Increase
in Intestinal Permeability
Clinical Science
(2001) 100, 627-633 (Printed in Great Britain)
Co-administration of the health food supplement, bovine colostrum,
reduces the acute non-steroidal anti-inflammatory drug-induced increase
in intestinal permeability.
Raymond J. PLAYFORD*, Christopher E. MACDONALD?, Denis P. CALNAN?,
David N. FLOYD?, Theo PODAS?, Wendy JOHNSON?, Anthony C. WICKS?, O.
BASHIR* and Tania MARCHBANK*
*Department of Gastroenterology, Imperial College School of Medicine,
Hammersmith Hospital, Du Cane Road, London W12 0NN, U.K., ?Department
of Gastroenterology, Leicester General Hospital, Gwendolen Road, Leicester
LE5 4PW, U.K., and ?SHS International Ltd., 100 Wavertree Boulevard,
Liverpool L7 9PT, U.K.
Key words: gastrointestinal
tract, intestinal injury, repair, nutrition.
Abbreviations: NSAID, non-steroidal anti-inflammatory drug; tds, three
times daily.
Correspondence: Professor R. J. Playford (e-mail r.playford@ic.ac.uk).
Non-steroidal
anti-inflammatory drugs (NSAIDs) are effective analgesics but cause
gastrointestinal injury. Present prophylactic measures are suboptimal
and novel therapies are required. Bovine colostrum is a cheap, readily
available source of growth factors, which reduces gastrointestinal
injury in rats and mice. We therefore examined whether spray-dried,
defatted colostrum could reduce the rise in gut permeability (a non-invasive
marker of intestinal injury) caused by NSAIDs in volunteers and patients
taking NSAIDs for clinical reasons. Healthy male volunteers (n = 7)
participated in a randomized crossover trial comparing changes in
gut permeability (lactulose/rhamnose ratios) before and after 5 days
of 50 mg of indomethacin three times daily (tds) per oral with colostrum
(125 ml, tds) or whey protein (control) co-administration. A second
study examined the effect of colostral and control solutions (125
ml, tds for 7 days) on gut permeability in patients (n = 15) taking
a substantial, regular dose of an NSAID for clinical reasons. For
both studies, there was a 2 week washout period between treatment
arms. In volunteers, indomethacin caused a 3-fold increase in gut
permeability in the control arm (lactulose/rhamnose ratio 0.36¡À0.07
prior to indomethacin and 1.17¡À0.25 on day 5, P < 0.01), whereas
no significant increase in permeability was seen when colostrum was
co-administered. In patients taking long-term NSAID treatment, initial
permeability ratios were low (0.13¡À0.02), despite continuing on the
drug, and permeability was not influenced by co-administration of
test solutions. These studies provide preliminary evidence that bovine
colostrum, which is already currently available as an over-the-counter
preparation, may provide a novel approach to the prevention of NSAID-induced
gastrointestinal damage in humans.
INTRODUCTION
Non-steroidal anti-inflammatory drugs (NSAIDs) are some of the most
commonly prescribed medicines used worldwide. Although of undoubted
efficacy for the treatment of musculoskeletal injury, chronic administration
of NSAIDs results in both gastric and intestinal damage. This includes
peptic ulceration and injury to the small and large intestine causing
increased permeability with blood and protein loss and stricture formation
[1-4].
Current strategies to reduce gastrointestinal side effects of NSAIDs
consist of co-administration of acid suppressants or prostaglandin
analogues. Although they are beneficial in reducing peptic ulceration,
they are less efficacious in limiting small intestinal damage [3].
In addition, diarrhoea can be a troublesome side effect from the use
of prostaglandin analogues, and these drugs are also relatively contraindicated
in young women because of their pro-abortive and teratogenic activity
[5]. Novel therapeutic approaches are therefore required.
Colostrum, the milk produced for the first few days after birth, is
a rich natural source of nutrients, antibodies and growth factors
for the suckling neonate. Some studies suggest it may be of value
in eliminating infection and stimulating growth of the neonatal gastrointestinal
tract [6,7]. Its value in the prevention and treatment of adult gastrointestinal
injury is, however, largely unexplored. We have shown recently [8],
using a combination of in vitro and in vivo animal models, that a
commercially available defatted bovine colostral preparation can reduce
NSAID-induced gut injury in rats and mice.
We have now further examined its potential clinical value for the
prevention and treatment of NSAID-induced enteropathy by measuring
changes in gut permeability in normal volunteers taking clinically
relevant doses of the NSAID indomethacin and also in patients taking
long-term NSAIDs for clinical reasons.
METHODS
Materials and ethics
Chemicals were obtained from Sigma unless otherwise stated. Local
ethical approval and patient consent was obtained for all studies.
Preparation of colostrum and whey protein solutions
The test solutions were identical to those used for the previously
published in vitro and in vivo studies [8], and were prepared by Viable
Bioproducts, Turku, Finland. The initial colostral and milk whey protein
solutions were treated in an identical fashion and were passed through
a microfilter (0.2 mm pore). The final colostral whey solution ('Bioenervi')
is free of fat (including polar lipids) and lactose, and is reduced
in most of the major milk proteins, including casein and lactalbumin,
with the remaining protein being relatively rich in immunoglobulins
and growth factors. The total protein content of the colostral solution
was 4.3 mg/ml. The concentrations of the various growth factors present
in the colostral preparation are incompletely defined, but include:
insulin-like growth factor-I and -II, at approx. 2 mg/l each; transforming
growth factor at 25 ¦Ìg/l; and epidermal growth factor at 6 ¦Ìg/l (data
supplied by SHS International Ltd, personal communication). The milk
whey (placebo) solution provided an isoproteinaceous solution (4.3
mg/ml), which has a similar appearance to the colostral preparation,
but is free of growth factor constituents (data supplied by SHS International
Ltd, personal communication).
Assessment of permeability
Assessment of intestinal permeability by quantifying unmediated absorption
of at least two sugars of different sizes provides a sensitive index
of intestinal damage [9]. We used lactulose as the disaccharide probe,
and rhamnose and mannitol as two alternative monosaccharide probes
in a hypo-osmolar formulation. Both rhamnose and mannitol have been
widely used and provide similar information regarding changes in 'paracellular
pathways'. However, as there are minor differences in their processing
in vivo [9], both sugars were included in the test drink.
Following an overnight fast, subjects emptied their bladders and then
drank a standardized sugar solution containing 5 g of lactulose, 2
g of mannitol and 1 g of rhamnose in a total of 450 ml of water (calculated
osmolality 69 osmol/kg of water). Subjects were allowed unlimited
intake of fluid after the first hour of the test to ensure adequate
urine output. The urine was collected and pooled over the next 5 h
and total volume recorded. Aliquots were centrifuged briefly to remove
gross debris and the supernatant frozen at -25 ¡ãC until later analysis.
Analyses of sugar content within the urine were based on the method
of S?rensen et al. [10], with minor modifications. The various sugars
were separated using HPLC and quantified using a pulsed amphometric
detector. Using this technique, sugars are oxidized on the gold electrode
at the working potential (E¡ä0 = 0.05 V), the current produced being
a measure of the amount of sugar present in the sample [11].
The system comprised of a Hewlett Packard 1100 series HPLC system
using a Dionex CarboPac PA10 anion-exchange analytical column (4.5¡Á250
mm) with an equivalent guard column. NaOH (50 mM, low in carbonate;
BDH-Merck Ltd) was used as the mobile phase (1 ml/min, isocratic conditions).
Sugars were detected using a Hewlett Packard 1049A Electrochemical
Detector with a gold working electrode and solid reference electrode.
The potentials were set as follows: E¡ä0 = 0.05 V, E¡ä1 = 0.6 V and
E¡ä2 =-0.8 V; and t1 = 120 ms, t2 = 120 ms, t3 = 400 ms. Data analyses
were performed using the Hewlett Packard Chemstation software.
Typically, the mannitol peak eluted from the column at approx. 2 min,
rhamnose at 4 min and lactulose at 9 min. Analysis of single- and
mixed-sugar standards in the concentration range 0.05 mg/ml to 50
mg/ml showed good chromatographic separation and proportional changes
in the area under the curve (results not shown).
Initial baseline urine samples, analysed following the preliminary
studies, showed no sugar peaks in these areas. However, when the same
separation protocol was used for the subsequent full studies, the
mannitol peak was sometimes obscured by an overlap from other urinary
constituents (Figure 1). We therefore used the lactulose/rhamnose
ratio as our index of intestinal injury, a combination that has been
recommended for assessing enteropathy induced by NSAIDs [12].
/cs/100/0627/cs1000627a01.gif
/cs/100/0627/cs1000627a01.gif
Elution profiles of urinary samples from a volunteer who has taken
a hypo-osmolar drink containing test sugars
Samples were run on an isocratic HPLC column and sugars detected using
pulsed amphometric detection. The peaks relating to lactulose (L)
and rhamnose (R) are well resolved, whereas the mannitol (M) peak
is lost in the non-specific early peak. Lower panel: the equivalent
result from the same subject who had a repeat test after 5 days of
indomethacin (50 mg, tds). In this second test, there is a marked
increase in the lactulose peak.
Study protocols
Normal volunteers (Study 1)
To determine the reproducibility of results, a single individual performed
permeability studies for 6 separate days (while not taking any test
treatments or NSAIDs). These samples were assayed to determine intra-patient
variation. In addition, a single sample was measured six times to
determine intra-assay variation.
To examine whether the colostral or control preparation influenced
permeability under basal conditions, four subjects underwent an initial
permeability assessment and then ingested either the colostral or
whey protein preparation [125 ml, three times daily (tds)] for 5 days
with a further assessment on the final day. No change in permeability
was seen (Figure 2).
/cs/100/0627/cs1000627a02.gif
/cs/100/0627/cs1000627a02.gif
Colostrum or control solution does not influence permeability when
given alone to normal volunteers
Four volunteers ingested control and test solution for 5 days without
taking NSAIDs. Permeability studies were performed at the beginning
and end of the study periods. Each subject's individual results are
shown by a different symbol.
Seven male volunteers
(26-38 years old) who were not intolerant of milk products, taking
NSAIDs, or suffering from conditions likely to affect intestinal permeability
(e.g. coeliac disease or previous intestinal surgery), were entered
into the study.
Subjects abstained from alcohol consumption and ingestion of any NSAID,
including aspirin, for 1 week prior to starting the study and throughout
the remainder of the test period. Following an initial baseline permeability
assessment, they received, in random order, the colostral preparation
(125 ml, tds) or control solution for 7 days. For the last 5 days
of each study arm, they also took indomethacin 50 mg, tds. At the
end of the test period intestinal permeability was reassessed. A 2
week 'washout' period was left between the two stages of the study.
Throughout the study, volunteers and patients were asked about symptoms
and compliance. Formal dyspepsia scoring was not undertaken, however,
as the standard validated questionnaires are not appropriate for short-term
studies.
Patient group (Study 2)
A total of 15 patients (seven male, eight female; mean age 61 years,
range 43-75) were recruited from the community (predominantly from
Latham House Surgery, Melton Mowbray, Leicestershire, U.K.). All had
been regularly taking a stable, substantive dose of a non-selective
NSAID without additional prophylaxis (eg. acid suppressant) for at
least 1 year. This comprised of Voltarol (75 mg or higher) in two
patients, Piroxicam (20 mg or higher) in three patients, Naproxen
(500 mg twice daily or higher) in five patients and Ibuprofen (1.2
g or higher) in five patients. The underlying conditions necessitating
NSAID usage were: osteoarthritis, in 11 patients; rheumatoid arthritis,
in three patients; and psoriatic arthropathy, in one patient. None
of the patients were taking any other drugs likely to alter intestinal
permeability or had previously suffered any clinical adverse events
due to NSAIDs. Patients did not undergo endoscopy prior to starting
the trial.
Patients were randomized to receive, in a double-blinded, randomized
control fashion, colostrum or control solution (125 ml, tds for 7
days) with a 2 week washout period between the two study arms. For
both arms of the study (colostrum or control), an initial baseline
assessment of intestinal permeability was performed prior to starting
the test solutions. Permeability was re-assessed after 7 days treatment.
Patients were assessed by telephone interview on day four and at the
end of treatment with a structured questionnaire to document consumption
of their NSAID, and test treatment and identify side effects (if any).
Statistics
Data were analysed by one- or two-way ANOVA as appropriate, using
presence of indomethacin and test solution as factors. When a significant
effect was found (P < 0.05), individual comparisons were performed
using t tests based on the residual and degrees of freedom obtained
from the ANOVA, a method equivalent to repeated-measures analyses,
which takes account of the fact that the data are paired. Comparison
of baseline values of Study 1 versus initial values of patients in
Study 2 were performed using a two-tailed unpaired t test.
RESULTS
Normal volunteers (Study 1)
For multiple measurements of a single sample, the coefficient of variation
was 5.9%. Measurement of the six serial samples from the same individual
gave a coefficient of variation of 7.7%. Administration of colostrum
or control solution to the individuals not taking NSAIDs had no effect
on their permeability results (Figure 2). Therefore although there
was a relatively broad normal range (0.17-0.81, see Figure 2 and baseline
values of Figure 3), in keeping with other published works (for example
[3]), intra-volunteer variation was small. It was for this reason
that each subject acted as their own control.
/cs/100/0627/cs1000627a03.gif
/cs/100/0627/cs1000627a03.gif
Influence of colostrum on indomethacin-induced increases in permeability
Seven volunteers participated in this double-blinded crossover study.
Each subject's individual results are shown by a different symbol.
The group means from each stage are also marked. Baseline permeability
values were similar prior to each arm of the study. In the control
(whey) arm, 5 days of indomethacin caused a 3-fold rise in lactulose/rhamnose
ratios (P < 0.01). Co-administration of the colostral preparation
prevented this increase.
All seven subjects
completed the study without protocol violations. One developed mild
nondescript upper-abdominal discomfort while taking the indomethacin
(control) arm but completed the course. No side effects due to ingestion
of the colostral preparation were reported.
Baseline permeability values were similar at the beginning of each
study arm (lactulose/rhamnose ratio 0.36¡À0.07 versus 0.42¡À0.10, means¡ÀS.E.M.,
P > 0.05; Figure 3). Permeability increased approx. 3-fold in response
to indomethacin in the control arm (P < 0.01 versus baseline value),
but showed no significant rise when colostrum was co-administered
(Figure 3). The order in which control and colostrum were administered
did not appear to influence results (although numbers are too small
to perform detailed statistical analysis).
Patient group (Study 2)
One subject developed a non-specific viral-type illness during the
washout period and was therefore withdrawn from the study. Of the
remaining patients, one developed mild oesophageal reflux-type symptoms
during their placebo-treatment week. A second patient reported improvement
in long-standing vague lower-abdominal pain while taking colostrum.
Baseline permeability assessments (assessed while patients continued
to take their regular NSAID therapy) gave results which were actually
lower than those seen in the volunteers of Study 1 prior to them starting
indomethacin (lactulose/rhamnose ratio 0.13¡À0.02, means¡ÀS.E.M., in
patients compared with 0.36¡À0.07 volunteers, P < 0.05). There was
however, some overlap between individuals in the two studies. Co-administration
of the colostral or control solution to patients taking NSAIDs had
no significant effect on their gut permeability (Figure 4).
/cs/100/0627/cs1000627a04.gif
/cs/100/0627/cs1000627a04.gif
Influence of colostrum on permeability in patients (n = 14) taking
NSAIDs long-term for clinical reasons
Individual results and group means are shown. Baseline permeability
values were low, despite all of the patients continuing to take their
NSAIDs. Values were actually somewhat lower than those seen in volunteers
not given NSAID (see Figure 2). Co-administration of the colostral
or control solution had no effect on these values.
DISCUSSION
We have used changes in gut permeability, a well validated indirect
method of investigating small intestinal injury, to examine the potential
clinical value of a commercial defatted colostral preparation in reducing
NSAID-induced enteropathy. The colostral preparation, but not a similarly
prepared whey protein solution, significantly reduced the increase
in permeability caused by short-term (5 day) exposure to indomethacin
in normal subjects. Patients taking long-term NSAIDs for clinical
reasons had initial permeability values that were low, being similar
or lower than those seen in normal subjects not given NSAIDs, and
were not influenced by co-administration of the colostral preparation.
Several methods are available to determine the degree of small intestinal
injury induced by NSAIDs, all of which have their drawbacks: enteroscopy
is an invasive procedure; 111In-labelled white cells require radioactive
exposure; and measurement of the neutrophil marker, calprotectin,
in the stool is still at a relatively early stage of development [13].
Measurement of gut permeability is a safe and simple investigation
to perform, but is an indirect method of assessing small intestinal
injury. Assessment of excretion of two molecules of different sizes,
such as a monosaccharide and a disaccharide, by HPLC with pulsed amphometric
detection, provides high sensitivity and allows correction for potential
confounding factors, such as changes in the rate of gastric emptying
and small intestinal transit.
Measurement of intestinal permeability has been used previously to
assess the degree of small intestinal damage in patients with coeliac
disease [14] and Crohn's disease [15], as well as injury caused by
NSAIDs. Several studies have shown that short term (1-7 days) administration
of clinically relevant doses of NSAIDs, such as indomethacin, naproxen
and ibuprofen, increase gut permeability by approx. 3-fold (e.g. [16]).
Our results from the control arm, using normal volunteers, are therefore
in keeping with published works.
NSAIDs are one of the most widely prescribed group of drugs used worldwide.
Point-prevalence studies, however, suggest that 10-30% of unselected
patients taking NSAID therapy have peptic ulceration [17], which can
often be asymptomatic [18]. In addition, up to 70% of patients taking
NSAIDs have some degree of enteropathy associated with low-grade blood
and protein loss [13,19-21], although it is only of clinical significance
in a much smaller percentage of patients. Specific cyclooxygenase-2
inhibitors have reduced gastric toxicity but are expensive and cannot
replace the use of aspirin as an anti-platelet agent, the use of which
continues to be a major contributor to the development of significant
gastrointestinal bleeding [22,23].
In the present study, the baseline permeability values of patients
taking long-term NSAIDs were low, being similar or lower than those
seen in control subjects not given an NSAID. This result is in keeping
with the report of Struthers et al. [24], but is at variance with
the report of Sigthorsson et al. [25] who found an approx. 2-fold
increase in permeability in patients taking similar doses of NSAIDs
to those in the present study. The reasons behind these different
results are unclear, although variations exist in the details of the
probes used and the osmolality of the test solutions. We specifically
ensured that our test solution was hypo-osmolar, as this has been
reported to maximize alterations in permeability changes induced by
NSAIDs [25]. As all of the volunteers in the short-term study showed
a marked rise in permeability, it is possible that the small intestine
of our patients taking NSAIDs chronically underwent adaptation. Adaptation
is a well recognized phenomenon, with regards to the disappearance
of gastric erosions, in patients who continue to take NSAIDs [26].
All of our patients were selected on the basis of having taken NSAIDs
long-term, without the requirement for additional prophylaxis. It
is therefore possible that those patients who suffer serious side
effects (such as chronic blood loss) fail to adapt appropriately.
Alternatively, because of the selection criteria, our patients may
represent a group who are not susceptible to the initial effects of
the NSAID which were seen in the volunteers. This idea is less likely,
however, as although the number of volunteers were small, all responded
in a similar manner when acutely exposed to indomethacin. Additional
differences existed between the patients and volunteers; the mean
age of patients was greater than that of volunteers and consisted
of both males and females. This last point was probably not of major
relevance as sub-analyses of the males alone showed similar results.
To address this area further, additional larger studies should probably
examine gut permeability in patients prior to starting NSAID therapy,
with serial measurements of side effects (dyspepsia scores etc.) and
permeability following randomization to control, or colostrum solution,
at the same time as NSAID therapy is started.
Colostrum is the milk produced by the mother for the first few days
after birth and is much richer in growth factors and antibodies than
ordinary milk [6,7,27]. Bovine colostral preparations are currently
available in the U.S.A. and throughout Europe as 'over-the-counter'
health food supplements. They do, however, contain large amounts of
potent growth factors which are biologically active [8]. Products
such as these are also termed 'functional foods' or 'nutraceuticals'
based on the realization that the distinction between food and drugs
is becoming blurred.
NSAIDs such as indomethacin cause damage to the gastrointestinal tract
by several mechanisms, including reduction of mucosal prostaglandin
levels, reduction of mucosal blood flow, stimulating neutrophil activation
and, possibly, also stimulating apoptosis [28]. It is likely that
many of these mechanisms will be influenced by the numerous growth
factors present in the colostrum preparation. There is now increasing
evidence that administration of multiple peptides can result in additive
or synergistic activity [29]. Orally administered colostrum-derived
preparations, therefore, appear to be an attractive therapeutic option
as they contain multiple growth factors in a formulation that provides
inherent protection against proteolytic digestion. Further, long-term
clinical studies appear warranted to examine its value in the prevention/treatment
of NSAID-induced gut injury, and also possibly for other ulcerative
conditions of the bowel, such as necrotizing enterocolitis and inflammatory
bowel disease, where therapies are sub-optimal and novel approaches
are required.
ACKNOWLEDGMENTS
We thank the Wellcome Trust and the Medical Research Council for funding.
Declaration of interest
The use of bovine colostrum for the prevention of NSAID-induced gut
injury has been patented by SHS International Ltd (No. 9619634.0),
who partially funded this work.
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Received 10 January
2001; accepted 9 March 2001
The Biochemical
Society and the Medical Research Society 2001
Articles
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