Dietary Sorbitol and Mannitol Food Conte
Dietary Sorbitol and Mannitol Food Conte
Dietary Sorbitol and Mannitol Food Conte
RESEARCH PAPER
Dietary sorbitol and mannitol: food content and distinct
absorption patterns between healthy individuals and
patients with irritable bowel syndrome
C. K. Yao, H.-L. Tan, D. R. van Langenberg, J. S. Barrett, R. Rose, K. Liels, P. R. Gibson &
J. G. Muir
Departments of Gastroenterology, Eastern Health and Central Clinical Schools, Monash University, Melbourne, Victoria, Australia
Keywords Abstract
hydrogen breath tests, intestinal absorption,
irritable bowel syndrome, mannitol, polyols, Background: Sorbitol and mannitol are naturally-occurring polyol isomers.
sorbitol malabsorption. Although poor absorption and induction of gastrointestinal symptoms by
sorbitol are known, the properties of mannitol are poorly described. We
Correspondence aimed to expand data on food composition of these polyols, and to com-
C. K. Yao, Department of Gastroenterology,
pare their absorptive capacities and symptom induction in patients with
Central Clinical School, Monash University, Level
irritable bowel syndrome (IBS) and healthy individuals.
6, The Alfred Centre, 99 Commercial Road,
Melbourne, VIC 3004, Australia. Methods: Food samples were analysed for sorbitol and mannitol content.
Tel.: +61 3 9903 0270 The degree of absorption measured by breath hydrogen production and gas-
Fax: +61 3 9903 0556 trointestinal symptoms (visual analogue scales) was evaluated in a rando-
E-mail: [email protected] mised, double-blinded, placebo-controlled study in 21 healthy and 20 IBS
subjects after challenges with 10 g of sorbitol, mannitol or glucose.
How to cite this article Results: Certain fruits and sugar-free gum contained sorbitol, whereas man-
Yao C.K., Tan H.-L., van Langenberg D.R., Barrett
nitol content was higher in certain vegetables. Similar proportions of
J.S., Rose R., Liels K., Gibson P.R. & Muir J.G.
patients with IBS (40%) and healthy subjects (33%) completely absorbed
(2013) Dietary sorbitol and mannitol: food
content and distinct absorption patterns between sorbitol, although more so with IBS absorbed mannitol (80% versus 43%;
healthy individuals and patients with irritable P = 0.02). Breath hydrogen production was similar in both groups after
bowel syndrome. J Hum Nutr Diet. lactulose but was reduced in patients with IBS after both polyols. No differ-
doi:10.1111/jhn.12144 ence in mean (SEM) hydrogen production was found in healthy controls
after sorbitol [area-under-the-curve: 2766 (591) ppm 4 h–1] or mannitol
[2062 (468) ppm 4 h–1] but, in patients with IBS, this was greater after sor-
bitol [1136 (204) ppm 4 h–1] than mannitol [404 (154) ppm 4 h–1;
P = 0.002]. Overall gastrointestinal symptoms increased significantly after
both polyols in patients with IBS only, although they were independent of
malabsorption of either of the polyols.
Conclusions: Increased and discordant absorption of mannitol and sorbitol
occurs in patients with IBS compared to that in healthy controls. Polyols
induced gastrointestinal symptoms in patients with IBS independently of
their absorptive patterns, suggesting that the dietary restriction of polyols
may be efficacious.
Sorbitol and mannitol are six-carbon polyol isomers capacity of sorbitol and mannitol in patients with IBS com-
with a similar molecular weight and size, differing only in pared to those in healthy individuals and assessing symp-
the orientation of one of their hydroxyl group (Le & tomatic responses in relation to patterns of absorption.
Mulderrig, 2001; see Figure S1). They appear to be partly
absorbed via passive diffusion across the small intestinal
Materials and methods
epithelium (Beaugerie et al., 1990; Krugliak et al., 1994).
Breath hydrogen studies indicate a high prevalence of sor- Measurement of sorbitol and mannitol content
bitol malabsorption in healthy adults, where 71% show A total of 73 foods from several food groups were screened
malabsorption after consumption of 10 g of sorbitol and for quantities of sorbitol and mannitol. As previously
20% report gastrointestinal symptoms of bloating, flatu- described in detail by Muir et al. (2009), the sampling and
lence and abdominal pain (Hyams, 1983). Some studies processing methods of the foods complied with the guide-
have extrapolated these findings to the absorption of lines of Food Standards Australia New Zealand. Triplicates
mannitol, and have assumed that a similar proportion of of the extracts from food samples were analysed for sorbi-
mannitol is absorbed; however, this has not been com- tol and mannitol content using high-performance liquid
pared directly (Wursch et al., 1989; Le & Mulderrig, chromatography (HPLC) with an evaporative light scatter-
2001). ing detector (ELSD) analytical technique. Sugar standards,
Short-chain carbohydrates called FODMAPs (Ferment- HPLC apparatus (consisting of ELSD Waters 2424, HPLC
able, Oligo-, Di-, Monosaccharide and Polyols) that are pump Waters 515, Waters auto sampler 717 plus and
slowly or poorly absorbed in the small intestine increase Waters column heater; Waters Corp, Milford, MA, USA)
luminal water content of the small and large intestine by and chromatographic procedure were performed as
virtue of their osmotic effect (Barrett et al., 2010; Marci- described in Muir et al. (2009). Samples were reanalysed if
ani et al., 2010) and are rapidly fermented by intestinal any of the triplicate measurement values differed by >5%
bacteria, resulting in increased gas production (Ong et al., from the mean of other samples (Muir et al., 2009). The
2010). The resultant luminal distension has been hypoth- relative SD for using HPLC measurement technique has
esised to trigger abdominal symptoms in patients with previously been calculated for sorbitol (3.76%) and man-
functional bowel disorders because of the visceral hyper- nitol (2.85%) (Muir et al., 2009). Food composition of
sensitivity and dysmotility that characterises such patients sorbitol and mannitol were constructed using standard
(Chey et al., 2001; Agrawal et al., 2008). Because sorbitol serving sizes and weights from FOODWORKS, version 6 (Xyris
and mannitol are also poorly or slowly absorbed in the Software Australia Pty Ltd, Highgate Hill, Australia).
small intestine and readily fermented by bacteria, it is
assumed that they will also induce symptoms in a similar
Subjects
way. However, it is not well established whether the mal-
absorption of sorbitol with or without fructose and, sub- Patients with IBS and no other co-existing gastrointestinal
sequently, the induction of symptoms occurs to a greater disorders were recruited from an outpatient breath testing
extent in patients with irritable bowel syndrome (IBS) centre at Box Hill Hospital (Box Hill, Victoria, Australia).
compared to controls because one study attributes a clear Healthy participants with no previous history of gastroin-
difference (Fernandez-Banares et al., 1993) and another testinal illness or symptoms were also recruited through
does not (Nelis et al., 1990). Regardless of the inconsis- advertisements in Box Hill Hospital. All participants were
tent findings, it is appropriate to restrict the intake of aged ≥18 years and not pregnant. None of them had been
sorbitol and mannitol-rich foods in symptomatic individ- treated with antibiotics in the previous 6 weeks, or pre- or
uals. However, knowledge of the sorbitol and mannitol probiotics in the 2 weeks leading up to the study. The
content in foods is limited and needs to be expanded to intake of nonsteroidal anti-inflammatory drugs and alcohol
prevent unnecessary restrictions. was recorded. During screening, a detailed history was
It was hypothesised that, first, as isomeric molecules, obtained to confirm that IBS patients met the Rome III
sorbitol and mannitol are absorbed similarly in the small diagnostic criteria (Longstreth et al., 2006). Written
intestine of healthy subjects and patients with IBS; second, informed consent was obtained from all participants prior
both would induce gastrointestinal symptoms predomi- to commencing the study. The study protocol was approved
nantly in patients with IBS; and third, symptom induction by the Eastern Health Research and Ethics Committee.
would be associated with the malabsorption of the polyol.
The present study therefore aimed to address the knowl-
Experimental design
edge gaps by quantifying the content of sorbitol and
mannitol naturally-occurring in various foods and also to Prior to entering the study, all subjects were initially chal-
address the hypothesis by examining patterns of absorptive lenged with 15 g of lactulose (15% w/v) for 2 h to ensure
that they produced adequate breath hydrogen, denoted as carbohydrate) (Rumessen et al., 1990). Responses were
a rise in breath hydrogen ≥10 ppm in two consecutive arbitrarily categorised as marked (61–100%), moderate
breath samples (Bate et al., 2010). Subjects who had a rise (31–60%), low (6–30%) or no (0–5%) malabsorption.
in breath methane ≥15 ppm from baseline were classified Oro-caecal transit time (OCTT), defined as the time (min)
as ‘methane producers’. This was followed by a routine from sugar ingestion of first breath hydrogen rise
breath hydrogen test with 35 g of fructose (17% w/v) to ≥10 ppm in two consecutive samples, was measured for
determine the presence of fructose malabsorption. lactulose (Bate et al., 2010).
The effects of a single dose (10 g) of sorbitol, mannitol
or glucose (as placebo) were investigated using a rando-
Assessment of gastrointestinal symptoms
mised, double-blinded, placebo-controlled, cross-over
design. Randomisation of the test sequence was per- Gastrointestinal symptoms were assessed by completing
formed with a computer-generated list of random num- bowel symptom questionnaires before and 4 h after sugar
bers and the sequence was kept by an independent ingestion. Symptoms were rated on 100-mm visual
investigator. The dose of 10 g was chosen to reflect a analogue scales (VAS) according to severity from 0 (no
realistic but high intake of the individual polyol that is symptoms) to 100 mm (worst it has been) for overall gas-
achievable through the diet (Muir et al., 2009; Barrett & trointestinal symptoms, abdominal pain/discomfort, bloat-
Gibson, 2010) and is also not likely to induce osmotic ing, wind, as previously applied (Francis et al., 1997). A
diarrhoea in healthy individuals (Hyams, 1983). The sug- composite score for abdominal symptoms was calculated by
ars were given as a colourless solution in 100 mL of water combining scores for abdominal pain, bloating and wind.
(10% w/v), made up in identical unmarked containers to Scores were corrected for the baseline level of symptoms.
ensure blinding of both participants and researchers. The
absorption of these sugars was then determined through
Statistical analysis
breath hydrogen testing. Each sugar challenge was fol-
lowed by a washout period of 1–7 days before crossing Because a per-protocol analysis was planned, only partici-
over to the next sugar challenge to allow symptoms pants who completed all three interventions were included
(if any) to return to baseline prior to re-challenge. in the final analysis. Primary end-points were the propor-
tion of individuals with malabsorption and their breath
hydrogen response to the sugar challenges. Secondary end-
Breath hydrogen testing
points included gastrointestinal symptom response to
Breath hydrogen testing was performed as previously out- polyol ingestion, the correlation of breath hydrogen-
lined in detail (Ong et al., 2010). Briefly, participants producing ability and OCTT for lactulose with polyol
were provided with a diet low in fibre and poorly- absorption/malabsorption, and the proportion of individu-
absorbed short-chain carbohydrates for 24 h. After an 8-h als with concomitant fructose and polyol malabsorption. A
fast, a baseline breath sample was taken before ingesting sample size of 20 participants in each group was required
the sugar solution. Thereafter, breath samples were col- to detect a 30% change in breath hydrogen response to the
lected at 15-min intervals into collection bags (Quintron polyol challenges, with a power of 80%. P ≤0.05 (two-
Instrument Co., Milwaukee, WI, USA) for 4 h. Subjects tailed) was considered statistically significant.
were instructed to refrain from smoking and strenuous The frequency of sugar malabsorption was compared
exercise during the test to minimise potential confound- using Fisher’s exact or a chi-squared test. Comparisons
ing of these variables on breath hydrogen responses between subject groups were performed with unpaired
(Thompson et al., 1985). Breath hydrogen and methane t-tests and the Mann–Whitney U-test for nonparametric
concentrations were analysed immediately using a gas data. Comparisons between sugar challenges were also
chromatograph (Microlyzer Model DP Plus; Quintron analysed using paired t-tests and the nonparametric Wil-
Instrument Co., Milwaukee, WI, USA). coxon signed-rank tests, respectively. Correlations were
A rise in breath hydrogen concentrations ≥10 ppm performed using Pearson’s and Spearman’s correlation for
above baseline in two consecutive breath samples was used nonparametric data. Effect sizes (eta squared statistic, r2)
to define malabsorption. Total breath hydrogen and were calculated and expressed as the mean difference
methane production for lactulose and test sugars were (MD) and 95% confidence interval (CI). Results are
estimated using the trapezoid rule to approximate the expressed as the mean (SEM) for parametric data, median
area-under-the-curve (AUC) against time (ppm h–1) for [interquartile range (IQR)] for nonparametric and dis-
each sugar (Kotler et al., 1982). The degree of sugar mal- continuous variables, and proportions as percentages
absorption was semi-quantitatively determined relative to (95% CI). Statistical tests for data analysis were computed
AUC after ingestion of 15 g of lactulose (a non-absorbable using SPSS, version 19.0 (IBM Corp., Armonk, NY, USA).
Table 1 Content of sorbitol and mannitol in various food groups shown as grams per 100 g edible portion and grams per serving
Sorbitol Mannitol
Table 1 (Continued)
Sorbitol Mannitol
Table 1 (Continued)
Sorbitol Mannitol
Average serving sizes were obtained from FOODWORKS, version 6 (Xyris Software Australia Pty Ltd).
Shaded boxes indicate: not analysed or no data available.
Comparisons were made with previously published composition data taken from Muir et al. (2009)* and Biesiekierski et al. (2011)†, as well as the
USDA Nutrition Composition Database (US Department of Agriculture Agricultural Research Service, 2011).
NSAID, nonsteriodal anti-inflammatory drug. Figure 2 Proportion (%) of subjects with malabsorption of sorbitol or
*Values are expressed as the median (interquartile range). mannitol in patients with irritable bowel syndrome (IBS) (n = 20) and
†
Fisher’s exact test; ‡Mann–Whitney U-test. healthy controls (n = 21). Bars represent 95% confidence intervals.
*Significantly different (P = 0.02) compared to healthy controls.
Figure 1 Comparison of 4-h overall gastrointestinal symptoms and composite scores of abdominal pain, wind and bloating, assessed by the
visual analogue scale (VAS) (Montalto et al.), after sorbitol, mannitol and glucose challenges in healthy (n = 18) and irritable bowel syndrome
(IBS) subjects (n = 20). Horizontal lines represent median VAS scores. Significant differences are shown: *P = 0.05 for overall symptoms after
sorbitol and **P ≤ 0.03 for overall symptoms after mannitol compared to glucose (Wilcoxon sign-ranked test). Significant results for IBS patients
compared to healthy controls are shown: †P < 0.01 and ‡P < 0.02.
Discussion
As 6-carbon isomers that are absorbed by passive diffu-
sion across the intestinal barrier, sorbitol and mannitol
might be anticipated to show similar absorption patterns
in any individual. Indeed, in agreement with a previous
study (Wursch et al., 1989), the absorption patterns in
healthy volunteers were similar; approximately 40% com-
Figure 3 Frequency (%) of subjects in the different categories of pletely absorbed each polyol and the patterns were con-
polyol malabsorption estimated using semi-quantitative analyses cordant in almost all of them. By contrast, the findings in
between patients with irritable bowel syndrome (IBS) (n = 20) and
a demographically-matched population of patients with
healthy controls (n = 21). *Statistically significant differences between
the proportion of patients with mannitol malabsorption and that in
IBS were very different. First, double the proportion
the healthy controls within each category (P = 0.02). (80%) completely absorbed mannitol. Second, the absorp-
tion patterns were discordant in that three out of five
(a)
(b)
Figure 5 Severity of overall gastrointestinal symptoms according to visual analogue scale (VAS) in relation to the degree of malabsorption for
sorbitol, mannitol and glucose in patients with irritable bowel syndrome (IBS) (n = 20). No correlation was observed for sorbitol (Spearman’s
r = 0.15, P = 0.55) or mannitol (r = 0.07, P = 0.97).
patients had different patterns of absorption for mannitol Perhaps the most intriguing observation was the discor-
and sorbitol. Third, the ability to absorb both sorbitol dance between sorbitol and mannitol absorption in
and mannitol is enhanced in patients with IBS, as shown patients with IBS but not in healthy controls. As shown
by lower total hydrogen production in those with malab- by the 4-h hydrogen production, mannitol absorption was
sorption, despite similar hydrogen production to lactu- almost three-fold greater than that of sorbitol, a finding
lose. Finally, both polyols appeared to trigger symptoms that has not been observed previously. This is unlikely to
independently of its absorption pattern. be artefactual because breath hydrogen tests have good
Previously, studies using breath hydrogen (Wursch reproducibility (Welsh et al., 1981; Barillas-Mury & Solo-
et al., 1989) or recovery in ileostomy effluent (Saunders mons, 1987) and the order of testing was randomised.
& Wiggins, 1981; Beaugerie et al., 1997) have consistently Two reasons for the discordance are possible. First, bacte-
demonstrated at least partial absorption of sorbitol and rial fermentation of mannitol may have different kinetics
mannitol, with estimates suggesting that an average of to those for sorbitol in the IBS group. Sorbitol has slower
26% and 40% of 10-g doses of sorbitol and mannitol, and more complex bacterial fermentation than rapidly
respectively, are absorbed. The present study has similarly fermentable sugars such as lactose and fructose (Mishkin
found evidence for substantial absorption of both polyols et al., 1997; Clausen et al., 1998). In support of this, the
in healthy and IBS subjects. What has not been reported pattern of hydrogen production after mannitol over the 4-
previously is that the degree of absorption of sorbitol and h period was different to that for sorbitol in IBS patients.
mannitol was at least two-fold greater from the small A comparison of the kinetics of fermentation of sorbitol
intestine in patients with IBS than in healthy controls, as and mannitol has not been reported. Another likely expla-
shown by a significantly lower hydrogen production. This nation, however, is that, despite the structural similarities
observation was not a reflection of different functional that exist between the two polyols, the different orienta-
capabilities of the intestinal microbiota in the two groups tion of the hydroxyl position in each polyol may result in
because their hydrogen-producing capacity was similar dissimilarities in polyol–water interactions (Grigera, 1988)
after lactulose and there was no evidence of diversion of and, subsequently, their passage across the intestinal bar-
gas production towards a methane pathway, as we previ- rier. In water, mannitol adopts a planar configuration that
ously observed in when a low FODMAP diet is consumed attracts more water molecules and may enhance its per-
(Ong et al., 2010). The reason for the differences must lie meation via water-filled intracellular pores (Grigera,
in the physiology of the intestine. It might reflect slower 1988). It is also possible that the unstirred water layer,
oro-caecal transit, as defined by the first rise of breath suggested to regulate osmotic gradients for the passive
hydrogen after lactulose (Madsen et al., 2006). For mole- uptake of water-soluble molecules (Barry & Diamond,
cules that are slowly and passively absorbed, this would 1984), is a key player in differentiating permeation rate
give more time for absorption to occur. Alternatively, the between sorbitol and mannitol. This unstirred water layer
differences in absorption patterns between healthy and has also been shown to be altered in disease. Strocchi
IBS subjects might reflect epithelial abnormalities, which et al. (1996) demonstrated that patients with coeliac dis-
have been reported in some subgroups of patients with ease were shown to have increased jejunal unstirred water
IBS (Marshall et al., 2004; Dunlop et al., 2006). Further layer thickness compared to healthy controls, reducing
enquiry is warranted to provide an explanation for these nutrient absorption. Alterations in this layer in patients
observations. with IBS have yet to be examined but may potentially
explain the discordance in sorbitol and mannitol absorp- polyols can be achieved in patients with IBS. Fruits, par-
tion. ticularly in their dried forms such as prunes and dried
As reported previously (Fernandez-Banares et al., 1993), pears, are concentrated sources of sorbitol that may be
an increase in abdominal symptoms was induced by sorbi- the major problem FODMAP, instead of the much-
tol and mannitol over the duration of the breath testing in maligned fructose in such sources. Existing food compo-
patients with IBS but not in healthy controls. However, the sition data indicating that certain vegetables are relatively
induction of symptoms for both polyols was independent rich sources of mannitol were confirmed. Amounts
of whether the polyol was malabsorbed and fermented. approaching 10 g day 1 mannitol can be derived from
Over this short duration, another mechanism other than large intake of these vegetables, particularly celery, cauli-
fermentation-driven gaseous distension of the intestine flower, mushrooms and snow peas. However, it may not
must underlie symptom exacerbation. Fluid distension of require such a dose when consumed in combination with
the small intestine is proposed because the slowly-absorbed sorbitol or other FODMAPs, as discussed above. In
polyols can exert an osmotic effect around most of the comparison with published data from the USDA, the
small intestine, as elegantly shown by magnetic resonance quantities of sorbitol in these fruits were quite similar to
methodology (Marciani et al., 2010). Hence, the implica- those reported in the present study, whereas there were
tion for dietary therapy is that these polyols can trigger some variations with respect to the mannitol content of
symptoms whether they enter the large bowel to be subse- food. These differences can be explained by several fac-
quently fermented or not, as a result of their slow rate of tors, including seasonal and climate variations, fruit or
absorption and osmotically-mediated distension of the vegetable varieties analysed, as well as differences in the
small intestinal. Breath testing to assess polyol absorption, quantification methodologies used (Makinen & Soderling,
as is frequently performed for fructose and lactose, may not 1980; Wrolstad & Shallenberger, 1981).
then be clinically useful or relevant. Alternatively, mannitol ConclusionsThe present randomised, double-blinded,
and sorbitol absorption might directly affect the function placebo-controlled cross-over study has demonstrated dis-
of the enteric nervous system via local osmolytic effects or tinct differences in the small intestinal handling of sorbi-
the involvement of inflammatory mediators. Perhaps mast tol and mannitol between healthy and IBS individuals. By
cell-histamine release, suggested as an explanation for ana- contrast to healthy subjects who appear to absorb both
phylactoid reactions to mannitol in several case reports polyols to an almost similar extent, patients with IBS not
(Findlay et al., 1983; Eggleston et al., 1987; Hegde & Venk- only have a greater ability to absorb both polyols, but
atesh, 2004), may be involved. also absorb mannitol more readily than sorbitol. The
Such an effect on symptom induction reinforces atten- mechanisms by which such differences occur require clar-
tion to those polyols in the design of dietary therapy to ification. Despite superior absorption, both sorbitol and
alleviate IBS symptoms. Thus, sorbitol and mannitol are mannitol specifically induced abdominal symptoms, sug-
appropriately included in the class of poorly absorbed gesting that mechanism(s) other than (or additional to)
short-chain carbohydrates, termed FODMAPs, for which their fermentation are involved. Such observations suggest
an accumulating evidence-base is now available as major that the dietary restriction of these polyols should be
dietary triggers of functional gut symptoms (Gibson & included in dietary restriction of FODMAPs for patients
Shepherd, 2010). The principles of the low FODMAP diet with IBS, irrespective of their ability to absorb them
indicate that individual FODMAPs have additive effects according to breath hydrogen results. Comprehensive
on symptoms and should not be considered separately food knowledge on polyol content not only eases the
but rather together in dietary interventions. The results of design of such dietary therapy, but also provides prebiotic
the present study suggest not only that both sorbitol and food sources for asymptomatic individuals. Additionally,
mannitol should be restricted in patients with IBS, but the role of xylitol and other commonly-used polyols in
also that this decision should be independent of the dem- the food industry (Zumbe et al., 2001) as dietary triggers
onstration of their malabsorption via breath hydrogen in IBS also warrants further study because evidence from
testing. Whether acute challenges with sorbitol and man- the healthy population cannot be extrapolated to this
nitol serve as a better guide of gastrointestinal tolerance patient population.
for patients who may benefit from such restrictions, as
recently suggested for fructose (Wilder-Smith et al.,
2013), would require further study. Acknowledgments
Food composition data from the present study rein- We would also like to thank all laboratory research staff
force previously published data showing that the intake and breath testing staff at Box Hill Hospital for the help
of up to 10 g day 1 from foods with naturally-occurring and technical support received.
Chey, W.Y., Jin, H.O., Lee, M.H., Sun, S.W. & Lee, K.Y.
Conflict of interests, source of funding and
(2001) Colonic motility abnormality in patients with
authorship irritable bowel syndrome exhibiting abdominal pain and
The authors declare that there are no conflicts of diarrhea. Am. J. Gastroenterol. 96, 1499–1506.
interest. Clausen, M.R., Jorgensen, J. & Mortensen, P.B. (1998)
No external funding was received for the present study. Comparison of diarrhea induced by ingestion of
JGM, JSB and PRG designed the study. KL and RR fructooligosaccharide idolax and disaccharide lactulose (role
conducted the food analysis. CKY, HLT and DRVL of osmolarity versus fermentation of malabsorbed
carried out the clinical study. CKY analysed and carbohydrate). Dig. Dis. Sci. 43, 2696–2707.
interpreted study data. CKY, JGM, JSB, DRVL and Dunlop, S., Hebden, J., Naesdal, J., Campbell, E., Olbe, L.,
PRG drafted and revised the manuscript for publication. Perkins, A.C. & Spiller, R.C. (2006) Abnormal intestinal
All authors approved the final manuscript submitted for permeability in subgroups of diarrhea-predominant irritable
publication. bowel syndromes. Am. J. Gastroenterol. 101, 1288–1294.
Eggleston, P.A., Kagey-Sobotka, A. & Lichtenstein, L.M.L.
(1987) A comparison of the osmotic activation of basophils
and human lung mast cells. Am. Rev. Respir. Dis. 135, 1043–
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