Test-based exclusion diets in gastro-esophageal reflux disease patients: A randomized controlled pilot trial

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1 Submit Mnuscript: Help Desk: DOI: /wjg.v20.i World J Gstroenterol 2014 December 7; 20(45): ISSN (print) ISSN (online) 2014 Bishideng Publishing Group Inc. All rights reserved. RANDOMIZED CONTROLLED TRIAL Test-bsed exclusion diets in gstro-esophgel reflux disese ptients: A rndomized controlled pilot tril Michele Cselli, Giovnni Zulini, Frncesc Cssol, Ndi Fusetti, Elen Zeni, Ntlin Lo Cscio, Cecili Sovi, Sergio Gullini Michele Cselli, Giovnni Zulini, Frncesc Cssol, Cecili Sovi, Deprtment of Medicl Sciences, Internl Medicine Institute, University of Ferrr, Ferrr, Itly Ndi Fusetti, Sergio Gullini, Deprtment of Gstroenterology, School of Gstroenterology, University of Ferrr, Ferrr, Itly Elen Zeni, Ntlin Lo Cscio, Center Study Assocition on Food Intolernce nd Nutrition of Ferrr, Ferrr, Itly Author contributions: Cselli M nd Gullini S designed the reserch; Cssol F, Fusetti N, Zeni E nd Lo Cscio N performed the reserch; Sovi C nd Zulini G nlyzed nd interpreted dt nd drfted the rticle. All uthors revised the rticle nd pproved its finl version. Correspondence to: Michele Cselli, MD, Deprtment of Medicl Sciences, Internl Medicine Institute, University of Ferrr, Vi Svonrol 9, Ferrr, Itly. csc@unife.it Telephone: Fx: Received: Jnury 6, 2014 Revised: April 29, 2014 Accepted: July 24, 2014 Published online: Abstrct AIM: To investigte the clinicl response of gstroesophgel reflux disese (GERD) symptoms to exclusion diets bsed on food intolernce tests. METHODS: A double blind, rndomized, controlled pilot tril ws performed in 38 GERD ptients prtilly or completely non-responders to proton pump inhibitors (PPI) tretment. Fsting blood smples from ech ptients were obtined; leukocytotoxic test ws performed by incubting the blood with pnel of 60 food items to be tested. The rection of leukocytes (rounding, vcuoliztion, lck of movement, flttening, frgmenttion or disintegrtion of cell wll) ws then evluted by opticl microscopy nd rted s follows: level 0 = negtive, level 1 = slightly positive, level 2 = modertely positive, nd level 3 = highly positive. A true diet excluding food items inducing moderte- severe rections, nd control diet including them ws developed for ech ptient. Then, twenty ptients received the true diet nd 18 the control diet; fter one month (T1) symptoms severity ws scored by the GERD impct scle (GIS). Hence, ptients in the control group were switched to the true diet, nd symptom severity ws re-ssessed fter three months (T2). RESULTS: At bseline (T0) the men GIS globl score ws 6.68 (rnge 5-12) with no difference between true nd control group (6.6 ± 1.19 vs 6.7 ± 1.7). All ptients rected modertely/severely to t lest 1 food (rnge: 5-19), with significntly greter number of food substnces inducing rection in controls compred with the true diet group (11.6 vs 7.0, P < 0.001). Food items more frequently involved were milk, lettuce, brewer s yest, pork, coffee, rice, sole sprgus, nd tun, followed by eggs, tomto, grin, shrimps, nd chemicl yest. At T1 both groups displyed reduction of GIS score ( true group 3.3 ± 1.7, -50%, P = 0.001; control group 4.9 ± 2.8, -26.9%, P = 0.02), lthough the GIS score ws significntly lower in true vs control group (P = 0.04). At T2, fter the diet switch, the control group showed further reduction in GIS score (2.7 ± 1.9, -44.9%, P = 0.01), while the true group did not (2.6 ± 1.8, -21.3%, P = 0.19), so tht the GIS scores didn t differ between the two groups. CONCLUSION: Our results suggest tht food intolernce my ply role in GERD symptoms development, nd leucocytotoxic test-bsed exclusion diets my be possible therpeutic pproch when PPI re not effective or indicted Bishideng Publishing Group Inc. All rights reserved. Key words: Gstro-esophgel reflux disese; Food intolernce; Leukocytotoxic test; Exclusion diet; Tretment Core tip: We previously observed tht gstro-esoph- 1 December 7, 2014 Volume 20 Issue 45

2 Zheng SZ et l. Tretment with sorfenib in ruptured HCC gel reflux disese (GERD) symptoms respond to exclusion diets bsed on food intolernce tests. In this rndomized controlled pilot tril we found tht ptient prtilly/completely non responders to proton pump inhibitors experience significnt improvement in symptoms, compred with controls, fter one month of exclusion diet bsed on leukocytotoxic test s results. These results indicte possible role of food intolernce in the etiopthogenesis of GERD symptoms, nd possible therpeutic ppliction of exclusion diets when PPI re not effective/indicted. Cselli M, Zulini G, Cssol F, Fusetti N, Zeni E, Lo Cscio N, Sovi C, Gullini S. Test-bsed exclusion diets in gstroesophgel reflux disese ptients: A rndomized controlled pilot tril. World J Gstroenterol 2014; 20(45): Avilble from: URL: v20/i45/00000.htm DOI: i INTRODUCTION Gstro-esophgel reflux disese (GERD) is n extremely common condition chrcterized by symptoms of hertburn nd cid regurgittion, presenting chronic relpsing disese course. It is more common in Western popultions, with high impct on ptients socil nd working life [1,2]. The etiopthogenesis of GERD remins lrgely unknown even though up to 20% of the dult popultion in Western Countries is ffected by reflux symptoms on week bsis [1]. Notbly, t lest 50% of GERD ptients remin on continuous medicl therpy [3]. This condition is known to predispose to n incresed risk of cncer [4,5]. Although the pthogenesis of this bckwrd displcement of gstrointestinl contents remins elusive, it is know tht bnorml contct of gstrointestinl contents with esophgel mucos, insufficient clernce of the esophgel body, lower esophgel sphincter incompetence, nd delyed gstric emptying hve puttive role in GERD pthogenesis. Despite severl exmintions (e.g., endoscopy, 24-h ph monitoring, brium esophgel rdiogrphy, proton pump inhibitor (PPI) test, gstroesophgel scintigrphy) re vilble for the dignosis of GERD, none of these tests is dignostic, nd current guidelines recommend to tret ptients younger thn 50 yers on the bsis of their symptoms [6,7]. Consequently, symptoms evlution nd score re fundmentl in dignosis nd therpy of GERD ptients, nd severl vlidted questionnires re currently used in the clinicl prctice [8]. The possible role of food intolernce in the etiopthogenesis of GERD hs been suggested by our group in recent retrospective report [9] in which we evluted the results of leukocytotoxic test for food intolernce using pnel of 60 food items. This test is bsed on the opticl evlution of leukocytes in blood smple tht hs come into direct contct with specific food sub- stnces. On the bsis of leukocytes observtion, degrees of rection to the food extrcts re rted ccording to the following scle: level 0 = negtive, level 1 = slightly positive, level 2 = modertely positive, nd level 3 = highly positive. These levels correspond to (1) the stte of the leukocytes, which rect by swelling, then developing vcuoles, nd finlly deteriorte; nd (2) the totl number of leukocytes tht rect. Currently, the dedicted tsk forces consider these tests to hve poor clinicl specificity nd sensitivity [10] we hypothesized tht the most importnt reson might be the very high frequency of mild positive results [9]. Therefore, we decided to exclude level 1 of the scle, directly strting from level 2. In this wy, we could demonstrte strong difference between GERD ptients nd controls, nd the test-bsed exclusion diet resulted effective in ll ptients [9]. On this bsis, we crried out this prospective rndomized controlled pilot tril with the following ims: (1) to evlute the prevlence of modertesevere leukocytotoxic rections in ptients with GERD symptoms; nd (2) to evlute the clinicl response to test-bsed exclusion diet compred to control diet. MATERIALS AND METHODS Ptients Outptients ttending the Deprtment of Gstroenterology of Ferrr Hospitl becuse of typicl GERD symptoms (hertburn nd regurgittion) were considered for recruitment. The severity of symptoms ws scored by the gstro-esophgel reflux disese impct scle (GIS) questionnire [11]. A score equl or mjor to 5, concerning only the first four clinicl questions (pin in the chest/behind the brestbone, regurgittion/cid tste in one s mouth, burning senstion in the chest/behind the brestbone, nd sore throt/horseness relted to hertburn or cid reflux) ws used s cut-off vlue for inclusion into the study. Among these ptients, only non-responders to PPI therpy or prtilly responders (i.e., ptients experiencing only slight reduction of symptoms fter 4 wk of tretment or hving n initil response to PPI tretment but with relpses of symptoms during the 4 wk of PPI tretment) were recruited. Ptients with lrm symptoms/ signs (dysphgi, unintentionl weight loss, norexi, recurrent vomiting, upper bdominl mss, nemi, hemtemesis or melen) nd ptients over 50 yers with fmily history of gstric/oesophgel crcinom were excluded. Ptients with clinicl history of celic disese or lctose intolernce were lso excluded. The study protocol ws pproved by the locl ethics committee nd ll ptients provided written informed consent. Methods The study used double blind, rndomized, controlled prllel design in which ptients were rndomized to either true or control test-bsed diet group. In both groups the diets were test-bsed, but while the true diets excluded ll the foods presenting moderte-severe rection t the leukocytotoxic test, the control diets 2 December 7, 2014 Volume 20 Issue 45

3 Tble 1 Generl chrcteristics of the study popultion t bseline (time 0) True diet group Control group Totl Ptients (n) Age 45 ± ± ± 9.1 Mles, n (%) 5 (25) 2 (11.1) 7 (18.4) Time 0: GIS 6.6 ± ± ± 1.8 P 1.3 ± ± ± 0.9 R 1.7 ± ± ± 0.8 B 1.9 ± ± ± 0.8 S 1.8 ± ± ± 0.9 Foods inducing rection 1 7 (6-12) 11.7 (7-19) 9.2 (6-19) Level 2 rection Level 3 rection Men number of foods inducing rection, rnge in prentheses. Dt re expressed s bsolute numbers (percentge) or men ± SD. excluded foods provoking no rections. In this wy we voided the possibility tht stndrdized not test-bsed control diet might exclude by chnce food provoking rection in tht ptient. At the time of enrolment, blood smple ws collected from ech ptient nd sent to the lbortory of the locl Center Study Assocition on Food Intolernce nd Nutrition, where the leukocytotoxic tests were performed. For these tests pnel of 60 food extrcts ws used (Antigeni s.r.l., Bologn, Itly) ccording to the mnufcturer s instructions. The buffy cot obtined by centrifuging blood ws suspended in mixture of sterile distilled wter nd serum, nd then plced on siliconized microscope slide previously coted with the dried extrct of the food to be tested. A stff member evluted by opticl microscopy (40 zoom) the unstined leukocytes t vrying intervls, up to two hours. Any lck of movement, rounding, vcuoliztion, flttening, frgmenttion, or disintegrtion of cells ws considered, nd rted s follows: level 0 = negtive, level 1 = slightly positive, level 2 = modertely positive, nd level 3 = highly positive, s previously sid. According to our previous study [9], we excluded level 1 response, nd considered only moderte-severe rections. In this wy we improved the specificity of the test (whose mjor criticism is relted to the extremely frequent positive rections) nd excluded the fewest foods s possible thus improving the ptients complince to the diet. Both true nd control diets were rrnged on the bsis of the test results. The true diets were produced excluding ll food ssocited with level 2-3 rections, while control diets were produced by eliminting only food tht provoked no rections. In this wy we excluded the possibility tht food item inducing moderte-severe rection might be csully excluded from the control diet. The proposed diets did not differ for cloric content. Ptients were llocted to one of the two diet sheets bsed on rndomiztion schedule developed by using rndom computer number genertor; both ptients nd clinicl/ dieticin stff were blinded to the group ssignment of ech ptient. Symptoms were ssessed t the time of recruitment (T0), nd fter one (T1) nd three months (T2). At T1, control diets were substituted by true diets, while ptients ssigned to true diet t T0 continued with the prescribed diet. At T1 nd T2 ech ptient fulfilled the GIS questionnire, ws visited by gstroenterologist, nd ws evluted by dieticin. Both the globl GIS score, nd the score for every single item (P for pin in the chest/behind the brestbone, R for regurgittion/ cid tste in one s mouth, B for burning senstion in the chest/behind the brestbone, nd S for sore throt/ horseness relted to hertburn or cid reflux) were considered. For ech item the score ws ssigned bsed on the frequency of tht specific symptom s follows: never = 0 points, sometimes = 1 point, often = 2 points, nd dily = 3 points. Sttisticl nlysis Continuous vribles were expressed s men ± SD or medin (interqurtile rnge) when necessry. Mens (between groups) were compred by one-wy ANOVA, while medins were compred by the Mnn-Whitney test. Mens (within group) were compred by pired-smples t test. Correltions between continuous vribles were tested by Person s correltion. Proportions were compred by the χ 2 test. All nlyses were performed by SPSS for Windows sttisticl pckge, version 13.0 (SPSS, Inc., Chicgo, IL, United Sttes). RESULTS From Mrch 2011 to December 2012 totl of 38 ptients were enrolled into the study (men ge: 47.5 yers; 18.4% mles). At bseline (T0), the men globl GIS score ws 6.68 points (rnge 5-12). All ptients were found to rect modertely/severely to t lest 1 food item (rnge 5-19). Tble 1 summrizes the principl chrcteristics of the ptients t bseline. No significnt difference emerged between the two groups s regrds to ge, gender, nd severity of symptoms. The number of food items inducing moderte-severe rection t leukocyotoxic test ws higher in the control compred with the true diet group (11.6 vs 7.0, P < 0.001). The food substnces more frequently involved in leukocytotoxic test positivity re reported in Tble 2. At T0, the men GIS globl score, s well the men sub-scores, were similr in the two groups of ptients (6.6 ± 1.9 vs 6.7 ± 1.7) (Figure 1). No specific dverse events, nor motivted drop out from the study were recorded in either group. Time 1 outcome: GIS score fter 1 mo of elimintion diet One month fter the beginning of the elimintion diet (T1), the true test-bsed diet group experienced n importnt reduction (-50%) in GIS globl score (from 6.6 ± 1.9 to 3.3 ± 1.7, P = 0.001). Ptients in the control diet group lso experienced significnt reduction in GIS globl score (-26.9%, from 6.7 ± 1.7 to 4.9 ± 2.8, P = 0.02), lthough it ws much smller compred to true diet group. As mtter of fct, t T1 the difference be- 3 December 7, 2014 Volume 20 Issue 45

4 Tble 2 Type of foods most frequently inducing test positivity Food Totl rections Level 2 Level 3 Milk Lettuce Brewer s yest Pork Coffee Rice Sole Asprgus Tun Egg Tomto Grin Shrimps Chemicl yest tween the men GIS scores in the two groups ws significnt, s regrds both the GIS globl score (3.3 ± 1.7 vs 4.9 ± 2.8, P = 0.04) nd the B sub-score (1.0 ± 0.7 vs 1.5 ± 0.8, P = 0.05) (Figure 1). Time 2 outcome: GIS score fter the diet switch Despite further reduction ws observed t T2 (-21.3%) in the true diet group the T2 didn t differ from the T1 GIS score (3.3 ± 1.7 vs 2.6 ± 1.8, P = 0.19) (Figure 1). On the contrry, further significnt reduction in GIS score ws observed mong ptients in the control group (-44.9%, 4.9 ± 2.8 vs 2.7 ± 1.9, P = 0.01). At T2, the men GIS globl scores s well s the sub-scores were not sttisticlly different between the two groups (dt not shown). DISCUSSION The etiopthogenesis of intestinl functionl diseses such s irritble bowel disese (IBS), functionl dyspepsi, nd GERD re fr from being well elucidted. In the lst yers, however, incresing dt hs been published consistent with possible role of food intolernce in these medicl conditions. The ttention hs been prticulrly focused on IBS, nd severl studies hve confirmed the possible effectiveness of test-bsed exclusion diets on IBS symptoms [12-14]. To our knowledge, this is the first controlled, double blind, study in which not only leukocytotoxic test hs been used to prepre test-bsed exclusion diet, but lso n ttempt to vlidte the test by control test-bsed diet hs been mde. Our preliminry dt seem to suggest tht pthogenetic mechnisms relted to food intolernce my ply role in the etiopthogenesis of GERD. The modifictions of the GIS score from T0 to T2 in the two groups of ptients clerly shows tht the entity of reduction in the true diet group t T1 is equl to the reduction observed for the control group t T2. This observtion seems to confirm the effectiveness of true test-bsed diet in reducing the impct of GERD symptoms of bout 4%-50%. Notbly, the significnt but smller reduction in GIS score from T0 to T1 observed GIS globl score T0 T1 T2 in the control group (-26.9%) is probbly due to plcebo effect, in the sme wy s the slight (not significnt) reduction of GIS scores in the true diet group from T1 to T2. Plcebo effect hs been reported to be prticulrly strong when the tretment consists in diet, in prticulr when the condition to cure is functionl disese [15,16]. However, lbeit plcebo effect might be present nd might justify the reduction of symptoms in ptients following the control diet, ptients following the true testbsed diet experienced significntly greter reduction in symptoms compred to control group, s did people in the control group fter the diet switch, indicting tht the effect of true diets cnnot be just ttributble to the plcebo effect. Our results suggest tht, lthough not ll GERD symptoms might be ttributed to food intolernce, this pthogenetic condition my ply role in GERD symptoms development. Thus, test-bsed exclusion diets my be considered n effective nd cost-effective therpeutic tool, poor of dverse events, nd prticulrly indicted when PPI tretment is not effective or not indicted. When considering only the moderte-severe rections, the leukocytotoxic test ppers to be effective in identifying the food substnces whose exclusion is ssocited with clinicl improvement of GERD symptoms. As corollry finding, the pnel of food items most frequently involved in leukocytotoxic rection ws similr to the one observed in our previous retrospective report [9], nd notbly different from the pnel of food previously relted to GERD symptoms (i.e., chocolte, mint, onions nd citrus fruit) confirming only the role of mint, dietry fts, coffee, nd tomto. We previously suggested tht rtionle for the use of leukocytotoxic test might be relted to the role of T regultory cells. In recent yers, the role of specific receptors nd specilized cells of innte immunity in the recognition nd identifiction of ntigens hs become evident. The complete recognition of n ntigen by this receptor "True" diet "Control" diet Figure 1 Histogrm compres the men globl GIS scores obtined in true diet group nd control diet group t T0 (bseline), T1 (one month fter receiving the diet) nd T2 (three months fter receiving the diet for true diet group, two months fter the diet switch for the control group). Error brs indicte the stndrd devition. P < 0.05 mong two vlues. 4 December 7, 2014 Volume 20 Issue 45

5 system is t the bsis of tolernce to food substnce or microorgnism. When n ntigen is not suitbly recognized, kind of dptive immune response my be ctivted (llergy or intolernce) closely depending on the efficiency of T regultor cell system. Consistent with this, intriguing dt [17] indicte tht T-regultory cells induce suppression of llergic disese by suppressing IgE nd inducing IgG4. We hve previously suggested [9] tht n upregultion of T-regultory cells my induce n increse in both IgG4 nd toxic rections in blood leukocytes, s result of T-regultory cell ctivity, nd these phenomen might represent the pthogenetic bses of intolernce. The regultion stte of T-regultory cells my be the key point: wheres n llergic rection my depend on down-regultion of T-regultory cells, n intolernce rection my result from n up- regultion of T-regultory cells. The outcome of this preliminry tril seem to suggest tht elimintion diet, bsed on moderte-severe rections of the used leukocytotoxic test, cn be effective in reducing the severity of GERD symptoms in ptients not responders or prtilly responders to PPI therpy. Since test-bsed exclusion diets re very cost-effective nd lck of serious dverse events, they could be considered s possible therpeutic pproch in GERD when PPI re not effective or not indicted. COMMENTS Bckground Gstro-esophgel reflux disese (GERD) is very common condition chrcterized by hertburn nd cid regurgittion, with chronic relpsing disese course. Although it is known to be cused by the bnorml contct between esophgel mucos nd gstric cid secretions, the ethiopthogenesis of this illness remin unknown. We hd previously hypothesized possible role of food intolernce, bsed on the results of leukocytotoxic tests. Ptients younger thn 50 yers, nd free from conditions configuring high risk, cn be simply treted on the bsis of their symptoms with proton pump inhibitors (PPI); however, there is proportion of ptients considered non-responders or prtilly responders who could benefit from new therpeutic pproches. Reserch frontiers The reserch hotspot is finding therpeutic option for GERD ptients who do not respond to PPI. Innovtions nd brekthroughs Leukocytotoxic test for food intolernce is one of the vilble methods to test the presence of intolernce towrds pnel of food substnces. It is considered to hve poor specificity nd sensitivity, but this problem might be overcome by considering only the moderte-strong positive rections. In this wy uthors produced true elimintion diets, free from the foods giving moderte-severe positive rections, nd control diets, free from foods giving no rections. They found tht GERD ptients following the true diet hd significnt improvement in symptoms compred with control group. Applictions Elimintion diet, bsed on moderte-severe rections of the leukocytotoxic test might be effective in reducing the severity of GERD symptoms in ptients not responders/prtilly responders to PPI tretment. Being very cost-effective, nd free from serious dverse event, elimintion diet might be considered s possible therpeutic pproch in GERD when PPI re not effective or not indicted. Terminology Leukocytotoxic test is bsed on the opticl evlution of leukocytes in blood smple tht hs come into direct contct with the food substnces. On the bsis of leukocytes observtion, degrees of rection to the food extrcts re rted ccording to the stte of the leukocytes, which rect by swelling, then developing vcuoles, nd finlly deteriorting, nd to the totl number of leukocytes tht rect. Elimintion diets re diets produced by excluding from the limentry hbits of the ptient specific food items. In the study true diets excluded food substnces giving moderte-severe positive rection, while control diets excluded foods giving no rections t the leukocytotoxic test. Peer review The uthors investigted the effect of the clinicl response of GERD symptoms to exclusion diets bsed on food intolernce tests in double blind, rndomized, controlled pilot tril in ptients who were prtilly or completely non-responders to PPI tretment. They suggest tht food intolernce my ply prt in GERD symptoms development nd leucocytotoxic test-bsed exclusion diets my be potentil therpeutic pproch when PPI therpy is less effective. With the limittion tht the test used for food sensitivity is of questionble utility, this is certinly n interesting study. It is lso fscinting tht both groups, those tht eliminted rective foods nd those tht eliminted un-rective foods, showed improvement in their GERD symptoms, indicting role of plcebo effect. REFERENCES 1 Dent J, El-Serg HB, Wllnder MA, Johnsson S. Epidemiology of gstro-oesophgel reflux disese: systemtic review. Gut 2005; 54: [PMID: DOI: / gut ] 2 Wiklund I. Review of the qulity of life nd burden of illness in gstroesophgel reflux disese. Dig Dis 2004; 22: [PMID: DOI: / ] 3 Ofmn JJ, Shw M, Sdik K, Grogg A, Emery K, Lee J, Reyes E, Fullerton S. Identifying ptients with gstroesophgel reflux disese: vlidtion of prcticl screening tool. Dig Dis Sci 2002; 47: [PMID: ] 4 Spechler SJ. Brrett esophgus nd risk of esophgel cncer: clinicl review. JAMA 2013; 310: [PMID: DOI: /jm ] 5 Ld MJ, Niemn DR, Hn M, Timrtn P, Alslhi O, Peyre CG, Jones CE, Wtson TJ, Peters JH. Gstroesophgel reflux disese, proton-pump inhibitor use nd Brrett s esophgus in esophgel denocrcinom: Trends revisited. 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6 syndrome: rndomised controlled tril. Gut 2004; 53: [PMID: DOI: /gut ] 13 Zr S, Mincher L, Benson MJ, Kumr D. Food-specific IgG4 ntibody-guided exclusion diet improves symptoms nd rectl complince in irritble bowel syndrome. Scnd J Gstroenterol 2005; 40: [PMID: DOI: / ] 14 Aydinlr EI, Dikmen PY, Tiftikci A, Sruc M, Aksu M, Gunsoy HG, Tozun N. IgG-bsed elimintion diet in migrine plus irritble bowel syndrome. Hedche 2013; 53: [PMID: DOI: /j x] 15 Dobrill G, Zncnell I, Benvenuti S, Comberlto M, Ampltz S, Di Fede F, De Guelmi A. [Diet nd drugs in the therpy of nonorgnic dyspepsi: the hypothesis nd fctul dt]. Minerv Gstroenterol Dietol 1996; 42: [PMID: ] 16 Hller D, Antoine JM, Bengmrk S, Enck P, Rijkers GT, Lenoir-Wijnkoop I. Guidnce for substntiting the evidence for beneficil effects of probiotics: probiotics in chronic inflmmtory bowel disese nd the functionl disorder irritble bowel syndrome. J Nutr 2010; 140: 690S-697S [PMID: DOI: /jn ] 17 Meiler F, Klunker S, Zimmermnn M, Akdis CA, Akdis M. Distinct regultion of IgE, IgG4 nd IgA by T regultory cells nd toll-like receptors. Allergy 2008; 63: [PMID: DOI: /j x] P- Reviewer: Herszenyi L, Prker W S- Editor: M N L- Editor: A E- Editor: M S 6 December 7, 2014 Volume 20 Issue 45