Saccharomyces cerevisiae CNCM I-3856 in irritable bowel

Transcription

1 Submit Mnuscript: Help Desk: DOI: /wjg.v23.i2.336 World J Gstroenterol 2017 Jnury 14; 23(2): ISSN (print) ISSN (online) 2017 Bishideng Publishing Group Inc. All rights reserved. META-ANALYSIS Scchromyces cerevisie CNCM I-3856 in irritble bowel syndrome: An individul subject met-nlysis Amélie Cyzeele-Decherf, Fnny Pélerin, Sébstien Leuillet, Benoit Douillrd, Bétrice Housez, Murielle Czubiel, Gunnrd K Jcobson, Peter Jüsten, Pierre Desreumux Amélie Cyzeele-Decherf, Fnny Pélerin, Peter Jüsten, Lesffre Humn Cre, Lesffre Group, Mrcq en Broeul, Frnce Sébstien Leuillet, Benoit Douillrd, Bétrice Housez, Murielle Czubiel, Biofortis - Mérieux NutriSciences, Sint Herblin, Frnce Gunnrd K Jcobson, Lesffre Yest Corportion, Lesffre Group, Milwukee, WI 53214, United Sttes Pierre Desreumux, CHU Lille, Deprtment of Gstroenterology, Clude Huriez Hospitl, Lille, Frnce Pierre Desreumux, Lille University North of Frnce, Lille, Frnce Pierre Desreumux, INSERM U995, Lille, Frnce Author contributions: All uthors hve mde substntil contributions to conception nd design of the study, cquisition of dt, nlysis nd interprettion of dt; Cyzeele-Decherf A, Leuillet S nd Housez B hve drfted the rticle nd other uthors hve mde criticl revisions relted to importnt intellectul content of the mnuscript; All uthors hve been involved for finl pprovl of the version of the rticle to be published. Conflict-of-interest sttement: No potentil conflicts of interest relevnt to this rticle were reported. Dt shring sttement: No dditionl dt re vilble. Open-Access: This rticle is n open-ccess rticle which ws selected by n in-house editor nd fully peer-reviewed by externl reviewers. It is distributed in ccordnce with the Cretive Commons Attribution Non Commercil (CC BY-NC 4.0) license, which permits others to distribute, remix, dpt, build upon this work non-commercilly, nd license their derivtive works on different terms, provided the originl work is properly cited nd the use is non-commercil. See: org/licenses/by-nc/4.0/ Mnuscript source: Unsolicited mnuscript Correspondence to: Amélie Cyzeele-Decherf, Clinicl Study Mnger, Lesffre Humn Cre, Lesffre Group, Mrcq en Broeul, Frnce. ce@lesffre.fr Telephone: Received: August 2, 2016 Peer-review strted: August 3, 2016 First decision: September 12, 2016 Revised: October 3, 2016 Accepted: October 19, 2016 Article in press: October 19, 2016 Published online: Jnury 14, 2017 Abstrct AIM To confirm previous conclusions on Scchromyces cerevisie (S. cerevisie ) CNCM I-3856 for irritble bowel syndrome (IBS) mngement. METHODS An individul ptient dt met-nlysis ws performed on two rndomized clinicl trils studying the effect of S. cerevisie CNCM I-3856 supplementtion on gstrointestinl (GI) symptoms in IBS subjects. A totl of 579 IBS subjects were included. Outcomes were the dily Likert scle scores of bdominl pin/discomfort nd bloting [re under the curve (AUC) nd weekly mens], responder sttus, nd bowel movements (stool frequency nd consistency). Sttisticl nlyses were conducted in Intent to Tret (ITT) popultion, IBS-C subjects nd IBS-C subjects with n bdominl pin/ discomfort score higher thn or equl to 2 t bseline ( IBS-C 2 subpopultion ). RESULTS S. cerevisie CNCM I-3856 significntly improved bdominl pin/discomfort nd bloting during the second month of supplementtion [AUC (W5-W8)] 336 Jnury 14, 2017 Volume 23 Issue 2

2 Cyzeele-Decherf A et l. Scchromyces cerevisie CNCM I-3856 in IBS with improvement up to the miniml cliniclly relevnt threshold of 10%: 12.3% reduction of bdominl pin/discomfort in the ITT popultion compred to the Plcebo group (P = ) hs been observed. In the IBS-C 2 subpopultion, there were 13.1% reduction of bdominl pin/discomfort nd 14.9% reduction of bloting compred to the Plcebo group (P = nd P = , respectively). GI symptoms significntly decresed during supplementtion but no sttisticl differences were reported between groups t the end of the supplementtion period. Responder sttus ws defined s subject who experienced decrese of 1 rbitrry unit (.u.) or 50% of the bdominl discomfort score from bseline for t lest 2 wk out of the lst 4 wk of the study. A significnt difference between groups ws reported in the ITT popultion, when considering the first definition: subjects in the Active group hd higher odds to be responder (reduction of 1.u. of bdominl pin/discomfort) compred with subjects in the Plcebo group (P = ). At the end of supplementtion period, stool consistency in the Active group of the ITT popultion ws significntly improved nd clssified s norml compred to Plcebo (respectively 3.13 ± u. vs 2.58 ± u., P = ). Similr results were seen in the IBS-C 2 subpopultion (Active group: 3.14 ± u. vs Plcebo group: 2.59 ± u., P = ). CONCLUSION This met-nlysis supports previous dt linking S. cerevisie I-3856 nd improvement of GI symptoms, in IBS overll popultion nd in the IBS-C nd IBS-C 2 subpopultions. Key words: Irritble bowel syndrome; Scchromyces cerevisie ; Constiption; Abdominl pin; Probiotics The Author(s) Published by Bishideng Publishing Group Inc. All rights reserved. Core tip: Since the gut microbiot is considered to ply role in the pthophysiology of Irritble Bowel Syndrome, the use of probiotics hs gined interest for the mngement of gstrointestinl symptoms of irritble bowel syndrome (IBS). However, the properties of probiotics re strin-dependent. We performed n individul ptient dt met-nlysis to ssess the effectiveness of Scchromyces cerevisie CNCM I-3856 on the mngement of IBS symptoms. Cyzeele-Decherf A, Pélerin F, Leuillet S, Douillrd B, Housez B, Czubiel M, Jcobson GK, Jüsten P, Desreumux P. Scchromyces cerevisie CNCM I-3856 in irritble bowel syndrome: An individul subject met-nlysis. World J Gstroenterol 2017; 23(2): Avilble from: URL: DOI: dx.doi.org/ /wjg.v23.i2.336 INTRODUCTION Irritble bowel syndrome (IBS) is common functionl gstrointestinl (GI) disorder with high prevlence, ffecting up to 20% of the popultion in some geogrphicl res [1]. Diverse GI symptoms occur in IBS, minly bdominl pin, bloting nd ltered bowel hbits. Subjects lso report some extr-gi symptoms nd n impired qulity of life [2]. According to Rome Ⅲ criteri, IBS dignosis is bsed on the presence of bdominl pin nd/or discomfort, ssocited with t lest two of the following: improvement with defection, onset ssocited with chnge in frequency of stool, onset ssocited with chnge in form of stool [3]. The dignosis is confirmed by the bsence of ny orgnic disorder. Some IBS subtypes re distinguished depending on the predominnt stool pttern: constiption-predominnt IBS (IBS-C), dirrhepredominnt IBS (IBS-D), mixed IBS (IBS-M) lternting constiption nd dirrhe, nd n un-subtyped IBS. To dte, the pthogenesis of IBS is still not cler. Different mechnisms my be implicted, such s ltered GI motility, viscerl hypersensitivity, intestinl brrier disorder, dysfunction of the brin-gut xis, intestinl inflmmtion nd disruption of the intestinl flor [2,4]. When investigting IBS, the gut microbiot is of gret interest. First, some IBS cses begin fter n cute episode of GI infection, which cn lter the gut microbiot s diversity [5,6]. Secondly, the intestinl microbiot is thought to be involved in most of the mechnisms of IBS [7]. Due to lck of stisfctory phrmcologicl tretments suitble for long-term dministrtion [8], both ptients nd cregivers turn to lterntive methods for the mngement of IBS. In such n pproch, probiotics prove to be n interesting nd promising option. Their supplementtion my help to counterblnce mechnisms involved in IBS [5,9] nd to llevite ssocited symptoms. Tody the chllenge is to identify which probiotic strins re relevnt for IBS mngement nd the conditions for their use (preprtions, doses, durtion). Scchromyces cerevisie (S. cerevisie) CNCM I-3856, proprietry yest strin from Lesffre, hs been studied for its beneficil properties in lleviting GI symptoms in IBS subjects. Two rndomized clinicl trils (RCTs) hve been conducted nd published [10,11] involving totl of 579 IBS subjects. We decided to perform n individul ptient dt (IPD) met-nlysis to confirm the previous findings nd strengthen conclusions on this prticulr yest strin. MATERIALS AND METHODS Design nd study selection Methods for sttisticl nlyses were pre-specified in Sttisticl Anlysis Pln. We evluted mnuscripts tht studied the effect of S. cerevisie CNCM I-3856 supplementtion on GI symptoms in IBS subjects. 337 Jnury 14, 2017 Volume 23 Issue 2

3 Cyzeele-Decherf A et l. Scchromyces cerevisie CNCM I-3856 in IBS Only the two forementioned clinicl trils were identified nd included in this met-nlysis. Study product The I-3856 strin of Schromyces cerevisie is proprietry, well-chrcterized strin of Lesffre, registered in the French Ntionl Collection of Cultures of Microorgnisms (CNCM). The S. cerevisie species hs been chrcterized by using phenotypic (API ID32C, Biomerieux SAS) nd genotypic referenced methods (genetic mplifiction nd sequencing of 26S DNA) [12,13]. Moreover, the strin I-3856 is identified thnks to the Polymerse Chin Rection (PCR) Interdelt typing technique [14], nd other genetic methods (e.g., complete genome sequencing). Dt collection All dt were provided by the sponsor of the trils. Uniform collection methods were employed in the two trils. Definition of outcomes Outcomes were defined s the dily Likert scle scores of bdominl pin/discomfort nd bloting (clculted on weekly bsis) over the common study period of both studies (8 wk) nd lso expressed s totl Are Under the Curve (AUC) [totl AUC (W0-W8) nd totl AUC (W5-W8)]. According to the bdominl score t bseline, responder sttus ws considered. A subject ws defined s responder if he/she experienced decrese of 1 rbitrry unit (.u.) or 50% of the bdominl discomfort score from bseline for t lest 2 wk out of the lst 4 wk of the study. Bowel movements, i.e., stool frequency nd consistency, were lso studied. Sttisticl nlysis Sttisticl nlyses were conducted, in first instnce, on the Intent to Tret (ITT) popultion. Two subpopultions of interest where then derived from this popultion: IBS-C subjects (IBS subjects with hrd or lumpy stools 25% nd loose (mushy) or wtery stools < 25% of bowel movements [3] ) nd IBS-C subjects with n bdominl pin/discomfort score higher thn or equl to 2 t bseline (referred s IBS-C 2 subpopultion in this pper). In both RCTs of this met-nlysis, subjects were included if they reported score of bdominl pin/discomfort rnging between 1 nd 6 (on 7-point Likert scle) t bseline. Nevertheless, only subjects presenting score 2 nd < 6 t bseline hve been considered in the IBS-C 2 subpopultion. IBS typology cn vry lot from one individul to nother, inducing gret vribility in symptoms scores intensity. The supplementtion with S. cerevisie CNCM I-3856 ims to be dministered to helthy subjects with medium level of bdominl pin/discomfort. IBS ptients who need follow-up t hospitl becuse of high-level of pin ( 6) re out of the scope of the present supplementtion. Inversely, subjects with low level of symptoms intensity (strictly below 2) cn t be considered s being improvble. In the ITT popultion, outcomes throughout the study period were nlyzed using fixed-effect repeted mesure model including the fctors Product, Week, IBS Type, Study nd interctions Product*Week, Product*Study nd Product*Week*Study [15,16]. An Anlysis of Covrince (ANCOVA), including fctors Product, IBS Type, Study, Product*Study nd the bseline vlue s covrite, ws conducted to nlyze totl AUCs. Finlly, Generlized Liner Model (GLM, binomil distribution) including fctors Product, Study, IBS Type nd interction Product*Study ws conducted to ssess the responder sttus. In the subpopultions, the sme sttisticl models, without the IBS Type effect, were run. Sttisticl nlyses were performed using SAS softwre version 9.3 (SAS Institute Inc., Cry, NC, United Sttes). RESULTS The two clinicl trils were published in 2015 nd 2016 in two different peer-reviewed journls. Chrcteristics of the trils re shown in Tble 1. Subjects Dt were obtined from 579 subjects, dignosed with IBS ccording to Rome Ⅲ criteri [3]. All IBS subtypes were represented in the two trils. Ptient chrcteristics for the 2 trils re listed in Tble 2. There re no significnt differences t bseline between the Plcebo nd Active groups on the totl popultion, nor on the IBS-C subpopultion nd the IBS-C 2 subpopultion. Gstrointestinl symptoms - Totl re under the curve Any chnge in GI symptoms throughout the supplementtion period ws nlyzed using AUC. Dt re presented in Figure 1 (bdominl pin/discomfort) nd Figure 2 (bloting). Over the 2 mo of supplementtion, no differences were determined by AUC (W0-W8) nlysis of bdominl pin/discomfort nd bloting between Active nd Plcebo groups of the ITT popultion nd the IBS-C subpopultion. A significnt difference between the Active nd Plcebo groups ws observed in the IBS-C 2 subpopultion on bdominl pin/discomfort (P = , diff[95%ci] = [-4.112;-0.080]) for AUC (W0-W8); nd trend ws reported on bloting (P = ) in fvor of the Active group. Considering the second month of supplementtion [AUC (W5-W8)], S. cerevisie CNCM I-3856 improved GI symptoms in ll nlyzed popultions. Abdominl pin/discomfort ws significntly reduced in the Active group compred to the Plcebo group in 338 Jnury 14, 2017 Volume 23 Issue 2

4 Cyzeele-Decherf A et l. Scchromyces cerevisie CNCM I-3856 in IBS Tble 1 Chrcteristics of the trils Tril Type of IBS Criteri Smple size Probiotic Probiotic dosge 1 Control Durtion of tretment Follow-up Pineton de Chmbrun et l [10] 2015 All types Rome Ⅲ 200 Scchromyces cerevisie CNCM I-3856 Spiller et l [11] 2015 All types Rome Ⅲ 379 Scchromyces cerevisie CNCM I cpsule (500 mg) of S. cerevisie/d CFU/g 2 cpsules of 500 mg of S. cerevisie/d CFU/g Plcebo 8 wk 3 wk Plcebo 12 wk - 1 The cpsules contined vible yest cells only, no excipient hs been dded. Probiotic products should contin the dequte mount of living cells to be efficient. Then, it is needed to mintin suitble level of vible cells during the product s shelf life. This living yest cells count is expressed most of time s minimum of colony forming unit per grm. This count of the yest strin CNCM I-3856 cells fter mnufcturing ws round CFU/g. It could slightly vry within the specifiction limits t relese depending on the btch even if the mnufcturing process nd the microbiologicl methods re vlidted. This vrition is due to the type of products (microbiologicl products obtined by fermenttion) nd due to the method vribility of vible cell counts (± 0.5 log). Moreover, it hs to be considered tht vible cell count slightly decreses with time (sensitivity to humidity nd temperture), which hs lredy been confirmed by stbility test progrm performed ccording interntionl conference on hrmonistion guidelines. Tht is why, n overdose is commonly dopted for probiotics. Bsed on these considertions, efficcy of probiotics is considered by the scientific community s similr when dosge remins within the sme log. CFU: Colony forming unit; IBS: Irritble bowel syndrome. Tble 2 Ptient chrcteristics for the 2 trils n (%) Plcebo group Active group Subjects, n Age (yr), men ± SD 45.3 ± ± Subject weight (kg), men ± SD 64.6 ± ± Subject height (cm), men ± SD ± ± 8.19 Subject BMI (kg/m²), men ± SD 23.9 ± ± 4.53 Hert rte (bpm), men ± SD 70.2 ± ± 9.08 Femle 244 (85.0) 245 (83.9) Smoker 65 (22.6) 75 (25.7) IBS-C 134 (46.7) 130 (44.5) IBS-C with n bdominl pin/discomfort score 2 t bseline 111 (38.7) 111 (38.0) IBS-D 55 (19.2) 56 (19.2) IBS-M 96 (33.4) 103 (35.3) BMI: Body mss index; IBS: Irritble bowel syndrome. the ITT popultion (-12.3%, P = , diff[95%ci] = [-1.305;-0.152]) nd in the IBS-C 2 subpopultion (-13.1%, P = , diff[95%ci] = [-2.100;-0.187]). A trend ws reported in the IBS-C subpopultion (-10.4%, P = ). Bloting ws significntly decresed during the second month of supplementtion in the ITT popultion (-9.2%, P = , diff[95%ci] = [-1.311;-0.175]); in the IBS-C popultion (-12.3%, P = , diff[95%ci] = [-1.714;-0.014]); nd in the IBS-C 2 subpopultion (-14.9%, P = , diff[95%ci] = [-2.143;-0.240]). Gstrointestinl symptoms - Scores over the study period In complementry pproch, dily Likert scle scores of bdominl pin/discomfort nd bloting were nlyzed on weekly bsis. At bseline, in the ITT popultion, the two groups were not different regrding the bdominl pin/discomfort scores (3.15 ± u. in the Active group vs 3.16 ± u. in the Plcebo group, P = ). Abdominl pin/discomfort ws significntly reduced throughout the study in the two study groups (between W0 nd W8, P < in both groups). At W8, lower bdominl pin/discomfort scores were reported in the Active group compred to Plcebo but the difference did not chieve sttisticl significnce (Active group: 2.14 ± u., Plcebo group: 2.31 ± u., P = ). In the IBS-C subpopultion, bdominl pin/discomfort significntly decresed between W0 nd W8 in both groups (Active group: 3.25 ± u. vs 2.23 ± u.; Plcebo group: 3.22 ± u. vs 2.40 ± u., P < in both groups). Similr evolution ws observed for bloting over the supplementtion period (Active group: 3.31 ± u. t W0 vs 2.25 ± u. t W8; Plcebo group: 3.36 ± u. t W0 vs 2.54 ± u. t W8, P < in both groups). In the IBS-C 2 subpopultion, slightly higher bdominl pin/discomfort ws expressed t bseline (3.54 ± u. in the Active group; 3.54 ± u. in the Plcebo group) s compred to the IBS-C subpopultion. Abdominl pin/discomfort scores significntly decresed from W0 to W8 in both groups 339 Jnury 14, 2017 Volume 23 Issue 2

5 Cyzeele-Decherf A et l. Scchromyces cerevisie CNCM I-3856 in IBS A B AUC (W0-W8) of bdominl pin/ discomfort intensity (.u. wk) AUC (W5-W8) of bdominl pin/ discomfort intensity (.u. wk) ITT IBS-C 2 0 ITT IBS-C 2 Figure 1 Are under the curve (W0-W8) (A) nd re under the curve (W5-W8) (B) of bdominl pin/discomfort in intent to tret popultion (ll irritble bowel syndrome subtypes) nd in irritble bowel syndrome-c subjects with n bdominl pin/discomfort score higher thn or equl to 2 t bseline (irritble bowel syndrome-c 2) under plcebo (white) or Scchromyces cerevisie CNCM I-3856 (grey) supplementtion. Significnt differences compred to plcebo re symbolized by P < IBS-C: Irritble bowel syndrome-c;.u.: Arbitrry unit; ITT: Intent to tret; AUC: Are under the curve. A B AUC (W0-W8) of bloting intensity (.u. wk) AUC (W5-W8) of bloting intensity (.u. wk) ITT IBS-C 2 0 ITT IBS-C 2 Figure 2 Are under the curve (W0-W8) (A) nd re under the curve (W5-W8) (B) of bloting in intent to tret popultion (ll irritble bowel syndrome subtypes) nd in irritble bowel syndrome-c subjects with n bdominl pin/discomfort score higher thn or equl to 2 t bseline (irritble bowel syndrome-c 2) under plcebo (white) or Scchromyces cerevisie CNCM I-3856 (grey) supplementtion. P < 0.05, Significnt differences, vs plcebo re symbolized. IBS-C: Irritble bowel syndrome-c;.u.: Arbitrry unit; ITT: Intent to tret; AUC: Are under the curve. (Active group: ± u.; Plcebo group: ± u., P < in both groups). Bloting significntly improved throughout the supplementtion period in both study groups (between W0 nd W8, P < in both groups). Abdominl pin/discomfort - Responder sttus Two definitions of responder sttus were pplied in this met-nlysis. In the ITT popultion, subjects in the Active group hd higher odds to be responder compred to subjects in the Plcebo group (P = , OR[95%CI] = [1.056;2.161]) when responders were defined by reduction of 1.u. of bdominl pin/discomfort score from W0 for t lest 2 wk between W5 nd W8. This difference ws not significnt nymore when responders were defined by reduction of 50% of bdominl pin/discomfort score. No significnt differences were reported between the Active nd Plcebo groups in both IBS-C nd IBS-C 2 subpopultions. Bowel movements Bowel movements re not reported in the ITT popultion becuse of the vriety of stool ptterns in regrd to the different IBS subtypes present in the study popultion. Stool consistency sttisticlly improved in the Active nd Plcebo groups of the IBS-C subpopultion during the supplementtion period. There ws sttisticlly significnt increse in the Bristol Stool Scle (BSS) score between W0 nd W8 in the Active group (2.41 ± u. vs 3.13 ± u., P < , diff[95%ci] = [0.391;1.114]) nd in the Plcebo group (2.24 ± u. vs 2.58 ± u., P = , diff[95%ci] = [0.032;0.771]) (Figure 3). Over the 8 wk of supplementtion, significnt product effect ws reported in the IBS-C subpopultion in fvor of S. cerevisie CNCM I-3856 (P < ) nd stool consistency ws significntly different from Plcebo from W2 340 Jnury 14, 2017 Volume 23 Issue 2

6 Cyzeele-Decherf A et l. Scchromyces cerevisie CNCM I-3856 in IBS Men dily bowel movement form (.u.) [IBS-C] b b b Men dily bowel movement form (.u.) [IBS-C 2] b b 2.0 W0 W1 W2 W3 W4 W5 W6 W7 W8 2.0 W0 W1 W2 W3 W4 W5 W6 W7 W8 t /wk t /wk Figure 3 Evolution of stool consistency in irritble bowel syndrome-c subjects during the 8-wk supplementtion with ctive product (Scchromyces cerevisie CNCM I-3856, white squres) or plcebo product (blck circles). Vlues re estimted mens, with stndrd error represented by verticl brs. P < 0.05, b P < 0.01, Significnt differences, vs plcebo re symbolized. IBS-C: Irritble bowel syndrome-c;.u.: Arbitrry unit. to W8. At the end of the supplementtion period, stool consistency in the Active group ws significntly higher nd clssified s norml compred to the Plcebo group (respectively 3.13 ± u. vs 2.58 ± u., P = , diff[95%ci]: [ ]). In the IBS-C 2 subpopultion, stool consistency improved in the sme wy. BSS scores incresed in Active nd Plcebo groups between W0 nd W8. A sttisticlly significnt difference ws reported in the Active group (W0: 2.35 ± u. vs W8: 3.14 ± u., P < , diff[95%ci]: [ ]) but not in the Plcebo group (2.25 ± u. vs 2.59 ± u., P = ) (Figure 4). A significnt product effect in fvor of S. cerevisie CNCM I-3856 ws pprent in the IBS-C 2 subpopultion over the supplementtion period (P = ) nd stool consistency ws significntly different from Plcebo during the second prt of the supplementtion (P < 0.05 from W4 to W8). Sttisticlly significnt product effects were irregulrly observed on stool frequency in the IBS-C subpopultion nd the IBS-C 2 subpopultion in fvor of the Active group. However the non-persistence of the effect nd the bsence of clinicl relevnce between Active vs Plcebo did not demonstrte ny benefits from S. cerevisie CNCM I-3856 supplementtion on this outcome. DISCUSSION Figure 4 Evolution of stool consistency in irritble bowel syndrome-c subjects with n bdominl pin/discomfort score higher thn or equl to 2 t bseline (irritble bowel syndrome-c 2) during the 8-wk supplementtion with ctive product (Scchromyces cerevisie CNCM I-3856, white squres) or plcebo product (blck circles). Vlues re estimted mens, with stndrd error represented by verticl brs. P < 0.05, b P < 0.01, Significnt differences, vs plcebo re symbolized. IBS-C: Irritble bowel syndrome-c;.u.: Arbitrry unit. Bsed on the dt of two RCTs investigting the benefits of S. cerevisie CNCM I-3856 on IBS symptoms mngement, this IPD met-nlysis confirmed some promising qulities of this yest strin to llevite GI symptoms. Anlysis of GI symptoms (bdominl pin/discomfort nd bloting) on week-by-week bsis demonstrted gret vribility in ptient complints over the supplementtion period which hs lredy been discussed by different uthors [17,18]. No significnt benefits of S. cerevisie CNCM I-3856 supplementtion were observed during the first month of supplementtion compred to plcebo. This point hs been previously reported by Pineton de Chmbrun et l [10] who mentioned potentil dely of ction of S. cerevisie. The yest my positively impct bdominl pin/discomfort due to n nlgesic effect, with dely before significnt effectiveness s reported in niml studies [19]. In rts, some significnt product effects were noted over the second month of study but the nlgesic effect ws trnsitory nd limited to the time of product dministrtion. From clinicl point of view, AUC dt provide relevnt informtion in regrd to overll subjective feelings. First, the AUC presents n overview of GI symptom intensity during the study period. This provides n indiction of symptom llevition over the supplementtion period. The present nlysis hrdly succeeded in demonstrting beneficil effect of S. cerevisie CNCM I-3856 on the globl AUC [AUC (W0-W8)] for bdominl pin/discomfort nd bloting. Sttisticlly positive effects were reported in the IBS-C 2 subpopultion, but not in the ITT popultion nd IBS-C subpopultion. An AUC ws lso clculted over the second month of supplementtion. This period ws chosen in order to ccount for the forementioned dely for significnt ction of the probiotic. Anlysis on this specific period [AUC (W5-W8)] confirmed the product effect ssocited with yest supplementtion, in comprison to plcebo, in ll nlyzed popultions. Additionlly, every sttisticlly significnt difference or trend ws relted to n improvement in the Active group from 9.2% nd up to 14.9% compred to Plcebo. This observtion is of gret interest from clinicl point of view: the 10% difference is considered s miniml cliniclly relevnt 341 Jnury 14, 2017 Volume 23 Issue 2

7 Cyzeele-Decherf A et l. Scchromyces cerevisie CNCM I-3856 in IBS threshold [20]. This mens tht S. cerevisie CNCM I-3856 improves IBS symptoms in significnt nd relevnt mnner in IBS ptients, in globl IBS popultion nd in the IBS-C subtype during the second month of consumption. Another pproch in vlidting the clinicl benefits of therpy consists of nlyzing the percentge of ptients who positively respond to the tretment. Vrious definitions of responder sttus re suggested by the literture [21]. In ddition, food nd drug uthorities hve since estblished some complete definitions for responder sttus [22,23]. Two different definitions of responder sttus were pplied in the two RCTs [10,11]. They were re-used in the present met-nlysis for consistency. Conclusions on responder sttus were limited to the ITT popultion who experienced n improvement of 1.u. of bdominl pin/discomfort for t lest 50% of the second month of supplementtion. One point limiting the positive conclusions on S. cerevisie CNCM I-3856 reltes to the plcebo response commonly reported in GI disorders. A metnlysis of plcebo-controlled RCTs conducted in IBS ptients reported men plcebo response rte of 37.5% [24]. This is consistent with previous metnlysis from Ptel et l [25] who observed tht 40.2% of ptients respond to plcebo. The plcebo effect is one fctor influencing the plcebo response rte, but it does not ffect it lone. The uthors of this metnlysis tried to determine the confounding fctors which my influence the plcebo response rte (durtion of therpy, run-in phse, single or multi-centre study, etc.); but, inconsistent dt were reported [24,25]. Tody, probiotics re n lterntive pproch being extensively reserched for the mngement of symptoms in IBS ptients. While the effects of probiotics on IBS physiopthology re still under scrutiny [9], mny clinicl trils investigting the benefits of one or more bcteril strins in IBS hve been published. Incresed resources re now vilble to exmine probiotic benefits in IBS mngement. It remins difficult to clerly conclude efficcy nd set up recommendtions for probiotics supplementtion becuse of the poor repetbility of the dt nd the difficulty in compring studies. Indeed, gret heterogeneity is observed between trils in terms of vriety of strins used, probiotic dosge, tretment durtion, outcome definitions, nd sttisticl nlyses. This point is highlighted in literture reviews nd met-nlyses [26-28]. In the bsence of comprble studies, met-nlyses re performed to integrte qulittive clinicl trils irrespective of the probiotic strins studied [26-31]. All uthors globlly gree s to the benefits of probiotics supplementtion in IBS ptients. Neither individul probiotic nor combintion of strins ws, however, identified s effective by itself nd conclusions were drwn for probiotics in generl. Some uthors directed their met-nlyses specificlly to Lctobcillus strins [32] or to Lctobcillus rhmnosus GG in children [33]. Only few trils were included in these met-nlyses (six trils investigting Lctobcillus strins nd three trils investigting Lctobcillus rhmnosus GG in children), but their conclusions cn be considered relevnt in light of the studies selected. Both uthors concluded on beneficil effect of Lctobcillus spp on IBS symptoms, nmely on frequency nd intensity of bdominl pin. However, no recommendtions for dose nd tretment durtion were proposed. In regrds to these met-nlyses, the present IPD met-nlysis demonstrtes two dvntges. First, the two RCTs were designed to evlute the sme probiotic strin, i.e., S. cerevisie CNCM I-3856, nd the methodologies were very similr. Study designs were double-blind, rndomized, plcebo-controlled to chieve high qulity studies, nd recommendtions for tretment tril design were pplied [21]. These points strengthen the integrtion of dt nd their nlyses s whole. Second, individul dt on ll subjects were compiled to perform new sttisticl nlyses, which provide more robust result thn metnlyses bsed on ggregte dt. The pooling of the two originl individul trils [10,11] for met-nlysis incresed the smple size nd thus the power of the sttisticl nlyses, in prticulr in the context of the nlysis in the IBS-C subpopultion. In ddition, this met-nlysis llowed nswering nd confirming questions not initilly rised by both studies nd consolidted previous results reported on S. cerevisie CNCM I In conclusion, this IPD met-nlysis confirms previous dt linking S. cerevisie CNCM I-3856 supplementtion nd improvement of GI symptoms in IBS overll popultion nd in the IBS-C nd IBS-C 2 subpopultions. Despite gret similrities in study designs, the two RCTs considered in the met-nlysis differ in terms of endpoints. The present observtions would gin in being vlidted by new RCT designed ccording to these met-nlysis conclusions. COMMENTS Bckground Irritble bowel syndrome (IBS) is common functionl gstrointestinl (GI) disorder with high prevlence. Its dignosis is bsed on the presence of bdominl pin nd/or discomfort ssocited with t lest two of the following: improvement with defection; onset ssocited with chnge in frequency of stool; onset ssocited with chnge in form of stool. With the lck of stisfctory phrmcologicl tretments suitble for long-term dministrtion, n lterntive pproch such s probiotic use my be of interest for IBS mngement. Reserch frontiers The intestinl microbiot ppers to ply key role in IBS, even if its impliction is not clerly identified. Probiotics re live microorgnisms tht confer helth benefit to the host. The present met-nlysis focuses on yest strin Scchromyces cerevisie (S. cerevisie) CNCM I Innovtions nd brekthroughs Two rndomized clinicl trils hve been included in this individul ptient dt met-nlysis. Dt on 579 subjects were compiled nd nlyzed to increse the power of the initil sttisticl nlyses. Results confirm the efficcy of S. cerevisie CNCM I-3856 supplementtion in subjects suffering from IBS for 342 Jnury 14, 2017 Volume 23 Issue 2

8 Cyzeele-Decherf A et l. Scchromyces cerevisie CNCM I-3856 in IBS the improvement of GI symptoms. Interesting results were reported in subjects chrcterized by IBS-C or by IBS-C with score of bdominl pin/discomfort 2 t bseline. Applictions The results suggest tht S. cerevisie CNCM I-3856 my be n lterntive pproch to del with GI symptoms ssocited with IBS. Terminology IBS is defined s recurrent bdominl pin or discomfort t lest 3 d per month in the lst 3 mo ssocited with 2 or more of the following: 1. Improvement with defection, 2. Onset ssocited with chnge in frequency of stool, 3. Onset ssocited with chnge in form (ppernce) of stool. Peer-review The study contents re interesting, being focused on the efficcy of S. cerevisie CNCM I-3856 supplementtion in subjects suffering from IBS for the improvement of GI symptoms. The title nd bstrct ccurtely convey the study contents. The objectives of the study re cler. The methods re pproprite nd well described, the dt re sound nd controlled. The discussion nd conclusions re well blnced nd dequtely supported by the dt. REFERENCES 1 Cnvn C, West J, Crd T. The epidemiology of irritble bowel syndrome. Clin Epidemiol 2014; 6: [PMID: DOI: /CLEP.S40245] 2 Sores RL. Irritble bowel syndrome: clinicl review. World J Gstroenterol 2014; 20: [PMID: DOI: /wjg.v20.i ] 3 Longstreth GF, Thompson WG, Chey WD, Houghton LA, Merin F, Spiller RC. Functionl bowel disorders. Gstroenterology 2006; 130: [PMID: DOI: /j.gstro ] 4 Sh L. Irritble bowel syndrome: pthogenesis, dignosis, tretment, nd evidence-bsed medicine. World J Gstroenterol 2014; 20: [PMID: DOI: /wjg.v20.i ] 5 Simrén M, Brbr G, Flint HJ, Spiegel BM, Spiller RC, Vnner S, Verdu EF, Whorwell PJ, Zoetendl EG. Intestinl microbiot in functionl bowel disorders: Rome foundtion report. Gut 2013; 62: [PMID: DOI: /gutjnl ] 6 Bennet SM, Ohmn L, Simren M. Gut microbiot s potentil orchestrtors of irritble bowel syndrome. Gut Liver 2015; 9: [PMID: DOI: /gnl14344] 7 Lee KN, Lee OY. Intestinl microbiot in pthophysiology nd mngement of irritble bowel syndrome. World J Gstroenterol 2014; 20: [PMID: DOI: /wjg.v20.i ] 8 Jdllh KA, Kullb SM, Snders DS. Constiption-predominnt irritble bowel syndrome: review of current nd emerging drug therpies. World J Gstroenterol 2014; 20: [PMID: DOI: /wjg.v20.i ] 9 Sntos AR, Whorwell PJ. Irritble bowel syndrome: the problem nd the problem of treting it - is there role for probiotics? Proc Nutr Soc 2014; 73: [PMID: DOI: /S ] 10 Pineton de Chmbrun G, Neut C, Chu A, Czubiel M, Pelerin F, Justen P, Desreumux P. A rndomized clinicl tril of Scchromyces cerevisie versus plcebo in the irritble bowel syndrome. Dig Liver Dis 2015; 47: [PMID: DOI: /j.dld ] 11 Spiller R, Pélerin F, Cyzeele Decherf A, Mudet C, Housez B, Czubiel M, Jüsten P. Rndomized double blind plcebo-controlled tril of Scchromyces cerevisie CNCM I-3856 in irritble bowel syndrome: improvement in bdominl pin nd bloting in those with predominnt constiption. United Europen Gstroenterol J 2016; 4: [PMID: DOI: / ] 12 Kurtzmn CP, Robnett CJ. Identifiction nd phylogeny of scomycetous yests from nlysis of nucler lrge subunit (26S) ribosoml DNA prtil sequences. Antonie Vn Leeuwenhoek 1998; 73: [PMID: ] 13 Kurtzmn CP, Robnett CJ. Identifiction of cliniclly importnt scomycetous yests bsed on nucleotide divergence in the 5 end of the lrge-subunit (26S) ribosoml DNA gene. J Clin Microbiol 1997; 35: [PMID: ] 14 Stndrdiztion ECf. Animl feeding stuffs: PCR typing of probiotic strins of Scchromyces cerevisie (yest) 15 Borenstein M, Hedges L, Rothstein H. Met-nlysis: Fixed effect vs rndom effects. Avilble from: URL: Anlysis.com 16 Whitehed A. Met-Anlysis of Controlled Clinicl Trils: John Wiley nd Sons, Ltd, Shh E, Pimentel M. Plcebo effect in clinicl tril design for irritble bowel syndrome. J Neurogstroenterol Motil 2014; 20: [PMID: DOI: /jnm ] 18 Musil F, Klosterhlfen S, Enck P. Plcebo responses in ptients with gstrointestinl disorders. World J Gstroenterol 2007; 13: [PMID: DOI: /wjg.v13.i ] 19 Rousseux C, Bouguen G, Dubuquoy C, Dubuquoy L, Vndekerckove P, Desreumux P. 274 Schromyces Cerevisie Cncm I-3856 Decreses Intestinl Pin Through PPAR Alph Activtion in the Gut. Gstroenterology 2010; 138: S-51 [DOI: /S (10) ] 20 Chng L, Lembo A, Sultn S. Americn Gstroenterologicl Assocition Institute Technicl Review on the phrmcologicl mngement of irritble bowel syndrome. Gstroenterology 2014; 147: e2 [PMID: DOI: /j.gstro ] 21 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 2006; 130: [PMID: DOI: /j.gstro ] 22 Food nd Drug Administrtion. Guidnce for Industry: Irritble Bowel Syndrome - Clinicl Evlution of Drugs for Tretment. US Deprtment of Helth nd Humn services, Food nd Drug Administrtion, Center for Drug Evlution nd reserch (CDER), 2012: Europen Medicines Agency. Guideline on the evlution of medicinl products for the tretment of irritble bowel syndrome. Europen Medicines Agency, 2014: Ford AC, Moyyedi P. Met-nlysis: fctors ffecting plcebo response rte in the irritble bowel syndrome. Aliment Phrmcol Ther 2010; 32: [PMID: DOI: /j x] 25 Ptel SM, Stson WB, Legedz A, Ock SM, Kptchuk TJ, Conboy L, Cnenguez K, Prk JK, Kelly E, Jcobson E, Kerr CE, Lembo AJ. The plcebo effect in irritble bowel syndrome trils: metnlysis. Neurogstroenterol Motil 2005; 17: [PMID: DOI: /j x] 26 Hoveyd N, Heneghn C, Mhtni KR, Perer R, Roberts N, Glsziou P. A systemtic review nd met-nlysis: probiotics in the tretment of irritble bowel syndrome. BMC Gstroenterol 2009; 9: 15 [PMID: DOI: / X-9-15] 27 McFrlnd LV, Dublin S. Met-nlysis of probiotics for the tretment of irritble bowel syndrome. World J Gstroenterol 2008; 14: [PMID: DOI: /wjg ] 28 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 2010; 59: [PMID: DOI: /gut ] 29 Didri T, Mozffri S, Nikfr S, Abdollhi M. Effectiveness of probiotics in irritble bowel syndrome: Updted systemtic review with met-nlysis. World J Gstroenterol 2015; 21: [PMID: DOI: /wjg.v21.i ] 30 Ford AC, Quigley EM, Lcy BE, Lembo AJ, Sito YA, Schiller LR, Soffer EE, Spiegel BM, Moyyedi P. Efficcy of prebiotics, probiotics, nd synbiotics in irritble bowel syndrome nd chronic idiopthic constiption: systemtic review nd met-nlysis. Am J Gstroenterol 2014; 109: ; quiz 1546, 1562 [PMID: DOI: /jg ] 343 Jnury 14, 2017 Volume 23 Issue 2

9 Cyzeele-Decherf A et l. Scchromyces cerevisie CNCM I-3856 in IBS 31 Ortiz-Lucs M, Tobís A, Sz P, Sebstián JJ. Effect of probiotic species on irritble bowel syndrome symptoms: A bring up to dte met-nlysis. Rev Esp Enferm Dig 2013; 105: [PMID: ] 32 Tiequn B, Gunqun C, Shuo Z. Therpeutic effects of Lctobcillus in treting irritble bowel syndrome: metnlysis. Intern Med 2015; 54: [PMID: DOI: /internlmedicine ] 33 Horvth A, Dziechcirz P, Szjewsk H. Met-nlysis: Lctobcillus rhmnosus GG for bdominl pin-relted functionl gstrointestinl disorders in childhood. Aliment Phrmcol Ther 2011; 33: [PMID: DOI: /j x] P- Reviewer: Lktos PL, Pni SP, Specchi ML S- Editor: Qi Y L- Editor: A E- Editor: Liu WX 344 Jnury 14, 2017 Volume 23 Issue 2

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