Clinical trial: Lactobacillus plantarum 299v (DSM 9843) improves symptoms of irritable bowel syndrome

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1 Online Submissions: doi:.3748/wjg.v8.i3.4 World J Gstroenterol August 4; 8(3): 4-48 ISSN (print) ISSN 9-84 (online) Bishideng. All rights reserved. BRIEF ARTICLE Clinicl tril: Lctobcillus plntrum 99v (DSM 9843) improves symptoms of irritble bowel syndrome Philippe Ducrotté, Prbh Swnt, Venktrmn Jynthi Philippe Ducrotté, Deprtment of Gstroenterology (Inserm UMR-73), Rouen University Hospitl nd Rouen University, 763 Rouen Cedex, Frnce Prbh Swnt, Deprtment of Gstroenterology, Lokmny Tilk Municipl Medicl College nd Lokmny Tilk Municipl Generl Hospitl, Mumbi 4, Indi Venktrmn Jynthi, Deprtment of Gstroenterology, Gov Stnley Hospitl, Chenni 68, Indi Author contributions: Ducrotté P designed the tril nd wrote the pper; Swnt P designed the tril nd recruited the ptients; nd Jynthi V designed the tril nd recruited the ptients. Supported by Rosell-Lllemnd Institute, Frnce nd Probi AB, Sweden Correspondence to: Dr. Philippe Ducrotté, Deprtment of Gstroenterology (Inserm UMR-73), Chrles Nicolle Rouen University Hospitl, Rue de Germont, 763 Rouen Cedex, Frnce. philippe.ducrotte@chu-rouen.fr Telephone: Fx: Received: My 6, Revised: April 4, Accepted: My 3, Published online: August 4, Abstrct AIM: To ssess the symptomtic efficcy of Lctobcillus plntrum 99v (L. plntrum 99v) (DSM 9843) for the relief of bdominl symptoms in lrge subset of irritble bowel syndrome (IBS) ptients fulfilling the Rome Ⅲ criteri. METHODS: In this double blind, plcebo-controlled, prllel-designed study, subjects were rndomized to dily receive either one cpsule of L. plntrum 99v (DSM 9843) or plcebo for 4 wk. Frequency nd intensity of bdominl pin, bloting nd feeling of incomplete rectl emptying were ssessed weekly on visul nlogue scle while stool frequency ws clculted. RESULTS: Two hundred nd fourteen IBS ptients were recruited. After 4 wk, both pin severity ( vs , P <.5) nd dily frequency ( vs , P <.5) were lower with L. plntrum 99v (DSM 9843) thn with plcebo. Similr results were obtined for bloting. At week 4, 78. % of the ptients scored the L. plntrum 99v (DSM 9843) symptomtic effect s excellent or good vs only 8. % for plcebo (P <.). CONCLUSION: A 4-wk tretment with L. plntrum 99v (DSM 9843) provided effective symptom relief, prticulrly of bdominl pin nd bloting, in IBS ptients fulfilling the Rome Ⅲ criteri. Bishideng. All rights reserved. Key words: Irritble bowel syndrome; Probiotics; Lctobcillus plntrum 99v; Clinicl tril; Abdominl pin Peer reviewer: John K Mrshll, MD, Associte Professor of Medicine, Division of Gstroenterology, McMster University Medicl Centre, Min Street West, Hmilton, Ontrio L8N 3Z5, Cnd Ducrotté P, Swnt P, Jynthi V. Clinicl tril: Lctobcillus plntrum 99v (DSM 9843) improves symptoms of irritble bowel syndrome. World J Gstroenterol ; 8(3): 4-48 Avilble from: URL: v8/i3/4.htm DOI: i3.4 INTRODUCTION Irritble bowel syndrome (IBS) is one of the most frequent digestive trct disorders encountered by generl prctitioners nd gstroenterologists. IBS is functionl bowel disorder chrcterized by chronic nd relpsing bdominl pin or discomfort ssocited with ltered bowel hbits. The primry im of ny tretment is the relief of bdominl pin which cn significntly impir the ptient s qulity of life. According to published guidelines, the min tretment options for bdominl pin include ntispsmodics or nti-depressnts t low dose while nti- 4 August 4, Volume 8 Issue 3

2 Ducrotté P et l. L. plntrum 99v (DSM 9843) nd irritble bowel syndrome dirrhel or lxtive drugs re given to improve trnsit disturbnces [,]. However, in mny cses, ll these options remin disppointing for the relief of bdominl pin. The therpeutic efficcy in IBS is probbly impcted by the heterogeneous pthogenesis of the disese which includes ltered intestinl motility, viscerl hypersensitivity, bnorml brin-gut interctions, food intolernce, ltered intestinl permebility nd post infectious nd/or inflmmtory chnges [3]. Recently, the deleterious role of qulittive or quntittive ltertions of gut microbiot t the onset of symptoms hs been emphsized. Therefore, rtionle exists to discuss the therpeutic use of probiotics, which re live microorgnisms conferring helth benefits to the host when ingested in dequte mounts [4]. Clinicl evidence regrding the efficcy of some probiotic strins to improve IBS symptoms hs recently emerged [5,6], lthough the mechnism of ction of probiotics on IBS symptoms is not completely understood. Some probiotics bind to smll nd lrge bowel epithelium nd my produce substnces with ntibiotic properties, while others compete for ttchment nd thereby reduce invsion by pthogenic orgnisms [7]. Probiotics lso modulte gstrointestinl luminl immunity by chnging the cytokine nd cellulr milieu from pro-inflmmtory to nti-inflmmtory stte [8]. They my lso convert undigested crbohydrtes into short chin ftty cids, which ct s nutrients for colonocytes nd ffect gut motility [4]. Lctobcillus plntrum 99v (L. plntrum 99v) (DSM 9843) is probiotic strin ble to reside in the humn colonic mucos in vivo due to specific mechnism of mnnose dhesion [7]. L. plntrum 99v (DSM 9843) lso increses the mount of crboxylic cid, prticulrly cetic nd propionic cids, in the stools of helthy volunteers [9]. The strin hs shown ntibcteril ctivity ginst severl potentil pthogenic gents such s Listeri monocytogenes, Escherischi coli, Yersini enterolytic, Enterobcter cloce nd Enterococcus feclis []. L. plntrum 99v (DSM 9843) lso hs beneficil immunomodultory ctivity vi n incresed interleukin- synthesis nd secretion in mcrophges nd T-cells derived from the inflmed colon. And recently, n experimentl study reported tht L. plntrum 99v (DSM 9843) incresed the trnscription nd excretion of the mucins MUC nd MUC3 in goblet cells [,]. Three single-centre studies hve tested the clinicl efficcy of L. plntrum 99v (DSM 9843) in IBS ptients [3-5]. Two trils hve demonstrted significnt benefits in comprison with plcebo on improvement of fltulence scores [3] nd reduction of bdominl pin [4] while the results of the third tril, bsed on only ptients, were not conclusive. The im of the present rndomized, double-blind, plcebo controlled clinicl tril ws to ssess the symptomtic efficcy of L. plntrum 99v (DSM 9843) in lrger subset of IBS ptients fulfilling the Rome Ⅲ criteri. MATERIALS AND METHODS Ptients Prticipnts (n = 4) were recruited by generl prctitioners in four clinicl centres in Indi: one in Mumbi, two in Chenni nd one in Bnglore. Subjects between 8-7 yers of ge with IBS ccording to the Rome Ⅲ criteri were eligible for inclusion. All subjects hd colonic exmintion t bseline to exclude ny orgnic disese while n intestinl infection ws excluded by stool cultures in ny ptient in whom this dignosis ws suspected. Subjects with severe chronic medicl disese including colorectl nd other gstrointestinl diseses were excluded. Pregnnt nd brest-feeding women nd ptients with dietry hbits which might interfere with the ssessment of the study product or ptients with known llergy to the study product components were lso excluded. Throughout the study, the subjects were not llowed to consume ny other probiotic nd were encourged not to chnge their usul dietry nd physicl exercise hbits. Study design This study ws designed s multicentre double blind, plcebo-controlled study with prllel groups to ssess the beneficil effects of dily consumption of L. plntrum 99v (DSM 9843) on IBS symptoms. Tretment durtion ws 4 wk with 3 follow-up visits t weekly intervls. The study protocol ws conducted in ccordnce with the Declrtion of Helsinki nd pproved by the locl Ethics Committee. All volunteers gve written informed consent prior to prticiption in the study. Study products The test product ws probiotic preprtion contining mixture of freeze-dried lctic cid bcteri nd excipients. The lctic cid bcteri strin ws L. plntrum 99v (DSM 9843). It is deposited t the DSM collection (Deutsche Smmlung von Mikrooorgnismen und Zellkulturen GmbH) under number DSM The test product contined billion colony-forming units (cfu) per cpsule in potto strch nd mgnesium sterte bse. The control product contined potto strch (97%) nd mgnesium sterte (3%). Both the test nd control products hd similr ppernce, texture nd tste. Both products were specificlly prepred for the study nd provided by the Rosell-Lllemnd Institute (Blgnc, Frnce). Assessments nd study endpoints The primry endpoint ws the improvement of the frequency of bdominl pin episodes. Secondry endpoints were chnges in severity of bdominl pin, chnges in frequency nd severity of bdominl bloting nd in feeling of incomplete rectl emptying. Both frequency of bdominl pin nd feeling of incomplete rectl emptying were ssessed weekly using four-point scle rnging from (only occsionl symptom) to 4 (dily symptom). Symptom severity (bdominl pin, bdominl bloting nd feeling of incomplete rectl emptying) ws rted on visul nlogue scle (VAS -) nd converted to 4 point scle rnging from (No pin, VAS = ) to 3 (Severe, VAS = 8 to ). The dily number of stools nd bloting episodes were clculted nd registered t ech visit. At the end 43 August 4, Volume 8 Issue 3

3 Ducrotté P et l. L. plntrum 99v (DSM 9843) nd irritble bowel syndrome Tble Bseline chrcteristics of the subjects between the two groups (men ± SD) Ptients enrolled n = 4 L. plntrum 99v (DSM 9843) (n =8) Plcebo (n =6) Age (yr) ± ± 3.3 NS Men/women 7/38 8/5 NS IBS durtion (yr) NS Abdominl pin frequency. ±..98±.9 NS Abdominl pin severity.4 ±.6. ±.63 NS Bloting severity.7 ±.6.4 ±.64 NS Stool frequency 3.94 ± ±.34 NS Pure vegetrins (%) 3.5. NS Dily yoghurt intke (%) NS No significnt differences were found between the groups for ll the vribles tested. NS: No significnt; L. plntrum 99v: Lctobcillus plntrum 99v. of the 4-wk tretment period, both the ptient s nd the prctitioner s opinion bout the overll efficcy of the tretment were recorded using 4-point scle, from poor to excellent. Regrding sfety ssessment, blood smples were tken t bseline nd week 4 in ech ptient for the ssessment of blood cell counts, glycemi, blood ure nitrogen nd liver function tests. Physicl exmintions nd verifiction of ny dverse events were performed t ech visit. Smple size nd rndomiztion The smple-size clcultion ws bsed on the min outcome, the frequency of bdominl pin episodes. The tril smple size required to detect significnt difference of % between the two groups with n 8% power nd 5% sttisticl significnce level ws clculted to be t lest seventy-nine ptients per group. Tking into ccount tht ll subjects who withdrew premturely were not replced, 4 subjects were rndomised ccording to computer-generted rndomiztion list in the rtio :. For ech site, rndomiztion chrts were provided to investigtors keeping : rtio. All investigtors, ptients nd monitors were blinded throughout the study. To ensure lloction concelment, pckging nd lbelling were performed by third prty, nd the rndomiztion code ws kept in secure plce during the study. Sttisticl nlysis All the nlyses of efficcy were performed with full nlysis set (FAS) popultion. The FAS popultion corresponds to ll rndomised subjects who took t lest one dose of the study drug nd who hd t lest one post-bseline efficcy ssessment. Overll ssessment of symptoms were nlysed using repeted-mesures nlysis of vrince (ANOVA) with time, tretment group, interction time x product nd bseline score s fixed fctors for ech period. RESULTS The flow chrt of the study is given in Figure. A totl P ITT FAS L. plntrum 99v n = 8 L. plntrum 99v n = 5 Lost to follow-up = Tretment interrupted = Lost to follow-up = 7 Plcebo n = 6 Plcebo n = 99 Figure Flow-chrt of the study. L. plntrum 99v: Lctobcillus plntrum 99v; FAS: Full nlysis set; ITT: Intention to tret. of 4 ptients were rndomized nd 8 subjects ssigned to receive L. plntrum 99v (DSM 9843) group nd 6 ptients the plcebo. Among these 4 subjects, were excluded, either becuse they did not complete the entire 4-wk double-blind period, or becuse they did not provide ny vilble dt bout the tretment period. A mjority of ptients were IBS-D ptients, 63.89% nd 6.3% in L. plntrum 99v (DSM 9843) nd plcebo groups, respectively. Bseline chrcteristics of the two groups re given in Tble. Frequency of digestive symptoms The men chnges over this 4-wk period of the frequency of ech digestive symptom re shown in Figure. The decrese of bdominl pin frequency ws significntly higher in the L. plntrum 99v (DSM 9843) group thn in the plcebo group t weeks 3 nd 4. At the end of week 4 the men frequency ws reduced significntly by 5.9% in the L. plntrum 99v group in comprison with the 3.6% reduction in the plcebo group. Overll reductions in stool frequency, bloting nd feeling of incomplete emptying frequency were lso significntly greter in the L. plntrum 99v (DSM 9843) group when compred with the plcebo group over the 4-wk period (P <.5). The effects of both tretments on stool frequency re shown in Figure 3. A significnt reduction of the dily number of stools ws observed with L. plntrum 99v (DSM 9843) fter the second week of tretment. Severity of digestive symptoms The chnge in men severity of bdominl pin over the 4-wk period ws nlysed on the VAS. At the end of the 4th week, the men score ws reduced by 45.% in the L. plntrum 99v (DSM 9843) group nd reduced by only 3.3% in the plcebo group (Figure A). The weekly nlysis of this score showed significntly lower scores t weeks, 3 nd 4 in the L. plntrum 99v (DSM 9843) group in comprison with plcebo. The decrese of the men scores of severity of bdominl bloting nd feeling of incomplete emptying were lso sttisticlly higher in the L. plntrum 99v (DSM 9843) group when compred to the plcebo group t weeks 3 nd 4 (Figure B nd C). 44 August 4, Volume 8 Issue 3

4 Ducrotté P et l. L. plntrum 99v (DSM 9843) nd irritble bowel syndrome A Men score of severity Severity Men frequency per dy Frequency Plcebo L. plntrum (DSM 9843) Bseline Week Week 3 Week 4 Bseline Week Week 3 Week 4 B. Severity Frequency Plcebo L. plntrum (DSM 9843) Men score of severity Men frequency per dy Bseline Week Week 3 Week 4 Bseline Week Week 3 Week 4 C Men score of severity Severity Men frequency per dy Frequency Plcebo L. plntrum (DSM 9843) Bseline Week Week 3 Week 4 Bseline Week Week 3 Week 4 Figure Chnges in frequency nd severity of symptoms in both groups. A: Abdominl pin; B: Bloting; C: Feeling of incomplete evcution. L. plntrum (DSM 9843): Lctobcillus plntrum 99v. P <.5 vs bseline group. Overll ssessment The percentge of ptients who considered the efficcy of the tretment they received s good or excellent ws significntly higher in the L. plntrum 99v (DSM 9843) group thn in the plcebo group (78.% vs 8.%) (Figure 4). Similr results were observed when the efficcy ws estimted by the investigtors (8.8% vs.%) (Figure 4). Comprtive efficcy ccording to dietry hbits Yoghurt consumption did not ffect the results nd did not induce ny difference between the two rms of tretment (dt not shown). The frequency of bdominl pin ws lso not different between the two rms when the vegetrin or non vegetrin sttus ws considered. However, the severity of the bdominl pin with L. plntrum 99v (DSM 9843) ws lower in the vegetrins thn in the non-vegetrins t weeks, 3 nd 4 (P <.5). Sfety No significnt side-effect ws reported in ny group during the 4 wk of tretment. The only dverse event reported ws trnsient vertigo onset by one of the ptients who received L. plntrum 99v (DSM 9843). No chnge in blood prmeters ws detected throughout the study. 45 August 4, Volume 8 Issue 3

5 Ducrotté P et l. L. plntrum 99v (DSM 9843) nd irritble bowel syndrome Plcebo L. plntrum (DSM 9843) Excellent Good Fir Poor Men frequency per dy % Bseline Week Week 3 Week 4 Plcebo L. plntrum 99v Plcebo L. plntrum 99v Figure 3 Chnges in stool frequency in both groups. L. plntrum (DSM 9843): Lctobcillus plntrum 99v. P <.5 vs bseline group. DISCUSSION The present plcebo-controlled tril demonstrted tht in n Indin popultion L. plntrum 99v (DSM 9843) is probiotic strin ble to relieve IBS symptoms, prticulrly bdominl pin nd bloting, in IBS ptients fulfilling the Rome Ⅲ criteri. Abdominl pin ws chosen s the primry end point becuse it is the mjor symptom leding to the seeking of medicl dvice by IBS ptients. This tril ws designed for group of IBS ptients of ny subtype, complining of moderte IBS symptoms nd recruited by generl prctitioners. Severl trils with probiotics hve involved minly IBS-D ptients but microbiologicl studies hve emphsized tht qulittive chnges of the microbiot exist in ll IBS sub-types [6]. Therefore, we considered tht ny IBS ptient, whtever the subtype, could be eligible to prticipte. In the present study, the mjority of recruited prticipnts were mles s compred to previous trils where pproximtely twothirds of study subjects were femles. The femle predominnce in IBS ptients reported in the West hs not been observed in Asin popultions, prticulrly in Indi. Two mjor recent community studies reported higher prevlence of IBS in the mle popultion. In Mumbi, mle prevlence ws 7.9% vs femle prevlence of 6.9%, nd in pn-indin study mle prevlence ws 4.3% vs femle prevlence of 4.% [7]. However, other popultion surveys in the Indin subcontinent hve reported n IBS prevlence of 8.5% using the Rome Ⅰ criteri nd demonstrted femle predominnce similr to Western countries [8]. The notble gender difference between the popultion of this study nd tht of previously published trils cn lso be explined by the fct tht, in the Indin subcontinent but not in other prts of Asi, men seem to hve greter ccess to helthcre [9]. However, dt bout the consulttion behviour of the community groups re not ll in greement. In the recent lrge survey conducted by the Indin Society of Gstroenterology Tsk Force (3 IBS ptients nd 45 community subjects in 8 centres), 33% of men nd 38% of women hd consulted doctor in the preceding mo []. Eting behviours of the ptients enrolled in this tril were lso somewht different from tht of Western IBS ptients Ptients Investigtors Figure 4 Overll ssessment of the tretment efficcy by the ptients nd by the investigtors. with high percentge of pure vegetrins nd with dily yoghurt consumption in lmost hlf of the cses. Due to the possible interctions between nutrients nd bcteri, we cnnot exclude tht this regimen might hve influenced the therpeutic results even if eting behviours were not different between the two groups. We hve even observed tht L. plntrum results on bdominl pin intensity were better in vegetrin thn in non vegetrin IBS ptients. This suggests tht the symptomtic effect of the strin could be, t lest prtly, relted to interctions between the luminl content nd L. plntrum or tht the strin ffects the luminl metbolism of nutrients. However, the design of our study does not llow us to conclude tht this is indeed the cse. This tril ws performed ccording to the Rome Ⅲ guidelines on design of trils for functionl GI disorders [] in order to demonstrte sttisticl superiority to plcebo with double-blind, plcebo-controlled prllel design nd outcome mesures including both the effect of the tretment on the min symptom, i.e., bdominl pin, nd globl ssessment of the tretment efficcy to obtin dequte relief. Severl clinicl trils testing the symptomtic efficcy of probiotics in IBS were longer thn this tril. However, durtion of tretment of 4 weeks follows not only the Rome Ⅲ guidelines but is lso the recommendtion of interntionl gencies []. One potentil wekness of this study ws the choice of fourpoint Likert scle to nlyze the frequency of symptoms insted of score such s the IBS symptom severity scle tht hs been shown to be responsive to tretment effect [3]. We enrolled ptients with moderte bdominl pin. Some studies hve suggested tht the chievement of stisfctory relief end-point ws significntly influenced by bseline symptom severity [3,4]. However, the concern tht bseline severity compromises the chievement of n end point, such s stisfctory relief, does not pper to ffect the current design of clinicl trils. For exmple, trils with 5-HT3 ntgonists [5] or ntidepressnt t low dose [6] or even with non phrmcologicl pproch [7] hve not confirmed the impct of bseline severity on the 46 August 4, Volume 8 Issue 3

6 Ducrotté P et l. L. plntrum 99v (DSM 9843) nd irritble bowel syndrome chievement of n dequte relief s tril end point [7,8]. In ccordnce with previous findings in mny trils, IBS ptients who received plcebo exhibited significnt improvement with time. However this improvement ws lower thn in the L. plntrum group nd the overll number of ptients in the plcebo group who considered themselves s improved ws low. Furthermore, in the present study, the plcebo results were lower thn tht clculted in recent met-nlysis of 73 rndomized controlled trils (RCTs) reporting pooled plcebo response of 37.5%. But the sme met-nlysis of the fctors ffecting plcebo response rte outlined tht rtes were significntly higher in Europen RCTs [9]. The percentge of ptients who considered the efficcy of the tretment s good or excellent ws very high (78.%) in the L. plntrum 99v (DSM 9843) group nd low in the plcebo group (8.%). This result cnnot be explined only by the greter effects of L. plntrum 99v (DSM 9843) vs plcebo on ech IBS symptom. This stisfction rte could lso be explined by possible efficcy of the strin on upper bdominl symptoms tht re very frequent in Indin IBS ptients. Indeed, the Indin Society of Gstroenterology Tsk Force hve outlined tht 49% of Indin IBS ptients reported epigstric pin, nd tht 7% complined of upper bdominl fullness or bloting rther thn pin []. Three studies using L. plntrum 99v (DSM 9843) hve been published prior to this tril. In the first study, Nobek et l [3] enrolled 6 IBS ptients nd compred L. plntrum 99v to plcebo to determine whether endogenous colonic flor could be ltered by probiotic consumption. Multiple secondry symptom-bsed end-points were lso evluted. The ctive tretment period lsted 4 wk fter -wk observtion period. Compred with plcebo, sttisticlly significnt decrese in fltulence ws observed during the second hlf of the tretment period but only 5/6 ptients were included in the nlysis of this secondry endpoint. In nother study, Niedzielin et l [4] enrolled 4 IBS ptients nd ssessed bdominl pin nd globl IBS symptoms s primry nd secondry outcomes, respectively. At 4 wk, / ptients in the L. plntrum 99v group compred to / in the control group hd complete resolution of their pin (P =.). Moreover, 9/ ptients in the L. plntrum 99v group compred to 3/ ptients in the control group lso experienced improvement in their globl IBS symptoms (P <.). In both trils, no dverse effects were identified. The finl study, performed by Sen et l [5], showed no significnt improvement but it ws pseudorndomized study with only ptients with cross-over design nd evluted chnges of composite score of IBS symptoms. At 8 wk, no significnt differences were identified between groups [5]. Given the significnt differences in the enrolled popultions, study designs, outcome vribles, nd sttisticl nlyses, it is difficult to mke comprisons cross the studies nd ll three previous studies suffered from multiple design flws. In conclusion, the present study shows the potentil benefit of prticulr strin L. plntrum 99v (DSM 9843), in the mngement of IBS. Further studies re wrrnted in order to identify the mechnism of the probiotic s potentil beneficil effect. ACKNOWLEDGMENTS We thnk the investigtors nd Sohm consultncy for the mngement of the study; We thnk lso Dr. Bhvesh Kotk, clinicl project coordintor for Rnbxy Lbortories Ltd, Indi nd Dr. Mnish Mldkr for his involvement s the clinicl project coordintor for Aristo Phrmceuticls Pvt Ltd, Indi. COMMENTS Bckground Lctobcillus plntrum 99v (L. plntrum 99v) (DSM 9843) is probiotic strin ble to reside in the humn colonic mucos in vivo, with n ntibcteril ctivity ginst severl potentil pthogenic gents nd n immunomodultory ctivity vi n incresed interleukin- synthesis nd secretion in colonic mcrophges nd T-cells. Reserch frontiers Recent studies hve highlighted disturbnces of the reltionship between the complex community of the gut microbiot nd their host in irritble bowel syndrome. The potentil to correct this using probiotics hs been suggested but the effective strins need to be determined. Innovtions nd brekthroughs After tretment of 4 wk, the relief or improvement of irritble bowel syndrome (IBS) symptoms ws greter with the L. plntrum 99v group thn with plcebo (P <.5) leding to greter ptient stisfction. Applictions L. plntrum 99v (DSM 9843) is suitble cndidte for the relief of moderte symptoms in ny IBS ptient. Peer review Overll this is well written pper reporting tril of resonble methodology. It should be published if uthors cn revise it in stisfctory mnner. REFERENCES Brndt LJ, Chey WD, Foxx-Orenstein AE, Schiller LR, Schoenfeld PS, Spiegel BM, Tlley NJ, Quigley EM. An evidencebsed position sttement on the mngement of irritble bowel syndrome. Am J Gstroenterol 9; 4 Suppl : S-35 Jones J, Boormn J, Cnn P, Forbes A, Gomborone J, Heton K, Hungin P, Kumr D, Libby G, Spiller R, Red N, Silk D, Whorwell P. British Society of Gstroenterology guidelines for the mngement of the irritble bowel syndrome. Gut ; 47 Suppl : ii-i9 3 Mertz HR. Irritble bowel syndrome. N Engl J Med 3; 349: Quigley EM, Flourie B. Probiotics nd irritble bowel syndrome: rtionle for their use nd n ssessment of the evidence to dte. Neurogstroenterol Motil 7; 9: McFrlnd LV, Dublin S. Met-nlysis of probiotics for the tretment of irritble bowel syndrome. World J Gstroenterol 8; 4: Moyyedi P, Ford AC, Tlley NJ, Cremonini F, Foxx-Orenstein AE, Brndt LJ, Quigley EM. The efficcy of probiotics in the tretment of irritble bowel syndrome: systemtic review. Gut ; 59: Johnsson ML, Molin G, Jeppsson B, Nobek S, Ahrné S, Bengmrk S. Administrtion of different Lctobcillus strins in fermented otmel soup: in vivo coloniztion of humn intestinl mucos nd effect on the indigenous flor. Appl Environ Microbiol 993; 59: 5-8 Ménrd S, Cndlh C, Bmbou JC, Terpend K, Cerf-Bensus- 47 August 4, Volume 8 Issue 3

7 Ducrotté P et l. L. plntrum 99v (DSM 9843) nd irritble bowel syndrome sn N, Heymn M. Lctic cid bcteri secrete metbolites retining nti-inflmmtory properties fter intestinl trnsport. Gut 4; 53: Jcobsen CN, Rosenfeldt Nielsen V, Hyford AE, Møller PL, Michelsen KF, Perregrd A, Sndström B, Tvede M, Jkobsen M. Screening of probiotic ctivities of forty-seven strins of Lctobcillus spp. by in vitro techniques nd evlution of the coloniztion bility of five selected strins in humns. Appl Environ Microbiol 999; 65: Johnsson ML, Nobek S, Berggren A, Nymn M, Björck I, Ahrné S, Jeppsson B, Molin G. Survivl of Lctobcillus plntrum DSM 9843 (99v), nd effect on the short-chin ftty cid content of feces fter ingestion of rose-hip drink with fermented ots. Int J Food Microbiol 998; 4: 9-38 Mck DR, Ahrne S, Hyde L, Wei S, Hollingsworth MA. Extrcellulr MUC3 mucin secretion follows dherence of Lctobcillus strins to intestinl epithelil cells in vitro. Gut 3; 5: Mck DR, Michil S, Wei S, McDougll L, Hollingsworth MA. Probiotics inhibit enteropthogenic E. coli dherence in vitro by inducing intestinl mucin gene expression. Am J Physiol 999; 76: G94-G95 3 Nobek S, Johnsson ML, Molin G, Ahrné S, Jeppsson B. Altertion of intestinl microflor is ssocited with reduction in bdominl bloting nd pin in ptients with irritble bowel syndrome. Am J Gstroenterol ; 95: Niedzielin K, Kordecki H, Birkenfeld B. A controlled, double-blind, rndomized study on the efficcy of Lctobcillus plntrum 99V in ptients with irritble bowel syndrome. Eur J Gstroenterol Heptol ; 3: Sen S, Mulln MM, Prker TJ, Woolner JT, Trry SA, Hunter JO. Effect of Lctobcillus plntrum 99v on colonic fermenttion nd symptoms of irritble bowel syndrome. Dig Dis Sci ; 47: Rjilić-Stojnović M, Bigi E, Heilig HG, Kjnder K, Kekkonen RA, Tims S, de Vos WM. Globl nd deep moleculr nlysis of microbiot signtures in fecl smples from ptients with irritble bowel syndrome. Gstroenterology ; 4: Gwee KA, Lu CL, Ghoshl UC. Epidemiology of irritble bowel syndrome in Asi: something old, something new, something borrowed. J Gstroenterol Heptol 9; 4: Mendis BL, Wijesiriwrden BC, Sheriff MH, Dhrmds K. Irritble bowel syndrome. Ceylon Med J 98; 7: Msud MA, Hsn M, Khn AK. Irritble bowel syndrome in rurl community in Bngldesh: prevlence, symptoms pttern, nd helth cre seeking behvior. Am J Gstroenterol ; 96: Ghoshl UC, Abrhm P, Bhtt C, Choudhuri G, Bhti SJ, Shenoy KT, Bnk NH, Bose K, Bohidr NP, Chkrvrtty K, Shekhr NC, Desi N, Dutt U, Ds G, Dutt S, Dixit VK, Goswmi BD, Jin RK, Jin S, Jynthi V, Kochhr R, Kumr A, Mkhri G, Mukewr SV, Mohn Prsd VG, Mohnty A, Mohn AT, Sthyprksh BS, Prbhkr B, Philip M, Veerrju EP, Ry G, Ri RR, Seth AK, Schdev A, Singh SP, Sood A, Thoms V, Tiwri S, Tndn M, Updhyy R, Vij JC. Epidemiologicl nd clinicl profile of irritble bowel syndrome in Indi: report of the Indin Society of Gstroenterology Tsk Force. Indin J Gstroenterol 8; 7: -8 Irvine EJ, Whitehed WE, Chey WD, Mtsued K, Shw M, Tlley NJ, Veldhuyzen vn Znten SJ. Design of tretment trils for functionl gstrointestinl disorders. Gstroenterology 6; 3: Committee for Proprietry Medicinl Products (CPMP). Points to consider on the evlution of medicinl products for the tretment of irritble bowel syndrome. London: CPMP, 3. Avilble from: URL: 3 Cmilleri M, Chng L. Chllenges to the therpeutic pipeline for irritble bowel syndrome: end points nd regultory hurdles. Gstroenterology 8; 35: Whitehed WE, Plsson OS, Levy RL, Feld AD, VonKorff M, Turner M. Reports of stisfctory relief by IBS ptients receiving usul medicl cre re confounded by bseline symptom severity nd do not ccurtely reflect symptom improvement. Am J Gstroenterol 6; : Andresen V, Montori VM, Keller J, West CP, Lyer P, Cmilleri M. Effects of 5-hydroxytryptmine (serotonin) type 3 ntgonists on symptom relief nd constiption in nonconstipted irritble bowel syndrome: systemtic review nd met-nlysis of rndomized controlled trils. Clin Gstroenterol Heptol 8; 6: Leventer SM, Rudibugh K, Frissor CL, Kssem N, Keogh JC, Phillips J, Mngel AW. Clinicl tril: dextofisopm in the tretment of ptients with dirrhoe-predominnt or lternting irritble bowel syndrome. Aliment Phrmcol Ther 8; 7: Lckner JM, Jccrd J, Krsner SS, Ktz LA, Gudleski GD, Holroyd K. Self-dministered cognitive behvior therpy for moderte to severe irritble bowel syndrome: clinicl efficcy, tolerbility, fesibility. Clin Gstroenterol Heptol 8; 6: Ameen VZ, Het AT, McSorley D, Spiegel BM, Chng L. Globl mesure of dequte relief predicts cliniclly importnt difference in pin nd is independent of bseline pin severity in IBS. Gstroenterology 7; 3: A-4 9 Ford AC, Moyyedi P. Met-nlysis: fctors ffecting plcebo response rte in the irritble bowel syndrome. Aliment Phrmcol Ther ; 3: S- Editor Cheng JX L- Editor A E- Editor Xiong L 48 August 4, Volume 8 Issue 3