Res. 28, 31-37. Tepper, R.E., Simon. D., Brandt, L.l, Nutovits, R., Lee, M.1., 1994. Intestinal permeability in patients with the human immunodeficiency virus. Amer. 1 Gastroenterol. 89, 878-882. Tibbie, 1, Sigthorsson, G., Fagerhol, M., Bjarnason, 1., 2000. Surrogate markers of intestinal inflammation are predictive for relapse in patients with inflammatory bowel disease. Gastroenterology 119, 15-22. Tibbie, J., Sigthorsson, G., Foster, R., Scott, D., Roseth, A., Bjarnason, 1., 1999. Faecal calprotectin: A simple method for the diagnosis of NSAID-induced enteropathy. Gut 45, 362-366. Travis, S., Menzies, I.S., 1992. Intestinal permeability: functional assessment and significance. Clin. Sci. 82, 471-488. Uil, 11, van Elburg, R.M., Janssens, P.M., Mulder, C.l, Heymans, H.S., 2001. Sensitivity of hyperosmolar or low -osmolar test solution for sugar absorption in recognising small intestinal mucosal damage in coeliac disease. Dig. Liver. Dis. 32, 195-200. Ukabam, S.O., Clamp, lR., Cooper, B.T., 1982. Abnormal intestinal permeability to sugars in patients with Crohn's disease of the terminal ileum and colon. Digestion 27, 70-74. Ukabam, S.O., Homeda, M.A., Cooper, B.1., 1986. Small intestinal permeability in Sudanese subjects: Evidence of tropical enteropathy. Trans. Roy. Soc. Trop. Med. Hyg. 40, 204207. Ukabam, S.O., Mann, R.1., Cooper, B.T., 1984. Small intestinal permeability to sugars in patients with atopic eczema. Brit. 1 Dermatol. 110, 649-652. van der Hulst, R.R., von Meyenfeldt, M.F., van Kreel, B.K., Thunnissen, F.B., Brummer, R.1., Arends, J.W., Soeters, P.B., 1998. Gut permeability, intestinal morphology, and nutritional depletion. Nutrition 14, 1-6. Van Der Meer, S.B., Forget, P.P., Heidendal, G.A., 1990. Small bowel permeability to 51CrEDT A in children with recurrent abdominal pain. Acta Paediat. Scand. 79, 422-426. van Elburg, R.M., Uil, J.J., van Aalderen, W.M., Mulder, C.1., Heymans, H.S., 1996. Intestinal permeability in exocrine pancreatic insufficiency due to cystic fibrosis or chronic pancreatitis. Pediat. Res. 39,985-991. Vogelsang, H., Oberhuber, G., Wyatt, 1, 1996. Lymphocytic gastritis and gastric permeability in patients with coeliac disease. Gastroenterology III, 73-77. Vukavic T., 1984. Timing of the gut closure. 1 Pediatr. Gastroenterol. Nutr. 3, 700-703. Wallace, Ll..; 1997. Nonsteroidal anti-inflammatory drugs and gastroenteropathy: the second hundred years. Gastroenterology 112, 1000-1016.

Intestinal barrier junction

693

Wallace, J.L., Granger, D.N., 1992. Pathogenesis ofNSAlD gastropathy: are neutrophils the culprits? Trends Pharmacol. Sci. 13,129-130. Walsh, D.S., Thavichaigam, P., Dheeradhada, e., Jiarakul, N., Pearce, F.e., Wiesmann, W.P., Cioffi, W.G., Webster, H.K., 1996. Prolonged alteration in gut permeability following nonthermal injury. Injury 27, 491-494. Weaver, L.T., 1988. The impact of milk and weaning diet on gastrointestinal permeability in English and Gambian infants. Transact of the Royal Soc. Trop. Med. Hyg. 82, 784-789. Weaver, L.T., Laker, M.F., Nelson, R., 1984. Intestinal permeability in the newborn. Arch. Dis. Child 59, 236-241. Welsh, F.K., Ramsden, C.W., MacLennan, K., Sheridan, M.B., Barclay, G.R., Guillou, P.l, Reynolds, lV., 1998. Increased intestinal permeability and altered mucosal immunity in cholestatic jaundice. Ann. Surg. 227, 205-212. Wheeler, P.G., Menzies, I.S., Creamer, B., 1978. Effect of hyperosmolar stimuli and coeliac disease on the permeability of the human gastrointestinal tract. Clin. Sci. Mol. Med. 54, 495-501. Whittle, B.lR., 1992. Unwanted effects of aspirin and related agents on the gastrointestinal tract. In: Vane, lR., Botting, R.M. (Eds.), Aspirin and other salicylates. Chapman & Hall Medical, London 465-509. Wicks, C; Somasundaram, S., Menzies, I.S., Bjarnason, I., Williams R., 1993. Intestinal function and postoperative enteral nutrition following liver transplants. Gut 34 (Suppl. I), S65. Wilairatana, P., Meddings, J.B., Ho, M., Vannaphan, S., Looareesuwan, S., 1997. Increased gastrointestinal permeability in patients with Plasmodium falciparum malaria. Clin. Inf. Dis. 24, 430-435. Willumsen, J.F., Darling, le., Kitundu, lA., Kingamkono, R.R., Msengi, A.E., Mduma, B., Sullivan, K.R., Tomkins, A.M., 1997. Dietary management of acute diarrhoea in children: effect of fermented and amylase-digested weaning foods on intestinal permeability. J. Pediat. Gastroenterol. Nutr. 24, 235-241. Wyatt, r, Vogelsang, H., Hubl, W., Waldhoer, T., Lochs, H., 1993. Intestinal permeability and the predictor of relapse in Crohn's disease. Lancet 341, 1437-1439. Yacyshyn, B., Meddings, L, Sadowski, D., Bowen-Yacyshyn, M.B., 1996. Multiple sclerosis patients have peripheral blood CD45RO+ B cells and increased intestinal permeability. Dig. Dis. Sci. 41, 2493-2498. Yacyshyn, B.R., Meddings, lB., 1995. CD45RO expression on circulating CDI9 + B cells in Crohn's disease correlates with intestinal permeability. Gastroenterology 108, 132-137. Zhang, Y., Lee, B., Thompson, M., Glass, R., Lee, R.C., Figueroa, D., Gilman, R., Taylor, D., Stephenson, C; 2000. Lactulose-mannitol intestinal permeability test in children with diarrhea caused by rota virus and cryptosporidium. Diarrhea Working Group, Peru. 1 Pediat. Gastroenterol. Nutr. 31, 16-21.