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IgG Food Intolerance Support Papers

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Paper 01 Dietary advice based on food specific IgG Results Geoffrey Hardman, Gillian Hart, University of York, Heslington, York, UK Nutrition and food science Vol 37 No 1 2007 pp 16-23

Paper 02 Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. W Atkinson, T A Sheldon, N Shaath, PJ Whorwell Gut 2004:53 1459-1464 doi: 10.1136 Paper 05 Food allergy in irritable bowel syndrome: new facts and old fallacies. E Isolauri, S.Rautava, M.Kalliomaki Gut 2004; 53 1391-1393 10.1136 Paper 06 A prospective audit of Food Intolerance among Migraine patients in primary care clinical practise. Trevor Rees, David Watson, Susan Lipscombe, Helen Speight, Peter Cousins, Geoffrey Hardman and Andrew J. Dowson. Headache care Vol.2 No 2 2005 105-110 Paper 07 Celiac Disease. Peter H.R Green M.D. and Christopher collier, M.D. PhD The New England Journal of Medicine 2007; 357:1731-43 Paper 08 Alterations of food antigen-specific serum immunoglobulins G and E in patients with irritable bowel syndrome and functional dyspepsia. X.L.Zuo, Y.Q. Li, W.J.Li, Y.T. Guo, X.F. Lu, J.M. Li and P.V. Desmond Clinical and Experimental Allergy, 37, 823-830 Paper 10 IgG Antibodies against Food Antigens are Correlated with Inflammation and Intima Media Thickness in Obese Juveniles M. Wilders-Truschnig, H.Mangge, C.Lieners, H.J.Gruber, C Mayer, W Marz Exp Clin Endocrinol Diabetes 2008; 116:241-245 Paper 12 A Vegan diet free of gluten improves the signs and symptoms of Rheumatoid Arthritis.. I Hafstöm, B.Ringertz, A. Spångberg, L. Von Zweigbergk, S. Brannemark, I. Nylander, J.Rönnelid, L.Laasonen, L.Klareskog. British Society of Rheumatology, 2001 pp 1175-1179 Paper 13 The gut-joint axis: cross reactive food antibodies in rheumatoid arthritis. M Hvatum, L Kanerud, R Hällgren, P Brandtzaeg Gut 2006:55 1240-1247 originally published online 16 feb 2006 Paper 14 Toward an understanding of Allergy and In-Vitro Testing By Mary James N.D Great Smokies Diagnostic Laboratory

IRRITABLE BOWEL SYNDROME

Food elimination based on IgG antibodies in irritable bowelsyndrome: a randomised controlled trialW Atkinson, T A Sheldon, N Shaath, P J Whorwell. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

See end of article forauthors’ affiliations. . . . . . . . . . . . . . . . . . . . . . .

Correspondence to:Dr P J Whorwell,Department of Medicine,University Hospital ofSouth Manchester,Manchester M20 2LR, UK;[email protected]

Revised version received13 April 2004Accepted for publication13 April 2004. . . . . . . . . . . . . . . . . . . . . . .

Gut 2004;53:1459–1464. doi: 10.1136/gut.2003.037697

Background: Patients with irritable bowel syndrome (IBS) often feel they have some form of dietaryintolerance and frequently try exclusion diets. Tests attempting to predict food sensitivity in IBS have beendisappointing but none has utilised IgG antibodies.Aims: To assess the therapeutic potential of dietary elimination based on the presence of IgG antibodies tofood.Patients: A total of 150 outpatients with IBS were randomised to receive, for three months, either a dietexcluding all foods to which they had raised IgG antibodies (enzyme linked immunosorbant assay test) ora sham diet excluding the same number of foods but not those to which they had antibodies.Methods: Primary outcome measures were change in IBS symptom severity and global rating scores. Non-colonic symptomatology, quality of life, and anxiety/depression were secondary outcomes. Intention totreat analysis was undertaken using a generalised linear model.Results: After 12 weeks, the true diet resulted in a 10% greater reduction in symptom score than the shamdiet (mean difference 39 (95% confidence intervals (CI) 5–72); p = 0.024) with this value increasing to26% in fully compliant patients (difference 98 (95% CI 52–144); p,0.001). Global rating also significantlyimproved in the true diet group as a whole (p =0.048, NNT=9) and even more in compliant patients(p = 0.006, NNT=2.5). All other outcomes showed trends favouring the true diet. Relaxing the diet led to a24% greater deterioration in symptoms in those on the true diet (difference 52 (95% CI 18–88); p = 0.003).Conclusion: Food elimination based on IgG antibodies may be effective in reducing IBS symptoms and isworthy of further biomedical research.

Irritable bowel syndrome (IBS) is a common disorder whichcauses abdominal pain, abdominal distension, and boweldysfunction, characterised by loose bowels, constipation, or

a fluctuation between these two extremes.1 This conditionsignificantly impairs quality of life and places a large burdenon health care resources.2 Treatment of IBS is largely basedon the use of antispasmodics, antidepressants, and medica-tions that modify bowel habit, depending on whetherconstipation or diarrhoea is the predominant problem.1 Thenotorious inadequacies of current drug therapy lead to muchpatient dissatisfaction and a tendency for patients to seek avariety of alternative remedies, especially of a dietary nature.IBS is likely to be a multifactorial condition involving a

number of different mechanisms although the prominence ofany particular factor may vary from patient to patient.1 3

However, patients often strongly believe that dietary intoler-ance significantly contributes to their symptomatology andsome sufferers seem to benefit from eliminating certain foodsfrom their diet. Detection of food intolerance is often difficultdue to its uncertain aetiology, non-specific symptomatology,and relative inaccessibility of the affected organ. Thus mostprevious studies have relied on the use of exclusion diets,which are extremely labour intensive and time consuming.4 5

Attempts to ‘‘test’’ for food intolerance in IBS have largelyfocused on ‘‘classic’’ food allergy based on the presence of IgEmediated antibody responses, although it appears that these‘‘immediate type’’ reactions are probably quite rare in thiscondition.6–10 It is therefore possible that adverse reactions tofood in patients with IBS might be due to some other form ofimmunological mechanism, rather than dietary allergy. Suchreactions could be mediated by IgG antibodies, whichcharacteristically give a more delayed response followingexposure to a particular antigen11 and have been implicatedin some cases of food hypersensitivity.12–14 However, thismechanism is controversial and is considered by some to be

physiological15–17 especially as IgG food antibodies can bepresent in apparently healthy individuals.18–20 It has pre-viously been suggested that IgG food antibodies may have arole in IBS21 and it was therefore the purpose of this study toformally evaluate, in a randomised controlled trial, thetherapeutic potential of an elimination diet based on thepresence of IgG antibodies to food in patients with IBS.

PATIENTS AND METHODSPatientsAll patients with uncomplicated IBS (all bowel habitsubtypes) attending the Gastroenterology Department atthe University Hospital of South Manchester were consideredeligible for the study, and those aged between 18 and75 years, who satisfied the Rome II criteria,22 were invited toparticipate. Tertiary care patients were excluded from thestudy. All patients had normal haematology, biochemistry,and endoscopic examination when indicated. Coeliac diseasewas excluded using the tissue transglutaminase test and ahydrogen breath test was used for excluding lactose intoler-ance. Patients were also excluded from participating in thestudy if they had any significant coexisting disease or ahistory of gastrointestinal surgery, excluding appendicect-omy, cholecystectomy, and hiatus hernia repair. The studywas approved by the local ethics committee and all patientsprovided written informed consent.

MethodsThe study used a double blind, randomised, controlled,parallel design in which patients were randomised to either a‘‘true’’ diet or a ‘‘sham’’ diet control group. At screening,

Abbreviations: IBS, irritable bowel syndrome; ELISA, enzyme linkedimmunosorbant assay; AU, arbitrary unit; HAD, hospital anxiety anddepression scale; QOL, quality of life; NNT, number needed to treat

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blood was taken and sent, with only a numerical identifier, toYorkTest Laboratories Ltd (York, UK) where an enzymelinked immunosorbant assay (ELISA) test was performed todetect the presence of IgG antibodies specific to a panel of 29different food antigens. This test has been described in detailelsewhere23 and involves specimens being diluted 1/50, 1/150,and 1/450 with each dilution applied to an allergen panel.Each test was calibrated using 0 arbitrary unit (AU) and25 AU standards prepared from a serum with a high IgG titreto a cow’s milk allergen extract. A positive control serum at45 AU was applied to each test. The test results were obtainedfrom the 1/150 dilution of the specimen. Where a highspecimen background was observed, the test results wereobtained from the 1/450 dilution. The threshold for a positive(reactive) result was selected as three times the backgroundsignal obtained by the same sample against a no foodallergen coated control well equivalent to 3 AU. Test resultswere scored as positive or negative only, relative to this cutoff.Staff based at the YorkTest Laboratories produced a true

and sham diet sheet for each patient. The sham dieteliminated the same number of foods to which a patientexhibited IgG antibodies but not those particular foods. Thegoal was to try and include in the sham diet an equallydifficult to eliminate staple food for every staple food in thetrue diet. Thus cow’s milk was (generally) replaced withpotato, wheat with rice, and yeast with whole egg, where thiswas possible. Nut reactivities were replaced with other nutsin the sham diet, and legumes with other legumes, but thiswas not systematised.The true and sham diet sheets for each patient were sent to

the University of York, again with only a number foridentification. Patients were allocated to one of the two dietsheets based on a randomisation schedule developed using arandom computer number generator. Thus patients wouldreceive either an elimination diet based on their truesensitivity results (true diet) or a sham diet. All patientsand clinical staff in the Gastroenterology ResearchDepartment and YorkTest Laboratory were blinded to thegroup assignment of all patients for the duration of the study.Patients were given their allocated diet sheet by staff at the

Gastroenterology Research Department and asked to elim-inate the indicated foods from their diet for a period of12 weeks. They also received a booklet with advice oneliminating the different foods and the telephone contactdetails of a free nutritional advisor whom they were able tocontact for further advice if necessary.Symptoms were assessed using a questionnaire scoring

system validated for use in IBS, including the IBS symptomseverity score (range 0–500).24 This is a system for scoringpain, distension, bowel dysfunction, and general well being,with mild, moderate, and severe cases indicated by scores of75–175, 175–300, and .300, respectively. A reduction inscore of 50 or over is regarded as a clinically significantimprovement.24 Non-colonic symptomatology,25 such aslethargy, backache, nausea, and urinary symptoms, wasassessed and scored using visual analogue scales (range 0–500). Quality of life (QOL) was measured using an instru-ment proven to be sensitive to change in IBS (range 0–500).26–28

Anxiety and depression were evaluated using the hospitalanxiety and depression scale (HAD).29 This instrument scoresanxiety and depression up to a maximum score of 21 for eachparameter, with a score above 9 indicating significantpsychopathology. Data on these measures were recorded atbaseline and after 4, 8, and 12 weeks of the dietaryintervention period. In addition, at 4, 8, and 12 weeks,patients were asked to give a global rating of their IBS usingthe question, ‘‘Compared with your IBS before you startedthe food elimination diet, are you now: terrible, worse,

slightly worse, no change, slightly better, better, or excel-lent?’’ The atopic status of all patients entering the study wasalso assessed.During the treatment phase, patients were allowed to take

concomitant medication provided it had been constant for sixmonths prior to the start of the study. They were encouragednot to alter medication use during the course of the trial butany changes were recorded. Any patient withdrawing fromthe study was encouraged to complete a final symptomquestionnaire at week 12 and their reasons for withdrawalwere recorded. At the end of 12 weeks, patients were asked toresume consumption of the foods they had been advised toeliminate in order to assess the effect of their reintroduction.Patients were then reassessed after four weeks using thesame measures and the result compared with their scores atthe end of the elimination phase.

Data analysisQuestionnaires were scored by an assessor blinded to therandomisation. The primary outcome measures were changesin IBS symptom severity score and global impact score at12 weeks. Changes in non-colonic symptoms, QOL, and HADscores were regarded as secondary outcome measures. Twosample t tests were used to establish whether there was anoverall difference in the change in continuous outcomemeasures between the two groups of patients. Patients wereanalysed according to the group to which they wererandomised, independent of their adherence to the diet.The global impact score, an ordered categorical variable, wasanalysed using a Wilcoxon Mann-Whitney test to comparethe numbers in the active and sham groups showingsignificant improvement (‘‘better’’ or ‘‘excellent’’), no sig-nificant change (‘‘slightly worse’’, ‘‘no change’’, or ‘‘slightlybetter’’), and significant deterioration (‘‘worse’’ or ‘‘terri-ble’’). The number needed to treat (NNT) was calculatedfrom the global impact score by calculating the reciprocal ofthe difference in probability of a significant improvementbetween the treatment and control groups. General linearmodelling in SPSS was used to explore whether there was a

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Figure 1 Study flow diagram.

1460 Atkinson, Sheldon, Shaath, et al

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relationship between the change in symptoms from baselineand treatment group, patient characteristics (for example,IBS subtype, history of atopy, number of foods to whichsensitive, and concomitant medication) and adherence to thediet.30

Sample size calculationIt was estimated that approximately 40% of the placebo armwould report a significant improvement in symptoms. It wascalculated that a sample size of 55 patients would be requiredin each group to detect, with 90% power, a difference of 30%points in the proportion reporting such an improvement (thatis, 70% in the treatment arm) as statistically significant at the5% level. Assuming a 20% dropout rate, a minimum of 138patients would need to be entered into the trial. Thus weaimed to recruit a total of 150 patients into the study.

RESULTSRecruitment of patients and their flow through each stage ofthe study is illustrated in fig 1, as recommended by the

CONSORT statement.31 In summary, between January 2001and July 2002, 176 patients were eligible for the study, ofwhich 26 (15%) were excluded from participation, leaving150 patients who were all found to be sensitive to at least onefood. Seventy five of these were randomised to receive anelimination diet based on their true food sensitivity resultsand 75 patients to a sham diet. Data from 131 (87%) patientswho gave 12 week data were available for the intention totreat analysis: 65 and 66 patients from the true and shamgroups, respectively.

Patient characteristicsThe patients were typical of those with IBS in secondary carepractice, the majority being women. Patients, on average, hadexperienced symptoms of IBS for over a decade and werefound to be sensitive to approximately 6–7 foods (range 1–19). Baseline demographic and clinical characteristics of thetwo groups, including the use of concomitant medication,were found to be similar with the exception of the IBSsymptom severity score which was slightly higher in thetreatment group (table 1). Thirty per cent of patients werefound to be atopic.The frequency of foods excluded from the diet is shown in

table 2. Adherence was lower in those on the true dietalthough no specific adverse events were recorded in eithergroup. Twenty four patients withdrew from the study in thetrue diet group (mainly because of difficulty in following thediet) and 13 from the sham diet group (for a variety ofreasons). However, 12 week data were obtained from 14 ofthose who withdrew in the true diet group and four in thesham diet group. There were no significant differences

Table 1 Baseline characteristics of the patients

Group True diet (n = 75) Sham diet (n = 75)

Age (y) (range, SD) 44 (17–72; 12.9) 44 (19–74; 15.2)No of males (%) 7 (9.3%) 13 (17.3%)No of foods to which sensitive 6.65 (3.66) 6.63 (4.1)Symptom duration (y) 11.5 (9.9) 10.1 (7.5)IBS symptom severity score 331.9 (70.8) 309.0 (78.5)Non-colonic features score 459.1 (160.7) 452.6 (170.1)Quality of life score 640.1 (252.6) 639.3 (222.3)HAD anxiety score 9.5 (4.6) 9.5 (4.5)HAD depression score 5.3 (3.4) 6.0 (3.6)No of diarrhoea predominant patients (%) 37 (52.1%) 41 (56.9%)No of constipation predominant patients (%) 19 (26.8%) 16 (22.2%)No of alternating predominant patients (%) 15 (21.1%) 15 (20.8%)

Results are expressed as mean (SD).HAD, hospital anxiety and depression scale.

Table 2 Frequency of foods excluded from the diet (% ofpatients)

Food Treatment group Sham group

Barley 26.7 9.3Corn 22.7 14.7Rice 8 54.7Rye 8 25.3Wheat 49.3 8Milk 84.3 1.3Beef 24 9.3Chicken 21.3 13.3Pork 5.3 36Cabbage 12 24Celery 5.3 21.3Haricot bean 17.3 14.7Pea 38.6 1.3Potato 9.3 61.3Soy bean 22.7 10.7Tomato 4 44Apple 1.3 33Orange 6.7 29.3Strawberry 0 20Almond 28 12Brazil nut 22.7 17.3Cashew nut 49.3 8Peanut 10.7 20Walnut 2.7 29.3Cocoa bean 1.3 21.3Shellfish 21.3 10.7Fish mix 17.3 28Whole egg 57.3 26.7Yeast 86.7 0

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Figure 2 Mean change in symptom severity scores at 12 weeksaccording to degree of adherence. Difference between the groups withhigh adherence: 101 (95% confidence interval 54, 147); ***p,0.001.

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between baseline characteristics of the 19 who were lost tofollow up and those for whom 12 week data were obtained.

Primary outcomesIBS symptom severityPatients in the true diet group experienced a 10% greaterreduction in symptom severity than those allocated to thesham diet, with change in scores of 100 and 61.5, respectively(mean difference 39 (95% confidence interval (CI) 5.2, 72.3);p=0.024): a standardised effect size of 0.52 (see fig 3A).There were no differences in the response to the diet in termsof age, sex, IBS bowel habit subtype, or IBS duration. Inaddition, there was no difference in response to the diet

between atopic and non-atopic patients. There was however astatistically significant interaction between treatment groupand both adherence to the diet and number of foods to whichpatients were sensitive. For patients sensitive to the averagenumber of foods who fully adhered to their allocated diet, a26% difference in reduction in symptom severity score wasobserved in favour of the true diet (a difference in score of 98(95% CI 52, 144), p,0.001: a standardised effect size of 1.3).This benefit increased by a further 39 points (12%) (95% CI 7,70; p= 0.016) for each food to which they were sensitiveover and above the average number. These results were notmaterially altered by carrying out an ANCOVA analysis (inwhich the final score is the dependent variable and thebaseline score is included as a covariate) instead of modellingchange in scores.30 The interaction between treatment groupand adherence is demonstrated in fig 2 which shows agreater reduction in symptoms with full adherence in thetrue diet but not in the sham diet group. Figure 3A and 3Bshow the average change in symptom severity score over12 weeks for the group as a whole and for those who fullyadhered, respectively. This reveals that most improvements insymptoms are fully achieved within two months.

Global impact scoreThe reported global rating of change by treatment group isshown in table 3. The difference in mean ranking (70.9 v60.3) was statistically significant (p=0.048). When this wasrepeated including only patients who fully adhered to theirdiets (table 3), a greater percentage difference favouring thetrue diet was found (p=0.001). The NNT was 9 in the groupas a whole and 2.5 in patients fully adherent to the diet.

Secondary outcome measuresAs can be seen from fig 4A and 4B, all data show changesfavouring the true diet group and are consistent with theresults for the primary outcomes. These trends were furtherstrengthened after adjustment for adherence and number offood sensitivities but only reached statistical significance fornon-colonic symptomatology (p=0.05). There were nosignificant changes in medication use during the course ofthe trial.

Reintroduction of eliminated foodsOf the 131 patients who gave 12 week data, 93 (41 in the trueand 52 in the sham diet groups) agreed to attemptreintroduction of foods they had been asked to eliminateand provided further follow up data on the primary outcomesmeasures. Of these, 62% reported full adherence and 37%moderate adherence to the previous elimination diet. MeanIBS symptom severity score increased (that is, worsening ofsymptoms) by 83.3 in the true group and by 31 in the sham

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Figure 3 (A) Average symptom severity scores over time for the groupas a whole. Difference in mean change from baseline at 12 weeks: trueversus sham 39 (95% confidence interval 5, 72); *p=0.024. (B) Averagesymptom severity scores over time for the full adherence group.Difference in mean change from baseline at 12 weeks: true versus sham98 (95% confidence interval 52, 144); ***p,0.001.

Table 3 Global impact score at 12 weeks

Treatment group

True diet(n (%))

Sham diet(n (%))

All patientsSignificantly worse 3 (4.7) 8 (12.1)No significant change 44 (67.2) 47 (71.2)Significantly improved 18 (28.1) 11 (16.7)Total 65 66 NNT = 9

Patients fully adhering to the dietSignificantly worse 1 (4.2) 5 (12.5)No significant change 10 (41.7) 29 (72.5)Significantly improved 13 (54.1) 6 (15)Total 24 40 NNT = 2.5


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group, a statistically significant difference of 52 (24%) (95%CI 18, 86; p=0.003). The change in global score followingreintroduction of foods is shown in table 4. This indicates areversal of the pattern observed during the active treatmentphase, with more patients in the true diet group showing

worsening of health compared with the sham diet group(p=0.047).

DISCUSSIONA clinically significant improvement in IBS symptomatologywas observed in patients eliminating foods to which theywere found to exhibit sensitivity, as identified by an ELISAtest for the presence of IgG antibodies to these foods. Thenumber needed to treat of 9 for the group as a whole and 2.5for patients closely adhering to the diet are both considerablybetter than the value of 17 achieved after three months oftreatment with tegaserod,32 a drug that has been recentlylicensed in the USA for use in IBS. IBS symptom severity andglobal rating scores were chosen as primary outcomemeasures in this study as they represented the most directmeasure of clinical improvement in this condition based onpatient self assessment. Rather than using the traditionalmethod of classifying global improvement as any valueexceeding adequate relief of symptoms, we used a muchstricter definition requiring patients to report symptoms asbeing either ‘‘better’’ or ‘‘excellent’’ compared with pretreat-ment levels. Despite this, the diet still achieved a significantimprovement. However, as might be expected, the placeboresponse using this end point was somewhat lower than thatusually reported in IBS treatment trials which have used lessdemanding criteria. The observation that patients on thesham diet also improved, although to a lesser extent,emphasises the importance of conducting double blindrandomised controlled trials of such non-drug interventionsin order to avoid overestimating their potential.Most patients with IBS have attempted at least some form

of dietary modification, which in some cases can be veryextreme. Conflicting results have been reported usingexclusion diets4 5 33–36 and this approach also suffers fromthe limitation that it has to be empirical. Thus potentiallyoffending foods can only be identified after their eliminationand subsequent reintroduction. This time consuming processwould be much reduced if the offending foods could beidentified beforehand. Attempts to do this using IgEantibodies have been disappointing8–10 but the results of thisstudy suggest that measuring IgG antibodies may be muchmore rewarding. The response to the IgG based diet in ourtrial did not correlate with atopic status, the prevalence ofwhich was found to be no greater than that occurring in thegeneral population.37

The observation that adherence to the diet is critical indetermining a good outcome in the ‘‘true’’ diet group but notthe ‘‘sham’’ group is indicative of the fact that the diet is an‘‘active treatment’’ which if not adhered to, does not seem tohave an effect. This notion is further supported by theobservation that a significantly greater deterioration wasobserved in subjects in the true diet group compared withthose in the sham group when they reintroduced eliminatedfoods at the end of the diet phase of the trial. Furthermore,the improvement of 98 in the symptom severity score in thosefully adherent in the true diet group is well above the value of

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Figure 4 (A) Mean change in the secondary outcome measures of non-colonic symptoms and quality of life for the group as a whole and the fulladherence group. (B) Mean change in the secondary outcome measuresof anxiety and depression for the group as a whole and the fulladherence group.

Table 4 Global rating following reintroduction of foodsrelative to the end of the elimination phase

Treatment group

True diet group(n (%))

Sham diet group(n (%))

Significantly worse 17 (41.5) 13 (25)No significant change 23 (56.1) 35 (67.3)Significantly improved 1 (2.4) 4 (7.7)Total 41 (100) 52 (100)

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50, which is regarded as being of clinical significance both invalidation studies24 and clinical practice.26–28 It was interestingto note that patients exhibiting a greater number ofsensitivities, as determined by the IgG test, experienced agreater symptom reduction if they adhered to the true but notthe sham diet.There is currently considerable interest in the concept that

at least in some patients, IBS may have an inflammatorycomponent.38–42 Most of the work in this area has centred onpost dysenteric IBS, with gut pathogens being viewed as theinitiators of this process which can be identified by subtlechanges on histology.38 However, if, as indicated in this study,IgG antibodies to food are important in the pathogenesis ofIBS in some patients, they too may be of relevance. Not allpatients exhibiting histological features consistent with postdysenteric IBS give a history of a previous dysenteric illness.This is usually assumed to be due to the fact that this hasbeen forgotten by the patient but our results may suggest analternative mechanism for immune activation and inflam-mation without the need for prior infection.It is now well recognised that up to 70% of patients with

IBS have evidence of hypersensitivity of the rectum,43 whichprobably extends to involve most of the gut in manyindividuals.44 It is possible that this hypersensitivity renderspatients more reactive to a low grade inflammatory processwhich would not necessarily cause symptoms in a normalindividual. This would explain why excluding foods to whichpatients have IgG antibodies might be particularly beneficialin IBS despite the fact that these antibodies may also bepresent in the general population. Indeed, if this mechanismis particularly important in IBS, it might be anticipated thatIgG food antibodies would be relatively common in thiscondition, as was the case in our study.Many patients with IBS would prefer a dietary solution to

their problem rather than having to take medication, and theeconomic benefits of this approach to health services areobvious. It is well known that patients expend large sums ofmoney on a variety of unsubstantiated tests in a vain attemptto identify dietary intolerances. The results of this studysuggest that assay of IgG antibodies to food may have a rolein helping patients identify candidate foods for eliminationand is an approach that is worthy of further biomedical andclinical research.

Authors’ affiliations. . . . . . . . . . . . . . . . . . . . .

W Atkinson, N Shaath, P J Whorwell, Department of Medicine,University Hospital of South Manchester, Manchester, UKT A Sheldon, Department of Health Sciences, University of York, York,UK

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12 el Rafei A, Peters SM, Harris N, et al. Diagnostic value of IgG4 measurementsin patients with food allergy. Ann Allergy 1989;62:94–9.

13 Host A, Husby S, Gjesing B, et al. Prospective estimation of IgG, IgG subclassand IgE antibodies to dietary proteins in infants with cow’s milk allergy. Levelsof antibodies to whole milk protein, BLG and ovalbumin in relation to repeatedmilk challenge and clinical course of cow’s milk allergy. Allergy1992;47:218–29.

14 Awazuhara H, Kawai H, Maruchi N. Major allergens in soybean and clinicalsignificance of IgG4 antibodies investigated by IgE and IgG4 immunoblottingwith sera from soybean-sensitive patients. Clin Exp Allergy 1997;27:325–32.

15 Barnes RMR, Johnson PM, Harvey MM, et al. Human serum antibodiesreactive with dietary proteins: IgG subclass distribution. Int Arch Allergy ApplImmunol 1988;87:184–8.

16 Lessof MH, Kemeny DM, Price JF. IgG antibodies to food in health anddisease. Allergy Proc 1991;12:305–7.

17 Husby S, Mestecky J, Moldoveanu Z, et al.Oral tolerance in humans. T cell butnot B cell tolerance after antigen feeding. J Immunol 1994;152:4663–70.

18 Haddad ZH, Vetter M, Friedmann J, et al. Detection and kinetics of antigen-specific IgE and IgG immune complexes in food allergy. Ann Allergy1983;51:255.

19 Husby S, Oxelius VA, Teisner B, et al. Humoral immunity to dietary antigens inhealthy adults. Occurrence, isotype and IgG subclass distribution of serumantibodies to protein antigens. Int Arch Allergy Appl Immunol1985;77:416–22.

20 Kruszewski J, Raczka A, Klos M, et al. High serum levels of allergen specificIgG-4 (asIgG-4) for common food allergens in healthy blood donors. ArchImmunol Ther Exp 1994;42:259–61.

21 Finn R, Smith MA, Youngs GR, et al. Immunological hypersensitivity toenvironmental antigens in the irritable bowel syndrome. Br J Clin Pract1987;41:1041–3.

22 Drossman DA, Corazziari E, Talley NJ, et al. Rome II: a multinationalconsensus document on functional gastrointestinal disorders. Gut1999;45:1–81.

23 Foster AP, Knowles TG, Hotston Moore A, et al. Serum IgE and IgG responsesto food antigens in normal and atopic dogs, and dogs with gastrointestinaldisease. Vet Immunol Immunopathol 2003;92:113–24.

24 Francis CY, Morris J, Whorwell PJ. The irritable bowel scoring system: Asimple method of monitoring IBS and its progress. Aliment Pharmacol Therap1997;11:395–402.

25 Whorwell PJ, McCallum H, Creed FH, et al. Non-colonic features of irritablebowel syndrome. Gut 1986;27:452–6.

26 Houghton LA, Heyman DJ, Whorwell PJ. Symptomatology, quality of life andeconomic features of irritable bowel syndrome—the effect of hypnotherapy.Aliment Pharmacol Ther 1996;10:91–5.

27 Gonsalkorale WM, Toner BB, Whorwell PJ. Cognitive change in patientsundergoing hypnotherapy for irritable bowel syndrome. J Psychosom Res2004;56:271–8.

28 Gonsalkorale WM, Houghton LA, Whorwell PJ. Hypnotherapy in irritablebowel syndrome: a large scale audit of a clinical service with examination offactors influencing responsiveness. Am J Gastroenterol 2002;97:954–61.

29 Zigmond AS, Snaith RP. The hospital anxiety and depression scale. ActaPsychiatr Scand 1983;67:361–70.

30 Everitt BS, Pickles A. Statistical aspects of the design and analysis of clinicaltrials. London: Imperial College Press Publishers, 2003:108–42.

31 Altman DG, Schulz KF, Moher D, et al. The revised CONSORT statement forreporting randomized trials: explanation and elaboration. Ann Intern Med2001;134:663–94.

32 Novick J, Miner P, Krause R, et al. A randomised, double blind, placebocontrolled trial of tegaserod in female patients suffering from irritable bowelsyndrome with constipation. Aliment Pharmacol Ther 2002;16:1877–88.

33 Niec AM, Frankum B, Talley NJ. Are adverse reactions to food linked toirritable bowel syndrome? Am J Gastroenterol 1998;93:2184–90.

34 Burden S. Dietary treatment of irritable bowel syndrome: current evidence andguidelines for future practice. J Hum Nutr Diet 2001;14:231–41.

35 Bentley SJ, Pearson DJ, Rix KJB. Food hypersensitivity in irritable bowelsyndrome. Lancet 1983;2:295–7.

36 McKee AM, Prior A, Whorwell PJ. Exclusion diets in irritable bowel syndrome:Are they worthwhile? J Clin Gastroenterol 1987;9:526–8.

37 Durham SR, Church MK. Principles of allergy diagnosis. In: Holgate ST,Church MK, Lichtenstein LM, eds. Allergy, 2nd edn. London: Mosby,2001:3–16.

38 Spiller RC, Jenkins D, Thornley JP, et al. Increased rectal mucosalenteroendocrine cells, T lymphocytes, and increased gut permeabilityfollowing acute Campylobacter enteritis and in post-dysenteric irritable bowelsyndrome. Gut 2000;47:804–11.

39 Gonsalkorale WM, Perrey C, Pravica V, et al. Interleukin 10 genotypes inirritable bowel syndrome: evidence for an inflammatory component? Gut2003;52:91–3.

40 Collins SM, Piche T, Rampal P. The putative role of inflammation in the irritablebowel syndrome. Gut 2001;49:743–5.

41 Collins SM. A case for an immunological basis for irritable bowel syndrome.Gastroenterology 2002;122:2078–80.

42 Chadwick VS, Chen W, Shu D, et al. Activation of the mucosal immune systemin irritable bowel syndrome. Gastroenterology 2002;122:1778–83.

43 Mertz H. Review article: visceral hypersensitivity. Aliment Pharmacol Ther2003;17:623–33.

44 Francis CY, Houghton LA, Whorwell PJ. Enhanced sensitivity of the whole gutin patients with irritable bowel syndrome. Gastroenterology1995;108:601(abstract).


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LEADING ARTICLE

Food allergy in irritable bowel syndrome: new facts and oldfallaciesE Isolauri, S Rautava, M Kalliomäki. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Gut 2004;53:1391–1393. doi: 10.1136/gut.2004.044990

The notion of food allergy in irritable bowel syndrome (IBS)is not new. However, recent evidence suggests significantreduction in IBS symptom severity in patients on eliminationdiets, provided that dietary elimination is based on foodsagainst which the individual had raised IgG antibodies.These findings should encourage studies dissecting themechanisms responsible for IgG production against dietaryantigens and their putative role in IBS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

See end of article forauthors’ affiliations. . . . . . . . . . . . . . . . . . . . . . .

Correspondence to:Dr E Isolauri, Departmentof Paediatrics, TurkuUniversity CentralHospital, 20520 Turku,Finland; [email protected]

Revised version received10 June 2004Accepted for publication19 June 2004. . . . . . . . . . . . . . . . . . . . . . .

Bringing empirical observations ad fontesadvances science. In astrophysics, the term‘‘black hole’’ was introduced to describe an

extremely dense star which had collapsed into asingularity under its own gravity. A black holeradiates nothing; it absorbs all matter and energyfalling within its sphere. The name was coinedonly after revisiting the initial theoreticalachievements of Karl Schwarzschild, whenobservations made outside the earth’s atmos-phere gave astrophysicists empirical x ray data ona new type of cosmic object. In allergology, incontrast, adherence to a paradigm wherebyallergy is defined by the presence of specific IgEantibodies has hampered disentanglement. As aresult, allergy remains a dubiously defined termwith no unambiguous empirical content orexplanatory power. The time has come to seizeupon the available empirical data and plungeinto the original theory of Clemens von Pirquet.The term allergy was introduced by von

Pirquet to denote a changed immunologicalreactivity which manifests itself on secondexposure to an antigen (reviewed by Kay1). Thisaltered reactivity is uncommitted, giving noindication of the direction of change; equallyharmful and protective immune reactivityreflects prior encounter (see fig 1). In modernterms, altered reactivity can be seen to evinceeither the most common mode of immuneresponse elicited by the intestinal immunesystem, tolerance, recently defined as anymechanism by which a potentially injuriousimmune response is prevented, suppressed, orshifted to a non-injurious class of immuneresponse,2 or abrogation of such an activelymaintained process, which is currently linkedto immunoinflammatory disease. Reassessmentof the original theory of allergy is important as itwould appear that it is not the immunologicalresources gained during antigen exposure, mea-surable by specific antibodies or specificallyresponding lymphocytes, which are decisive for

the presence or absence of disease, but thecomplex cascade of events determining their use.The notion of food allergy in irritable bowel

syndrome (IBS) resurfaces in scientific thinkingin this issue of Gut3 on the basis of a solidrandomised placebo controlled trial conducted byAtkinson and colleagues (see page 1459).Determination of serum IgG antibodies againstfoods was used to guide the construction ofelimination diets.The presence of specific IgG class antibodies is

often accepted as uncommitted or protective‘‘altered reactivity’’, unlike those of the IgE class.Detection of antigen specific IgE is invariablytaken as an attribute of causality, a conditioncalled ‘‘IgE mediated disease’’ and, more speci-fically, of ‘‘allergy’’.1 However, empirical data areaccumulating to suggest that transient increasesin antigen specific IgE antibodies prevail in mosthealthy asymptomatic children during the firstfive years of life.4 Secondly, generation of theseantibodies (sensitisation) on antigen exposuremay not necessarily induce clinical disease(atopic disease).5 Thirdly, reducing the risk ofatopic disease does not necessitate reduction ofsensitisation6–8 and, finally, resolution or aggra-vation of clinical disease is not invariablyassociated with a corresponding alteration inantibody concentration. Bearing these limita-tions in mind, however, the clinician maysuccessfully profit from determination of specificIgE to complete the clinical history in an attemptto identify potential offending antigens in asymptomatic patient’s diet for the explicitdiagnostic elimination-challenge procedure.9

This is precisely what Atkinson et al did, withspecific IgG antibodies.3 They identified a sig-nificant reduction in IBS symptom severity inpatients on elimination diets, provided thatdietary elimination was based on foods againstwhich the individual had raised IgG antibodies;fully compliant patients showed the best clinicalimprovement. The reverse pattern was observedafter reintroduction of the respective foods.

‘‘IBS appears to result from an interplaybetween susceptibility genes and impairedgut barrier functions, immunological dysre-gulation, together with bacterial and viralinfections and other environmental factors’’

In common with allergic disease, IBS appearsto result from an interplay between susceptibility

Abbreviations: IBS, irritable bowel syndrome; PRR,pattern recognition receptor

1391

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genes and impaired gut barrier functions, immunologicaldysregulation, together with bacterial and viral infectionsand other environmental factors. It is no easy matter todescribe succinctly ‘‘gut barrier function’’. In the gastro-intestinal tract, the external and internal environments are inclose proximity. The dilemma of the mucosal surface of theintestine is to fend off the constant challenge from antigens,such as microorganisms, in mounting a brisk response topathogens, and to enable assimilation of innocuous antigensderived from food. In order to perform these opposingfunctions, the intestine is in a state of continuous immuneresponsiveness, and a delicate balance is generated andmaintained between concomitant facilitation and suppres-sion of inflammatory responses.Gut barrier function consists of physiological and immu-

nological factors which exclude and degrade antigens andrestrict their adherence, penetration, and transfer. Antigenpresenting cells, and more precisely dendritic cells, are pivotalin directing mucosal immune responses.10–12 Three dendriticcell derived signals are required for an effective T cellresponse.11 The nature of signal 1 depends on the antigenin question and its processing; necessary costimulatorymolecules create the second signal and the pericellularcytokine milieu is the basis of the third. On antigenrecognition, maturation of dendritic cells and secretion ofcytokines and chemokines occur. These secretions direct thepolarisation of a naı̈ve T helper cell to type 1, type 2, or aregulatory T cell and thus regulate other adaptive immuneresponses, such as B cell derived immunoglobulin produc-tion.11 Tolerance to lumenal dietary and microbial antigens islikely to be achieved through those dendritic cells whichinduce production of regulatory T cells secreting interleukin10 and transforming growth factor b.13 These cytokinespromote gut barrier function by suppressing the productionof both T helper 1 and 2 cytokines,14 overexpression of whichis associated with increased gut permeability.15 16 Moreover,the anergic T cells induced by interleukin 10 exposeddendritic cells appear to be able to suppress other T cells inan antigen specific manner.17 Transforming growth factor bdownregulates both T helper 1 and 2 responses directly18 andindirectly by modulating the activity of antigen presentingcells19 and favouring the development of regulatory T cells.20

After intestinal priming, these cells migrate to the periphery,thus mediating peripheral tolerance on reactivation. In

addition to its effects on T cell function, transforming growthfactor b is a key factor in IgA production21 and thuscontributes to maintenance of gut barrier function and toimmune responses at other mucosal surfaces also. Takentogether, ‘‘gut barrier function’’ strongly depends on antigenprocessing and presentation and the cytokine milieu in themucosal immune system, and determines the nature of theimmune response (that is, tolerance or inflammation)elicited to a particular antigen.

‘‘Inflammation can cause profound alterations in thefunction of smooth muscle and enteric nerves as well asin deeper neuromuscular layers’’

In certain circumstances, such as metabolic stress, thepeaceful coexistence across the barrier is disturbed and aninflammatory response ensues.22 Abrogated barrier functionof the gut mucosa leads to greater antigen transfer when theroutes of transport are also altered, thereby evoking aberrantimmune responses and release of proinflammatory cytokineswith further impairment of barrier function. Inflammationcan cause profound alterations in the function of smoothmuscle and enteric nerves as well as in deeper neuromuscularlayers.23 Indeed, a subtle inflammatory response and exag-gerated sensitivity to that type of response has beensuggested to be causative in IBS. In view of recently reportedalterations in the immunological defence in IBS,24 thetrigger(s) of the vicious circle can be depicted among theintraluminal antigens.In this issue of Gut, Atkinson and colleagues3 describe IgG

antibody responses to dietary antigens of clinical significanceand an apparent causal relation to symptoms in IBS, in afashion resembling the elimination-challenge procedure infood allergy. To broaden this concept, it is intriguing tospeculate that IBS may perhaps also be associated with IgGantibodies against other intraluminal antigens such as thosefrom the indigenous microbiota, partially analogously to lossof tolerance to gut microbiota in inflammatory boweldisease.25 26

The human gastrointestinal tract harbours a complexcollection of microorganisms which form the individualmicrobiota typical for each person. Defence is facilitated byperistalsis, secretion of mucus and antimicrobial peptidessuch as defensins and cathelicidins, and commensal induced

Inflammation

Normalrange

IBS?

Th1IBD

Th2Allergicdisease

AntigenExposure

Consolidation of immune reactivity

Naïuncommitted

Toleranceve

Figure 1 An attempt to reformulate the original conception of the immunological basis of allergy. On exposure to dietary and microbial antigens, thenaı̈ve immune system matures either to establish appropriate immune reactivity and tolerance or, in the case of lack of suppressive and regulatorysignals, develops inflammatory disease expressed as Th1 skewed autoimmune reactivity (for example, inflammatory bowel disease (IBD)) or Th2skewed allergic disease. The exact nature of immune reactivity in irritable bowel syndrome (IBS) on this axis remains elusive.

1392 Isolauri, Rautava, Kalliomäki

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IgA.27 28 Intestinal epithelial cells further contribute to thehomeostasis of gut barrier function by a scarcity of bothpattern recognition receptors (PRRs; for example, toll-likereceptors and nucleotide binding oligomerisation domainproteins) and their coreceptors, expression of active negativeregulators of PRR signalling, and secretion of the suppressivecytokines interleukin 10 and transforming growth factor b.13

All of these characteristics assist in preventing unnecessaryand even hazardous systemic immunity to commensals whileallowing local protective mucosal immune responses. Inaddition, some specific strains of non-pathogenic bacteriahave been shown to attenuate intestinal inflammation byselective inhibition of intracellular signalling pathwayselicited by diverse potentially deleterious stimuli.29 30 Ahealthy gut microbiota is thus an indispensable componentof ‘‘gut barrier function’’.

‘‘A healthy gut microbiota is thus an indispensablecomponent of gut barrier function’’

The findings of Atkinson and colleagues3 should encouragestudies dissecting the mechanisms responsible for IgGproduction against dietary antigens and their putative rolein IBS. This may serve not only IBS research but also that intoallergy and allergic diseases. In the perspectives of bothnormal gut barrier function and the vague findings in a fewstudies of probiotic supplementation in IBS,31–33 we suggestthat the possible role of the gut microbiota in the pathogen-esis of IBS may deserve closer attention. If the host-microbecross talk is misinterpreted in IBS, a working target for noveltherapeutic interventions beyond elimination diets could beprovided in modulating the composition and/or activity of thegut microbiota and promoting gut immune defence. Researchinterest in the science of nutrition is directed towardsimprovement of defined physiological functions beyond thenutritional impact of food. The search for active non-nutritivecompounds is also a focus for research in the treatment andprevention of allergic diseases.

Authors’ affiliations. . . . . . . . . . . . . . . . . . . . .

E Isolauri, S Rautava, Department of Paediatrics, University of Turku andTurku University Central Hospital, FinlandM Kalliomäki,Massachusetts General Hospital East, Combined Programin Pediatric Gastroenterology and Nutrition, Charlestown,Massachusetts, USA

REFERENCES1 Kay AB. Concepts of allergy and hypersensitivity. In: Kay AB, ed. Allergy and

allergic diseases. Oxford: Blackwell Science Ltd, 1997:23–35.2 Weiner HL. Oral tolerance: immune mechanisms and the generation of Th3-

type TGF-beta-secreting regulatory cells. Microbes Infect 2001;3:947–54.3 Atkinson W, Sheldon TA, Shaath N, et al. Food elimination based on IgG

antibodies in irritable bowel symdrome: a randomised controlled trial. Gut2004;53:1459–64.

4 Kulig M, Bergmann R, Klettke U, et al. Natural course of sensitization to foodand inhalant allergens during the first 6 years of life. J Allergy Clin Immunol1999;103:1173–9.

5 Lau S, Illi S, Sommerfeld C, et al. Early exposure to house-dust mite and catallergens and development of childhood asthma: a cohort study. Lancet2000;356:1392–7.

6 Kalliomäki M, Salminen S, Kero P, et al. Probiotics in the primary preventionof atopic disease: a randomised, placebo-controlled trial. Lancet2001;357:1076–9.

7 Riedler J, Braun-Fahrländer C, Eder W, et al. Exposure to farming in early lifeand development of asthma and allergy: a cross-sectional survey. Lancet2001;358:1129–33.

8 Jones CA, Holloway JA, Popplewell EJ, et al. Reduced soluble CD14 levels inamniotic fluid and breast milk are associated with the subsequent developmentof atopy, eczema, or both. J Allergy Clin Immunol 2002;109:858–66.

9 Bock SA. Diagnostic evaluation. Pediatrics 2003;111:1638–44.10 Pulendran B, Banchereau J, Maraskovsky E, et al. Modulating the immune

response with dendritic cells and their growth factors. Trends Immunol2001;22:41–7.

11 Kapsenberg ML. Dendritic-cell control of pathogen-driven T-cell polarization.Nat Rev Immunol 2003;3:984–93.

12 Stagg AJ, Hart AL, Knight SC, et al. The dendritic cell: its role in intestinalinflammation and relationship with gut bacteria. Gut 2003;52:1522–9.

13 Nagler-Anderson C, Bhan AK, et al. Control freaks: immune regulatory cells.Nat Immunol 2004;5:119–22.

14 Rissoan MC, Soumelis V, Kadowaki N, et al. Reciprocal control of T helper celland dendritic cell differentiation. Science 1999;283:1183–6.

15 Heyman M, Darmon N, Dupont C, et al. Mononuclear cells from infantsallergic to cow’s milk secrete tumor necrosis factor a, altering intestinalfunction. Gastroenterology 1994;106:1514–23.

16 Berin MC, Yang PC, Ciok L, et al. Role for IL-4 in macromolecular transportacross human intestinal epithelium. Am J Physiol 1999;276:C1046–52.

17 Steinbrink K, Graulich E, Kubsch S, et al. CD4(+) and CD8(+) anergic T cellsinduced by interleukin-10-treated human dendritic cells display antigen-specific suppressor activity. Blood 2002;99:2468–76.

18 Lúdviksson BR, Seegers D, Resnick AS, et al. The effect of TGF-beta1 onimmune responses of naive versus memory CD4+ Th1/Th2 T cells.Eur J Immunol 2000;30:2101–11.

19 Takeuchi M, Alard P, Streilein JW. TGF-beta promotes immune deviation byaltering accessory signals of antigen-presenting cells. J Immunol1998;160:1589–97.

20 Toms C, Powrie F. Control of intestinal inflammation by regulatory T cells.Microbes Infect 2001;3:929–35.

21 Stavnezer J. Regulation of antibody production and class switching by TGF-beta. J Immunol 1995;155:1647–51.

22 Nazli A, Yang PC, Jury J, et al. Epithelia under metabolic stress perceivecommensal bacteria as a threat. Am J Pathol 2004;164:947–57.

23 Collins SM, Piche T, Rampal P. The putative role of inflammation in the irritablebowel syndrome. Gut 2001;49:743–5.

24 Gonsalkorale WM, Perrey C, Pravica V, et al. Interleukin 10 genotypes inirritable bowel syndrome: evidence for an inflammatory component? Gut2003;52:91–3.

25 Duchmann R, Kaiser I, Hermann E, et al. Tolerance exists towards residentintestinal flora but is broken in active inflammatory bowel disease (IBD). ClinExp Immunol 1995;102:448–55.

26 Lodes MJ, Cong Y, Elson CO, et al. Bacterial flagellin is a dominant antigen inCrohn disease. J Clin Ivest 2004;113:1296–306.

27 Otte J-M, Kiehne K, Herzig K-H. Antimicrobial peptides in innate immunity ofthe human intestine. J Gastroenterol 2003;38:717–26.

28 Macpherson AJ, Uhr T. Induction of protective IgA by intestinal dendritic cellscarrying commensal bacteria. Science 2004;303:1662–5.

29 Haller D, Jobin C. Interaction between resident luminal bacteria and the host:can a healthy relationship turn sour? J Pediatr Gastroenterol Nutr2004;38:123–36.

30 Kelly D, Campbell JI, King TP, et al. Commensal anaerobic gut bacteriaattenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-cand RelA. Nat Immunol 2004;5:104–12.

31 Nobaek S, Johansson M-L, Molin G, et al. Alteration of intestinal microflora isassociated with reduction in abnormal bloating and pain in patients withirritable bowel syndrome. Am J Gastroenterol 2000;95:1231–8.

32 Sen S, Mullan MM, Parker TJ, et al. Effect of Lactobacillus plantarum 299v oncolonic fermentation and symptoms of irritable bowel syndrome. Dig Dis Sci2002;47:2615–20.

33 Kim HJ, Camilleri M, McKinzie S, et al. A randomized controlled trial of aprobiotic, VSL#3, on gut transit and symptoms in diarrhoea-predominantirritable bowel syndrome. Aliment Pharmacol Ther 2003;17:895–904.

Food allergy in IBS 1393

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HEADACHE CARE

VOL. 2, NO. 2, 2005, 105–110

© 2005 LIBRAPHARM LIMITED

1742–3430

doi:10.1185/174234305X14962

ORIGINAL ARTICLE

A Prospective Audit of Food Intolerance among Migraine Patients in Primary Care Clinical PracticeTrevor Rees1, David Watson2, Susan Lipscombe3, Helen Speight4, Peter Cousins4, Geoffrey Hardman5 and Andrew J. Dowson61Hawthorns Surgery, Sutton Coldfield, West Midlands, UK2Hamilton Medical Group, Aberdeen, Scotland3Park Crescent New Surgery, Brighton, East Sussex, UK4YORKTEST Laboratories Ltd (YTL), Osbaldwick, York, UK5Centre for Health Economics, University of York, York, UK6King’s Headache Service, King’s College Hospital, London, UK

Address for correspondence: Dr Andrew J. Dowson, The King’s Headache Service, King’s College Hospital, Denmark Hill, London SE5 9RS, UK. Tel./Fax: +44-1428-712546; email: [email protected]

Key words: Diet – Food intolerance – Migraine – Primary care

This prospective audit was set up to investigate whether migraine sufferers have evidence of IgG-based food intolerances and whether their condition can be improved by the withdrawal from the diet of specific foods identified by intolerance testing. Migraine patients were recruited from primary care practices and a blood sample was taken. Enzyme-linked immunosorbent assays (ELISA) were conducted on the blood samples to detect food-specific IgG in the serum. Patients identified with food intolerances were encouraged to alter their diets to eliminate appropriate foods and were followed up for a 2-month period. Endpoints included identification of the specific foods that the patients were intolerant to, assessing the proportion of patients who altered their diet and the benefit obtained by these patients at 1 and 2 months. Patients reported the level of benefit on a 6-point scale, where 0 = no benefit and 5 = high benefit. Sixty one patients

took part in the audit and 39 completed 2 months of investigation. The mean number of foods identified in the IgG test was 5.3 for all participants and 4.7 for those successfully altering their diet. About 90% of patients changed their diet to a greater or lesser extent following the identification of possible food intolerances. A marked proportion of the migraine patients benefited from the dietary intervention, approximately 30% and 40% reporting considerable benefit at 1 and 2 months, respectively. Also, over 60% of patients who reintroduced the suspect foods back into their diets reported the return of their migraine symptoms. This investigation demonstrated that food intolerances mediated via IgG may be associated with migraine and that changing the diet to eradicate specific foods may be a potentially effective treatment for migraine. Further clinical studies are warranted in this area.

S U M M A R Y

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106 A Prospective Audit of Food Intolerance among Migraine Patients in Primary Care Clinical Practice © 2005 LIBRAPHARM LTD – Headache Care 2005; 2(2)

Introduction

Dietary components are frequently proposed as precip-itating factors for migraine, particularly in children and adolescents1,2. Many different foods have been implic-ated as potential triggers for migraine attacks, including chocolate, cheese, red wine and many others3. However, evidence for this interaction is mostly anecdotal and based on patient reports4. Open studies indicated that low-fat5 and high carbohydrate6 diets could lead to improvements in migraine frequency and/or severity. In contrast, no controlled study has confirmed the incidence of food-evoked migraine attacks. A controlled study with chocolate failed to show that it provoked migraine attacks7. An alternative concept of the relationship of food with migraine is that food cravings occur during the prodrome phase; the food intake thus being a consequence of the attack rather than a cause of it8.

Migraine may be precipitated by food via chemical or immunological mechanisms. Dietary components may affect phases of the migraine process by influencing release of serotonin and noradrenaline, causing vaso-constriction or vasodilatation, or by direct stimulation of trigeminal ganglia, brainstem and cortical neuronal pathways1. Immunological reactions may be mediated by Immunoglobulin E (IgE [classical food allergies occurring immediately after eating]) or, more controv-ersially, by Immunoglobulin G (IgG [food intolerance involving a delayed allergic reaction 2–120 hours after eating]). Available evidence indicates that an IgE mechanism is relatively unimportant in food-induced migraine9 and a review of the clinical literature established no clear evidence of an immune dysfunction in migraine sufferers10. However, the role of a putative IgG mechanism is presently unknown.

The usual way to treat food intolerance is by food elimination and re-challenge procedures, which are imprecise, lengthy and inefficient. As a more efficient alternative to this approach, an enzyme-linked immunosorbent assay (ELISA) test to a panel of 113 food allergen extracts has been developed (YORKTEST Laboratories Ltd [YTL], York, UK). This detects raised food-specific IgG in the serum of people with one or more, usually chronic, conditions. Patients with raised IgG levels to specific foods are advised to remove these from their diets and their progress is monitored with a series of questionnaires. An independent audit of patients treated in this way between February 1998 and August 1999 showed that approximately 50% of all patients reported a high or relatively high response to dietary therapy, based on their levels of food-specific IgGs11. A randomised, controlled clinical trial has demonstrated beneficial effects of this form of dietary therapy on symptom relief for irritable bowel syndrome12.

The present audit was set up to investigate whether migraine sufferers have evidence of IgG-based food intolerances and whether their condition can be improved by the withdrawal from the diet of specific foods identified by intolerance testing.

Patients and Methods

Patients

Established adult migraine patients (age > 18 years) were recruited from primary care clinical practices by their GPs. Patients were required to have high-impact headaches. Patients were diagnosed with episodic migraine (≤ 15 days of headache per month) or chronic migraine (> 15 days of headache per month), according to the GP’s usual practices. All patients provided their written informed consent to take part in the audit.

Study Design

This prospective audit investigated whether migraine patients identified in primary care clinical practice exhibited food intolerances measured as elevated IgG levels to specific foods. The audit also investigated the effect of withdrawing foods associated with high IgG levels on patients’ migraine attacks over a 2-month period.

Primary care physicians were briefed on the rationale and objectives of the audit at a meeting of the UK charity Migraine in Primary Care Advisors (MIPCA) and agreed to participate. Each physician recruited up to 20 migraine patients and provided them with information about the audit. Before entering the study, all patients completed a baseline questionnaire to record demography and allergy history and a Headache Impact Test (HIT-613) questionnaire to record headache severity.

Patients who completed the initial questionnaires were sent a validated blood testing kit by YTL. Patients took a blood sample by skin prick as detailed in the leaflet enclosed with the testing kit and returned the kit to YTL by mail. The blood samples were processed by YTL on receipt of the questionnaires and blood kit. ELISA tests on blood samples were used to detect food-specific IgG in the serum of the blood samples. Results of the ELISA tests were sent directly to the patients by YTL, together with a guidebook on food intolerances and their treatment14.

Patients were free to change their diets to eliminate specific foods identified by the ELISA tests as possibly causing intolerance, either on their own initiative or after consultation with their GP or other healthcare professional. Patients had access by telephone to a

© 2005 LIBRAPHARM LTD – Headache Care 2005; 2(2) A Prospective Audit of Food Intolerance among Migraine Patients in Primary Care Clinical Practice Rees et al. 107

professional dietitian to help them with any dietary alterations that they wished to implement. Follow-up questionnaires were sent to patients after 1 and 2 months to monitor their progress (investigation period).

Study Endpoints and Statistical Analyses

The main study endpoints were:

Demographic data on the patient population, and details of their allergy and headache histories, analysed as descriptive statistics.Identification of the specific foods to which the patients could be intolerant, identified from the ELISA tests of IgG levels and analysed as descriptive statistics.The proportion of patients who altered their diet due to their ELISA test results, analysed as descriptive statistics.The benefit obtained at 1 and 2 months by the patients who altered their diet compared with the situation before diet alteration, analysed as descriptive statistics. Patients reported their level of benefit on a 6-point scale, where 0 = no benefit and 5 = high benefit.

Results

Patient Disposition

Sixty-one patients from six UK GP practices (range 1–17 per centre) were recruited into the audit and completed baseline assessments. In the investigation period, 46 patients (75.4%) continued in the study to 1 month and 39 (63.9%) to 2 months.

Baseline Demography and Headache Severity

Table 1 shows the demography of the patients who took part in the study. The average age was 45.2 years (range 21–68) and most patients (80%) were women.

•

•

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The majority of patients (78.0%) were in full-time education or employment. In examining the allergy history, 15 patients (24.6%) were aware of foods they felt they were allergic to, 42 (68.9%) were in contact with pets, 12 (20.0%) were in contact with chemicals or occupational dust, 52 (86.7%) were currently taking medication and 21 (34.4%) knew about medications they felt they were allergic to. Fifteen patients (24.6%) were current smokers and 18 (29.5%) had given up smoking. Forty three patients (72.9%) drank alcohol but only eight drank over seven units per week and only one drank more than 14 units per week.

Most patients had suffered from headache for a considerable time; 64% for ≥ 10 years, 20% for 5–10 years and 16% for < 5 years. Patients were severely affected by their headaches (Table 2). Eighty two per cent ‘very often’ or ‘always’ had severe pain, while 67% were ‘very often’ or ‘always’ limited in their usual activities during their headaches. Between 87% and 90% of patients were too tired to work, felt irritation and suffered from lack of concentration at least sometimes during their attacks. Patients reported a mean of 10.1 symptoms (range 1–24) associated with their headaches. Over 80% of patients reported that their headaches interfered with sleep, leisure and overall comfort. The mean weighted HIT score at baseline was 64.9 (range 48–78), corresponding to severe impact13.

Gender Male 12 20.0%Female 48 80.0%

Age group Under 30 10 16.7%30 to 39 9 15.0%40 to 49 14 23.3%50 to 59 21 35.0%60 and over 6 10.0%

Employment status Retired 3 5.1%Sick/disabled 4 6.8%Housewife 3 5.1%Part time 2 3.4%Full time skilled 25 42.4%Full time semi-skilled 17 28.8%Full time unskilled 2 3.4%Student 2 3.4%Unemployed 1 1.7%

Proportion of patients (%) Headache severity

Never Rarely Sometimes Very often Always

Severe pain 2 0 16 61 21Limit to usual activities 0 2 31 51 16Desire to lie down 2 0 18 41 39Too tired to work 5 8 51 31 5Irritation 5 7 33 39 16Lack of concentration 3 7 38 40 12

Table 1. Baseline demography (n = 61)

Table 2. Severity of patients’ headaches: pain intensity, impact on daily activities and mood alterations


Identification of Food Intolerances

Food intolerances identified by IgG testing were analysed for the 61 patients who took part in the study and for the 39 who completed the 2 months of investigation. In the total study population, 60 of 61 patients (98.4%) had reactions to a total of 48 different foods, with an average of 5.3 (range 0–17) reactions per patient. In the patients who completed 2 months, 38 of 39 patients (97.4%)

had reactions to a total of 36 different foods, with an average of 4.7 (range 0–17) reactions per patient. Table 3 shows the distribution of food intolerances in these two populations. The most frequently reported intolerances (in over 10% of patients in either population) were to cow’s milk, yeast, egg white, egg yolk, wheat, gluten (gliadin), corn, cashew nuts, mollusc mix, brazil nut, cranberry and garlic (Table 3), and were similar in prevalence in the two populations.

Positive ELISA test ( n [%]) Food

Whole study population ( n = 61)

Patients completing 2 months( n = 39)

Cow’s milk 52 (85.2%) 34 (87.2%) Yeast 37 (60.7%) 22 (56.4%) Egg white 34 (55.7%) 23 (59.0%) Egg yolk 20 (32.8%) 13 (33.3%) Wheat 19 (31.1%) 12 (30.8%) Gliadin 16 (26.2%) 10 (25.6%) Corn 15 (24.6%) 8 (20.5%) Cashew 12 (19.7%) 7 (17.9%) Mollusc mix 10 (16.4%) 3 (7.7%) Brazil nut 9 (14.8%) 6 (15.4%) Cranberry 7 (11.5%) 5 (12.8%) Garlic 5 (8.2%) 4 (10.3%) Beef 3 (4.9%) 2 (5.1%) Pork 3 (4.9%) 1 (2.6%) Ginger 3 (4.9%) 2 (5.1%) Buckwheat 4 (6.6%) 1 (2.6%) Crustacean mix 5 (8.2%) 1 (2.6%) Rye 2 (3.3%) 2 (5.1%) Millet 3 (4.9%) 2 (5.1%) Rice 1 (1.6%) 1 (2.6%) Soya bean 5 (8.2%) 3 (7.7%) Hazelnut 4 (6.6%) 3 (7.7%) Mustard seed 1 (1.6%) 1 (2.6%) Salmon/trout 2 (3.3%) 1 (2.6%) Plaice/sole 3 (4.9%) 1 (2.6%) Peanut 3 (4.9%) 2 (5.1%) Chicken 3 (4.9%) 1 (2.6%) Lentils 3 (4.9%) 1 (2.6%) Pea 2 (3.3%) 1 (2.6%) Almond 5 (8.2%) 3 (7.7%) Cola nut 3 (4.9%) 1 (2.6%) Duck 1 (1.6%) 0Lamb 3 (4.9%) 1 (2.6%) Turkey 2 (3.3%) 0White fish 3 (4.9%) 1 (2.6%) Kiwi 4 (6.6%) 2 (5.1%) Pineapple 2 (3.3%) 0Sunflower seed 2 (3.3%) 0Oat 2 (3.3%) 0Haricot bean 3 (4.9%) 2 (5.1%) Coconut 1 (1.6%) 1 (2.6%) Tea 1 (1.6%) 0Carrot 1 (1.6%) 0Barley 1 (1.6%) 0Tuna 1 (1.6%) 0Sesame seed 1 (1.6%) 0Coffee 1 (1.6%) 0Avocado 1 (1.6%) 0

Table 3. Food intolerances in the audit population: number and proportion of patients with a positive ELISA test to IgG from various foodstuffs

© 2005 LIBRAPHARM LTD – Headache Care 2005; 2(2) A Prospective Audit of Food Intolerance among Migraine Patients in Primary Care Clinical Practice Rees et al. 109

Proportion of Patients who Altered their Diets

Of the 46 patients who returned the questionnaire after 1 month of investigation, 41 (89.1%) patients changed their diets to eliminate foods identified by the IgG testing and 5 (10.9%) did not. Of those who changed their diet, 19 (46.3%) reported that they altered their diets a lot and 22 (53.7%) reported they had made a ‘reasonable attempt’ to avoid the specified foods.

Of the 39 patients who returned the questionnaire after 2 months of investigation, 22 (56.4%) reported that they altered their diets a lot and 13 (33.3%) reported they had made a ‘reasonable attempt’ to avoid the specified foods. Two patients reported that they did not change their diet at all.

Benefit Obtained from Changing Diets

Figures 1 and 2 show the level of benefit reported by patients after 1 and 2 months, respectively, using the 6-point scale (0 = no benefit and 5 = high benefit). After 1 month, 27.5% of patients reported considerable benefit (scoring 4 or 5), while 30.0% reported little or no benefit (scoring 0 or 1). Of 18 patients who had retried foods they had stopped taking, five (27.8%) reported a strong return of migraine symptoms and seven (38.9%) a slight return. After 2 months, 38.2% of patients reported considerable benefit (scoring 4 or 5), while 32.4% reported little or no benefit (scoring 0 or 1). Of 26 patients who had retried foods they had stopped taking, seven (26.9%) reported a strong return of migraine symptoms and 11 (42.3%) a slight return.

A limited post hoc analysis was conducted to investigate the factors possibly associated with benefit. Of the 13 patients who reported considerable benefit from dieting after 2 months, nine (69.2%) said they had dieted strictly after 1 month and 12 (92.3%) after 2 months. Of the 11 patients who reported little or no benefit after 2 months, only two (18.2%) had dieted strictly after 1 month and five (45.5%) after 2 months. Compared to those who did not benefit, the patients who benefited were more likely to have suffered from bloating and sleep deprivation and to have never smoked (although all patients had given up at least 10 years previously). Those who reported no benefit from dieting were more likely to be trying other remedies as well, including avoiding chocolate and taking sumatriptan and homeopathic remedies. However, none of the above differences was testable for statistical significance due to the small number of patients involved.

Discussion

To our knowledge, this is the first investigation of possible IgG-mediated food intolerances in migraine patients. The patients who took part were all severely affected by their

migraine, reporting high levels of pain and impact on their everyday activities. This is a group of patients who are typically poorly managed in primary care15 and for whom new management initiatives would be welcome.

Almost all patients had multiple food intolerances in this investigation, identified as positive food-specific IgG test results. Typically, individuals were positive to at least one of cow’s milk, egg and yeast, together with a small number of more individual reactions. These results are similar to those reported for other conditions11,12. Of the patients who took part in the investigation, about 90% changed their diet to a greater or lesser extent at both 1 and 2 months.

A marked proportion of the migraine patients benefited from dietary intervention by cutting out foods for which they had an elevated IgG level. Approx-imately 30% and 40% reported considerable benefit at 1 and 2 months, respectively. Reinforcing this is the fact that over 60% of patients who re-introduced the suspect foods back into their diets reported the return of their migraine symptoms. These results are encouraging and indicate that changing diet to counteract food intoler-

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Figure 1. Benefit of the diet after 1 month of the investigation: proportion of patients reporting their level of benefit on a 6-point scale, where 0 = no benefit and 5 = high benefit

Figure 2. Benefit of the diet after 2 months of the investigation: proportion of patients reporting their level of benefit on a 6-

point scale, where 0 = no benefit and 5 = high benefit


ances may be an effective treatment for at least some migraine sufferers.

However, it is not yet possible to recommend this approach for general clinical use. This investigation was a small audit to establish a possible relationship between food intolerances and migraine. In this it was successful, although benefits experienced by patients may have been due (in part or in whole) to a placebo effect. There remains a series of questions that need to be answered before we have proof of this concept:

Do migraine sufferers differ from unaffected people or people with other disorders in the pattern of IgG that circulates?Do symptomatic reports of food intolerance correlate with the IgG data?Are migraine sufferers able to self-identify food intolerances?Does allergen avoidance lead to an improvement in migraine and can this be confirmed by re-challenge?

We suggest two follow-up studies that may answer these questions. Whether migraine patients differ from the general population and whether self-reported allergies correlate with food intolerances in migraine sufferers can be examined in a blinded study investigating the pattern of IgG-related food intolerances in migraine patients (with and without a history of allergy) and matched healthy controls without migraine. A small placebo-controlled study can then be used to study the effect of diet alteration on migraine symptoms. The study requires a re-challenge phase, and robust, validated endpoints, over a 3-month evaluation time.

In conclusion, this pilot audit demonstrated that migraine attacks may be related to food intolerances mediated via IgG and that changing the diet to eradicate specific foods may be a potentially effective treatment for migraine. Further clinical studies are required to confirm these findings and examine the clinical importance of this treatment approach.

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Acknowledgements

The authors are pleased to acknowledge the help of Dr Frances Carter during the setting up and running of this audit. The audit was conducted by MIPCA, with help and sponsorship from the Migraine Action Association and YORKTest Laboratories Ltd.

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adolescent migraine. Pediatr Neurol 2003;28:9-15 2. Leira R, Rodriguez R. Diet and migraine. Rev Neurol 1996;

24:534-8 3. Breslau N, Rasmussen BK. The impact of migraine: Epidemiology,

risk factors, and co-morbidities. Neurology 2001;56(Suppl. 1): 4-12

4. Peatfield RC. Relationships between food, wine, and beer-precipitated migrainous headache. Headache 1995;35: 355-7

5. Bic Z, Blix GG, Hopp HP et al. The influence of a low-fat diet on incidence and severity of migraine headaches. J Womens Health Gend Based Med 1999;8:623-30

6. Hasselmark L, Malmgren R, Hannerz J. Effect of a carbohydrate-rich diet, low in protein-tryptophan, in classic and common migraine. Cephalalgia 1987;7:87-92

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10. Kemper RH, Meijler WJ, Korf J et al. Migraine and function of the immune system: a meta-analysis of clinical literature published between 1966 and 1999. Cephalalgia 2001; 21:549-57

11. Sheldon TA. Independent audit of IgG food intolerance tested patient survey. British Allergy Foundation, 2000

12. Atkinson W, Sheldon TA, Shaath N et al. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Gut 2004;53:1459-64

13. Kosinski M, Bayliss MS, Bjorner JB et al. A six-item short-form survey for measuring headache impact: the HIT-6. Qual Life Res 2003;12:963-74

14. YORKTEST guidebook on food intolerances and their treatment. York, UK: YORKTEST Laboratories Ltd, 2002

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CrossRef links are available in the online published version of this paper:http://www.cmrojournal.com

Paper HC-0047_2, Accepted for publication: 27 January 2005Published Online: 18 February 2005

doi:10.1185/174234305X14962

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T h e n e w e ng l a nd j o u r na l o f m e dic i n e

n engl j med 357;17 www.nejm.org october 25, 2007 1731

review article

Medical Progress

Celiac DiseasePeter H.R. Green, M.D., and Christophe Cellier, M.D., Ph.D.

From the Department of Medicine, Colum-bia University College of Physicians and Surgeons, New York (P.H.R.G.); and the Department of Gastroenterology, Euro-pean Georges Pompidou Hospital, René Descartes Paris V University, Assistance Publique–Hôpitaux de Paris, INSERM U793, Paris (C.C.). Address reprint re-quests to Dr. Green at the Department of Medicine, Columbia University College of Physicians and Surgeons, 180 Fort Washington Ave., Rm. 956, New York, NY 10032, or at [email protected].

N Engl J Med 2007;357:1731-43.Copyright © 2007 Massachusetts Medical Society.

Celiac disease is a unique autoimmune disorder, unique because the environmental precipitant is known. The disorder was previously called celiac sprue, based on the Dutch word sprue, which was used to describe a dis-ease similar to tropical sprue that is characterized by diarrhea, emaciation, aphthous stomatitis, and malabsorption.1,2 Celiac disease is precipitated, in genetically pre-disposed persons, by the ingestion of gluten, the major storage protein of wheat and similar grains.3 Originally considered a rare malabsorption syndrome of child-hood, celiac disease is now recognized as a common condition that may be diag-nosed at any age and that affects many organ systems. The therapy for the disease is a gluten-free diet; however, the response to therapy is poor in up to 30% of patients, and dietary nonadherence is the chief cause of persistent or recurrent symptoms. Small intestinal adenocarcinoma, refractory sprue, and enteropathy-associated T-cell lymphoma are complications of celiac disease that must be ruled out when alarm-ing symptoms such as abdominal pain, diarrhea, and weight loss develop despite a strict gluten-free diet.

Patho genesis

Celiac disease results from the interaction between gluten and immune, genetic, and environmental factors (Fig. 1).

The Role of Gluten

Celiac disease is induced by the ingestion of gluten, which is derived from wheat, barley, and rye. The gluten protein is enriched in glutamine and proline and is poor-ly digested in the human upper gastrointestinal tract. The term “gluten” refers to the entire protein component of wheat; gliadin is the alcohol-soluble fraction of gluten that contains the bulk of the toxic components. Undigested molecules of gliadin, such as a peptide from an α-gliadin fraction made up of 33 amino acids, are resis-tant to degradation by gastric, pancreatic, and intestinal brush-border membrane proteases in the human intestine and thus remain in the intestinal lumen

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