nature publishing group 1547

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CLINICAL AND SYSTEMATIC REVIEWS

INTRODUCTION Irritable bowel syndrome (IBS) and chronic idiopathic consti-

pation (CIC) are functional bowel disorders. Both conditions

are common, with a prevalence of between 5 and 20 % in the

general population, depending on the criteria used to defi ne

their presence ( 1,2 ). IBS and CIC are more common in women

( 2,3 ), and IBS occurs more frequently in younger individuals

( 1 ), whereas the prevalence of CIC increases with age ( 2 ). Evi-

dence for any eff ect of socioeconomic status is uncertain. Th e

cause of these functional bowel disorders remains unclear, but

Effi cacy of Prebiotics, Probiotics, and Synbiotics in Irritable Bowel Syndrome and Chronic Idiopathic Constipation: Systematic Review and Meta-analysis Alexander C . Ford , MBChB, MD 1 , 2 , Eamonn M.M. Quigley , MD, FRCP, FACP, FACG, FRCP 3 , Brian E. Lacy , MD, PhD 4 ,

Anthony J. Lembo , MD 5 , Yuri A. Saito , MD, MPH 6 , Lawrence R. Schiller , MD, MSHS, RFF, FACG, AGAF 7 , Edy E. Soff er , MD 8 ,

Brennan M.R. Spiegel , MD, MSHS, RFF, FACG, AGAF 9 and Paul Moayyedi , MBChB, PhD, MPH, FACG 10

OBJECTIVES: Irritable bowel syndrome (IBS) and chronic idiopathic constipation (CIC) are functional bowel disorders. Evidence suggests that disturbance in the gastrointestinal microbiota may be implicated in both conditions. We performed a systematic review and meta-analysis to examine the effi cacy of prebiotics, probiotics, and synbiotics in IBS and CIC.

METHODS: MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched (up to December 2013). Randomized controlled trials (RCTs) recruiting adults with IBS or CIC, which compared prebiotics, probiotics, or synbiotics with placebo or no therapy, were eligible. Dichotomous symptom data were pooled to obtain a relative risk (RR) of remaining symptomatic after therapy, with a 95 % confi dence interval (CI). Continuous data were pooled using a standardized or weighted mean difference with a 95 % CI.

RESULTS: The search strategy identifi ed 3,216 citations. Forty-three RCTs were eligible for inclusion. The RR of IBS symptoms persisting with probiotics vs. placebo was 0.79 (95 % CI 0.70 – 0.89). Probiotics had benefi cial effects on global IBS, abdominal pain, bloating, and fl atulence scores. Data for prebiotics and synbiotics in IBS were sparse. Probiotics appeared to have benefi cial effects in CIC (mean increase in number of stools per week = 1.49; 95 % CI = 1.02 – 1.96), but there were only two RCTs. Synbiotics also appeared benefi cial (RR of failure to respond to therapy = 0.78; 95 % CI 0.67 – 0.92). Again, trials for prebiotics were few in number, and no defi nite conclusions could be drawn.

CONCLUSIONS: Probiotics are effective treatments for IBS, although which individual species and strains are the most benefi cial remains unclear. Further evidence is required before the role of prebiotics or synbiot-ics in IBS is known. The effi cacy of all three therapies in CIC is also uncertain.

SUPPLEMENTARY MATERIAL is linked to the online version of the paper at http://www.nature.com/ajg

Am J Gastroenterol 2014; 109:1547–1561; doi: 10.1038/ajg.2014.202; published online 29 July 2014

1 Leeds Gastroenterology Institute, St James ’ s University Hospital , Leeds , UK ; 2 Leeds Institute of Biomedical and Clinical Sciences, University of Leeds , Leeds , UK ; 3 Division of Gastroenterology and Hepatology, Department of Medicine, Houston Methodist Hospital , Houston , Texas , USA ; 4 Dartmouth-Hitchcock Medical Center, Gastroenterology, One Medical Center Drive , Lebanon , New Hampshire , USA ; 5 The Beth Israel Deaconess Medical Center , Boston , Massachusetts , USA ; 6 Division of Gastroenterology and Hepatology, Mayo Clinic , Rochester , Minnesota , USA ; 7 Digestive Health Associates of Texas, Baylor University Medical Center , Dallas , Texas , USA ; 8 Division of Gastroenterology at Cedars-Sinai, University of Southern California , Los Angeles , California , USA ; 9 Department of Gastroenterology, VA Greater Los Angeles Healthcare System , Los Angeles , California , USA ; 10 Gastroenterology Division, McMaster University, Health Sciences Center , Hamilton , Ontario , Canada . Correspondence: Alexander C. Ford , MBChB, MD, Leeds Gastroenterology Institute, St. James ’ s University Hospital , Room 125, 4th Floor, Bexley Wing, Beckett Street , Leeds LS9 7TF UK . E-mail: alexf12399@yahoo.com Received 25 February 2014; accepted 30 April 2014

see related editorial on page 1563

CME

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visceral hypersensitivity ( 4,5 ), disturbances in gastrointestinal

(GI) fl ora ( 6,7 ), and chronic immune activation leading to a

low-grade mucosal infl ammation ( 8 – 11 ) have all been impli-

cated in the pathogenesis of IBS and CIC.

Eff ective pharmacological therapies for IBS and CIC exist

( 12 – 15 ), but the duration of most treatment trials is < 6 months,

meaning that no therapy has been proven to alter the natural

history of either condition in the long term. In addition, many

patients do not respond to, or become dissatisfi ed with, conven-

tional therapies ( 16,17 ). Modulating the GI fl ora, as a means of

improving symptoms, may therefore be an attractive treatment

option. Probiotics, which are live or attenuated microorganisms

that may have benefi cial eff ects in humans, have been widely stud-

ied in IBS ( 18 ). Some probiotics appear to have anti-infl ammatory

properties ( 19 ), or the ability to modulate visceral hypersensitiv-

ity ( 20,21 ). Prebiotics are ingredients in food that remain undi-

gested, and which may stimulate either the growth or the activity

of bacteria that are also benefi cial to human health. Examples of

prebiotics include fructo-oligosaccharides and inulin. Synbiotics

are combinations of prebiotics and probiotics, with a potentially

synergistic action.

In our previous systematic review and meta-analysis ( 18 ), con-

ducted to inform the American College of Gastroenterology ’ s

monograph on the management of IBS ( 22 ), we summarized all

available evidence for the use of probiotics in IBS. At this time,

there was limited information concerning the effi cacy of either

prebiotics or synbiotics in IBS, or the benefi t of any of these three

treatments in CIC. However, in the intervening 4 years, there has

been a considerable amount of evidence published. We have there-

fore re-examined this issue.

METHODS Search strategy and study selection We updated our previous systematic review and meta-analysis

examining the effi cacy of probiotics in IBS ( 18 ), and also per-

formed a search for studies that reported on the eff ectiveness of

prebiotics and synbiotics in IBS, as well as prebiotics, probiotics,

and synbiotics in CIC. A search of the medical literature was con-

ducted using MEDLINE (1946 to December 2013), EMBASE and

EMBASE Classic (1947 to December 2013), and the Cochrane

central register of controlled trials. Randomized placebo-control-

led trials examining the eff ect of prebiotics, probiotics, and synbi-

otics in adult patients (over the age of 16 years) with IBS or CIC

were eligible for inclusion ( Box 1 ). Duration of therapy had to

be at least 7 days. Th e diagnosis of IBS or CIC could be based on

either a physician ’ s opinion or symptom-based diagnostic criteria,

supplemented by the results of investigations to exclude organic

disease, where studies deemed this necessary.

Subjects were required to be followed up for at least 1 week, and

studies had to report response to therapy as either dichotomous

or continuous data. For IBS, dichotomous assessment could be

in the form of either an assessment of global symptom cure or

improvement, or abdominal pain cure or improvement, aft er

completion of therapy: preferably as reported by the patient, but

if this was not recorded then as documented by the investiga-

tor or via questionnaire data. Continuous data of interest were

the eff ect of therapy on IBS symptom scores at the end of study.

For CIC, outcomes of interest were a dichotomous assessment

of overall response to therapy, or continuous data in the form

of mean number of stools per week during therapy, preferably

as reported by the patient, but if this was not recorded then as

documented by the investigator or via questionnaire data. In

studies that included patients with IBS or CIC among patients

with other functional GI disorders, or studies that did not report

these types of dichotomous or continuous data, but were other-

wise eligible for inclusion in the systematic review, we attempted

to contact the original investigators in order to obtain further

information .

Th e literature search was performed as part of a broader exer-

cise to inform the update of the American College of Gastroenter-

ology ’ s (ACG) monograph on the management of IBS and CIC.

Specifi cally, studies on IBS were identifi ed with the terms irrita-

ble bowel syndrome and functional diseases, colon (both as medi-

cal subject heading (MeSH) and free text terms), and IBS , spastic

colon , irritable colon , or functional adj5 bowel (as free text terms).

Studies on CIC were identifi ed with constipation or gastrointes-

tinal transit (both as medical subject headings (MeSH) and free

text terms), or functional constipation , idiopathic constipation , and

chronic constipation , or slow transit (as free text terms). Th ese were

Box 1. Eligibility criteria

Randomized controlled trials

Adults (participants aged > 16 years)

Diagnosis of IBS or CIC based on either a clinician ’ s opinion, or meeting specifi c diagnostic criteria (Manning, Kruis score, Rome I, II, or III), supplemented by negative investigations where trials deemed this necessary.

Compared prebiotics, probiotics, or synbiotics with placebo.

Minimum duration of therapy 7 days.

Minimum duration of follow-up 7 days.

Dichotomous assessment of response to therapy in terms of effect on global IBS symptoms or abdominal pain following therapy, or response to therapy for CIC, or continuous data in the form of effect on IBS symptom scores at study end or effect on mean number of stools per week for CIC (Preferably patient-reported, but if this was not available then as assessed by a physician or question-naire data).

© 2014 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

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Prebiotics, probiotics, and synbiotics in IBS and CIC

measure used to defi ne symptom improvement or cure following

therapy, duration of follow-up, proportion of female patients, and

proportion of patients according to predominant stool pattern for

IBS. Data were extracted as intention-to-treat analyses, with all

dropouts assumed to be treatment failures, wherever trial report-

ing allowed this.

Assessment of risk of bias Th is was performed independently by two investigators, with

disagreements resolved by discussion. Risk of bias was assessed

as described in the Cochrane handbook ( 23 ), by recording the

method used to generate the randomization schedule and conceal

allocation, whether blinding was implemented, what proportion

of patients completed follow-up, whether an intention-to-treat

analysis was extractable, and whether there was evidence of selec-

tive reporting of outcomes.

Data synthesis and statistical analysis Data were pooled using a random-eff ects model ( 24 ), to give a

more conservative estimate of the eff ect of prebiotics, probiotics,

or synbiotics, allowing for any heterogeneity between studies.

Th e impact of prebiotics, probiotics, or synbiotics in IBS was

expressed as a relative risk (RR) of global IBS symptoms or

abdominal pain persisting with intervention compared with

control, with 95 % confi dence intervals (CIs), or a standardized

mean diff erence (SMD) in global and individual IBS symptom

scores at study end, with 95 % CIs. Th e impact of prebiotics,

probiotics, or synbiotics in CIC was expressed as a RR of no

response with intervention compared with control, with 95 %

CIs, or a weighted mean diff erence in the mean number of stools

per week at the end of study, with 95 % CIs . Adverse events data

were also summarized with RRs. Th e number needed to treat

(NNT) and the number needed to harm, with 95 % CIs, were

calculated from the reciprocal of the risk diff erence of the meta-

analysis.

Heterogeneity between studies was assessed using both the I 2

statistic with a cutoff of ≥ 50 % and the χ 2 -test with a P value < 0.10,

used to defi ne a signifi cant degree of heterogeneity ( 25 ). In cases in

which the degree of statistical heterogeneity was greater than this

between trial results in this meta-analysis, possible explanations

were investigated using sensitivity analyses according to the type

of prebiotic, probiotics, or synbiotic used, trial setting, criteria used

to defi ne IBS or CIC, whether the method of randomization or

combined using the set operator AND with studies identifi ed with

the following terms: Saccharomyces , Lactobacillus , Bifi dobacterium ,

Escherichia coli , probiotics, synbiotics, or prebiotics (both as MeSH

and free text terms).

Th ere were no language restrictions, and abstracts of the papers

identifi ed by the initial search were evaluated by the lead reviewer

for appropriateness to the study question, with all potentially rel-

evant papers obtained and evaluated in detail. Foreign language

papers were translated where necessary. Abstract books of con-

ference proceedings between 2001 and 2013 were hand-searched

to identify potentially eligible studies published only in abstract

form. Th e bibliographies of all identifi ed relevant studies were

used to perform a recursive search of the literature. Articles were

independently assessed by two reviewers using predesigned eli-

gibility forms, according to the prospectively defi ned eligibility

criteria. Any disagreement between investigators was resolved by

consensus.

Outcome assessment Th e primary outcomes assessed were the eff ect of prebiotics,

probiotics, or synbiotics compared with placebo on global IBS

symptoms or abdominal pain aft er cessation of therapy, or eff ect

on overall response to therapy for CIC. Secondary outcomes

included the eff ect of prebiotics, probiotics, or synbiotics on

global IBS symptom scores and individual IBS symptom scores

at the end of study, including abdominal pain, bloating, urgency,

or fl atulence, or eff ect on mean number of stools per week for

CIC. We also examined numbers of adverse events as a result of

prebiotics, probiotics, or synbiotics.

Data extraction All data were extracted independently by two reviewers on to a

Microsoft Excel spreadsheet (XP professional edition; Microsoft ,

Redmond, WA) as dichotomous outcomes (global IBS symptoms

persistent or unimproved, or abdominal pain persistent or unim-

proved, or response or no response to therapy for CIC; Box 2 ),

or mean symptom scores or mean number of stools per week at

study end, along with a s.d.. In addition, the following clinical data

were extracted for each trial: setting (primary, secondary, or terti-

ary care-based), number of centers, country of origin, prebiotic,

probiotic, or synbiotic used (including strain and species where

applicable), duration of therapy, total number of adverse events

reported, criteria used to defi ne IBS or CIC, primary outcome

Box 2. Data extraction methodology

Outcome of interest: improvement in global IBS symptoms preferable, if this was not reported then improvement in abdominal pain.

Reporting of outcomes: patient-reported was preferable, if this was not available then investigator-reported .

Time of assessment: upon completion of therapy.

Denominator used: true intention-to-treat analysis, if this was not available then all evaluable patients .

Cutoff used for dichotomization: any improvement in global IBS symptoms or abdominal pain for Likert-type scales. Any response to therapy for CIC.

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Ford et al.

concealment of allocation were reported, level of blinding, and risk

of bias of included trials. We compared individual RRs between

these analyses using the Cochran ’ s Q statistic. Th ese were explora-

tory analyses only, and may explain some of the observed variabil-

ity, but the results should be interpreted with caution.

Review Manager version 5.1.4 (RevMan for Windows 2008,

the Nordic Cochrane Centre, Copenhagen, Denmark) and

StatsDirect version 2.7.7 (StatsDirect, Sale, Cheshire, UK) were

used to generate Forest plots of pooled RRs, risk diff erences,

and SMDs for primary and secondary outcomes with 95 % CIs,

as well as funnel plots. Th e latter were assessed for evidence of

asymmetry, and therefore possible publication bias or other

small study eff ects, using the Egger test ( 26 ), if there were

suffi cient ( ≥ 10) eligible studies included in the meta-analysis,

in line with recent recommendations ( 27 ).

RESULTS Th e search strategy generated a total of 3,216 citations, of

which 73 published articles appeared to be relevant, and were

retrieved for further assessment ( Figure 1 ). Of these, 30 articles

were excluded for various reasons, leaving 43 eligible articles.

Agreement between reviewers for the assessment of trial eligi-

bility was excellent (kappa statistic = 0.93). We identifi ed only

one randomized controlled trial (RCT) that evaluated the preb-

iotic trans-galacto-oligosaccharide in IBS ( 28 ). Th is study was

excluded from further analysis, as the data were not extract-

able. We identifi ed 35 RCTs of probiotics in IBS ( 19,29 – 62 ), and

two studies of synbiotics ( 63,64 ). Th ere was only one trial of

prebiotics in CIC ( 65 ), three of probiotics ( 66 – 68 ), and two of

synbiotics ( 69,70 ).

Effi cacy and safety of probiotics in IBS Th e 35 RCTs of probiotics in IBS involved 3,452 patients ( 19,29 – 62 ).

Th e proportion of women in the trials ranged between 26 and

100 % . Fourteen trials were at a low risk of bias ( 30,35,36,41,43,

45 – 47,49,50,57 – 60 ), with the remainder being unclear. Nineteen

trials used a combination of probiotics, eight Lactobacillus , three

Bifi dobacterium , two E. coli , one Streptococcus , one Saccharomyces ,

and one either Lactobacillus or Bifi dobacterium . Detailed charac-

teristics of included RCTs are provided in Table 1 .

Effi cacy of probiotics in the treatment of IBS: effect on persistence of symptoms Th ere were 23 RCTs comparing probiotics with placebo for the

treatment of IBS ( 30,31,33 – 41,43,44,46,49,51,53 – 55,57 – 60 ),

evaluating 2,575 patients, which gave outcomes as a dichoto-

mous variable. Overall, 777 (55.8 % ) of 1,392 patients assigned

to probiotics reported persistent or unimproved IBS symptoms

following therapy, compared with 865 (73.1 % ) of 1,183 allocated

to placebo. Th e RR of IBS symptoms persisting or remaining

unimproved aft er treatment with probiotics vs. placebo was 0.79

(95 % CI 0.70 – 0.89), with statistically signifi cant heterogeneity

detected between studies ( I 2 = 72 % , P < 0.001; Figure 2 ). Th ere

was no statistically signifi cant asymmetry detected in the funnel

plot (Egger test, P = 0.36), to suggest publication bias or other

small study eff ects. Th e NNT with probiotics was 7 (95 % CI

4 – 12.5). When only the 12 RCTs at a low risk of bias that

provided dichotomous data were considered in the analysis,

the eff ect of probiotics was still statistically signifi cant (RR of

persistent or unimproved symptoms = 0.82; 95 % CI 0.69 – 0.98).

Combination probiotics were assessed in 12 RCTs ( 30,31,33,35

,37,43,44,46,54,55,57,59 ), comprising 1,197 patients, with a signi-

fi cant eff ect on symptoms (RR = 0.81; 95 % CI 0.67 – 0.98; Figure 2 ),

but with signifi cant heterogeneity between studies ( I 2 = 72 % ,

P < 0.001). Th e NNT with combination probiotics was 8 (95 % CI

4 – 50). In terms of the diff erent combinations tested, three trials

used the same combination of L. paracasei ssp paracasei F19,

L. acidophilus La5, and B. lactis Bb12 in 269 patients ( 30,57,59 ),

with no benefi t over placebo (RR = 0.92; 95 % CI 0.76 – 1.11).

Excluded (n = 30) because:

No extractable data reported = 9Not the intervention of interest = 5No placebo arm = 4Dual publication = 3Not randomized = 3Review article = 2Crossover study with no extractable data = 3

Enrolled healthy women = 1

Studies identified in literaturesearch (n = 3216)

Studies retrieved for evaluation(n = 73)

Eligible studies (n = 43):Synbiotics in IBS (n = 2)Prebiotics in IBS (n = 0)Probiotics in IBS (n = 35)

Combinationprobiotics = 19

•

••••

••

Lactobacillus = 8Bifidobacterium = 3Escherichia = 2Bifidobacterium orLactobacillus = 1

Saccharomyces = 1Streptococcus = 1

Synbiotics in CIC = 2Prebiotics in CIC = 1Probiotics in CIC = 3

Excluded (title and abstract revealednot appropriate) (n = 3143)

••••••

•

•

Figure 1 . Flow diagram of assessment of studies identifi ed in the updated systematic review and meta-analysis.

© 2014 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

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Prebiotics, probiotics, and synbiotics in IBS and CIC

Tabl

e 1

. C

hara

cter

isti

cs o

f ra

ndom

ized

con

trol

led

tria

ls o

f pr

obio

tics

vs.

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bow

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crui

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used

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% f

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diag

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ic c

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for

IBS

P

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use

d an

d du

rati

on o

f th

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dolo

gy

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e ( 4

0 )

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mar

k, p

rimar

y ca

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s “ s

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fi can

tly

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(78

), M

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d co

ncea

lmen

t of

allo

catio

n ar

e no

t sta

ted.

Dou

ble-

blin

d. O

ther

IBS

med

icat

ions

are

allo

wed

.

O ’ M

ahon

y ( 1

9 )

Eire

, sec

onda

ry c

are

and

adve

rtis

ing

Con

tinuo

us s

cale

for

IBS

sym

ptom

s 80

(64

), R

ome

II M

alte

d dr

ink

cont

aini

ng L

. sa

livar

ius

UC

C43

31 (

1 × 10

10 li

ve b

acte

ria / d

rink)

or

B.

infa

ntis

356

24 (

1 × 10

10 li

ve b

acte

ria / d

rink)

o.

d. fo

r 8

wee

ks

Met

hod

of r

ando

miz

atio

n is

sta

ted.

Met

hod

of c

on-

ceal

men

t of a

lloca

tion

is n

ot s

tate

d. D

oubl

e-bl

ind.

N

o ot

her

IBS

med

icat

ions

allo

wed

.

Kim

( 46

) K

orea

, sec

onda

ry

care

C

ontin

uous

sca

le fo

r IB

S sy

mpt

oms

40 (

26),

clin

ical

dia

gnos

is

Med

ilac

DS

( Bac

illus

sub

tilis

and

S

. fa

eciu

m )

for

4 w

eeks

M

etho

d of

ran

dom

izat

ion

and

conc

ealm

ent o

f al

loca

tion

are

not s

tate

d. B

lindi

ng is

not

sta

ted.

U

ncle

ar if

oth

er IB

S m

edic

atio

ns a

re a

llow

ed.

Sim

ren

( 56 )

Sw

eden

, adv

ertis

ing

Con

tinuo

us s

cale

for

IBS

sym

ptom

s 66

(63

), R

ome

II R

ose

hip

drin

k (4

00 m

l) co

ntai

ning

L.

plan

taru

m D

SM 9

843

(5 ×

10 7

c.f.u

. / ml)

o.d.

fo

r 6

wee

ks

Met

hod

of r

ando

miz

atio

n an

d co

ncea

lmen

t of

allo

catio

n ar

e no

t sta

ted.

Dou

ble-

blin

d. U

ncle

ar if

ot

her

IBS

med

icat

ions

are

allo

wed

.

Who

rwel

l ( 60

) U

K, p

rimar

y ca

re

Ade

quat

e re

lief o

f IB

S sy

mpt

oms,

an

d co

ntin

uous

sca

le fo

r IB

S sy

mpt

oms

362

(100

), R

ome

II O

ne c

apsu

le c

onta

inin

g B

. in

fant

is 3

5624

(1

× 10

6 liv

e ba

cter

ia / c

apsu

le, 1

× 10

8 liv

e ba

cter

ia / c

apsu

le, o

r 1 ×

10 10

live

bac

teria

/ ca

psul

e) o

.d. f

or 4

wee

ks

Met

hod

of r

ando

miz

atio

n an

d co

ncea

lmen

t of

allo

catio

n ar

e st

ated

. Dou

ble-

blin

d. L

oper

amid

e fo

r di

arrh

ea a

nd b

isoc

odyl

for

cons

tipat

ion

are

allo

wed

.

Guy

onne

t ( 42

) Fr

ance

, prim

ary

care

C

ontin

uous

sca

le fo

r IB

S sy

mpt

oms

274

(75)

, Rom

e II

Ferm

ente

d m

ilk (

125

g) c

onta

inin

g B

. ani

mal

is

DN

173

010

(1.2

5 × 10

10 c

.f.u.

/ 125

g)

S. t

her-

mop

hilu

s (1

.2 ×

10 9

c.f.u

. / 125

g)

and

L. b

ulga

ri-cu

s (1

.2 ×

10 9

c.f.u

. / 125

g)

b.i.d

. for

6 w

eeks

Met

hod

of r

ando

miz

atio

n an

d co

ncea

lmen

t of

allo

catio

n ar

e no

t sta

ted.

Dou

ble-

blin

d. O

ther

IBS

med

icat

ions

are

allo

wed

(no

t fi b

er o

r fe

rmen

ted

dairy

pro

duct

s).

Dro

uaul

t-H

olow

acz

( 35 )

Fr

ance

, not

sta

ted

Satis

fact

ory

relie

f of g

loba

l IB

S sy

mpt

oms,

and

con

tinuo

us s

cale

for

IBS

sym

ptom

s

106

(76)

, Rom

e II

One

sac

het c

onta

inin

g B

. lo

ngum

LA

101

, L.

acid

ophi

lus

LA 1

02, L

. la

ctis

LA

103

, and

S.

ther

mop

hilu

s LA

104

(1 ×

10 10

c.f.

u. / s

ache

t)

o.d.

for

4 w

eeks

Met

hod

of r

ando

miz

atio

n an

d co

ncea

lmen

t of

allo

catio

n ar

e st

ated

. Dou

ble-

blin

d. U

ncle

ar if

ot

her

IBS

med

icat

ions

are

allo

wed

.

Tabl

e co

ntin

ued

on fo

llow

ing

page

The American Journal of GASTROENTEROLOGY VOLUME 109 | OCTOBER 2014 www.amjgastro.com

1552R

EV

IEW

Ford et al.

Tabl

e 1

. C

onti

nued

Stu

dy

Cou

ntry

and

re

crui

tmen

t C

rite

ria

used

to

defi n

e sy

mpt

om

impr

ovem

ent

follo

win

g th

erap

y S

ampl

e si

ze (

% f

emal

e) a

nd

diag

nost

ic c

rite

ria

for

IBS

P

robi

otic

use

d an

d du

rati

on o

f th

erap

y M

etho

dolo

gy

Enck

( 37

) G

erm

any,

prim

ary

care

50

% im

prov

emen

t in

IBS

glob

al

sym

ptom

s 29

7 (4

9), K

ruis

sco

re

Aut

olys

ate

of c

ells

and

cel

l fra

gmen

ts o

f E

nter

ococ

cus

faec

alis

DSM

1644

0 an

d E

sche

rich

ia c

oli D

SM17

252

(3.0

-9.0

× 10

7 c.

f.u. / 1

.5 m

l) × 0.

75 m

l t.i.

d. fo

r 1

wee

k, th

en

1.5

ml t

.i.d.

for

wee

ks 2

and

3, t

hen

2.25

ml

t.i.d

. for

wee

ks 3

– 8

Met

hod

of r

ando

miz

atio

n an

d co

ncea

lmen

t of

allo

catio

n ar

e no

t sta

ted.

Dou

ble-

blin

d. O

ther

IBS

med

icat

ions

are

allo

wed

(no

t ant

ispa

smod

ics)

.

Kaj

ande

r ( 4

5 )

Finl

and,

prim

ary

care

C

ontin

uous

sca

le fo

r IB

S sy

mpt

oms

86 (

93),

Rom

e II

Milk

-bas

ed d

rink

(1.2

dl)

cont

aini

ng L

. rh

am-

nosu

s G

G A

TCC

531

03, L

. rh

amno

sus

Lc70

5 D

SM 7

061,

P.

freu

denr

eich

ii , a

nd B

. an

imal

is

Bb1

2 D

SM 1

5954

(1 ×

10 7

c.f.u

. / ml)

o.d.

for

20 w

eeks

Met

hod

of r

ando

miz

atio

n an

d co

ncea

lmen

t of

allo

catio

n ar

e st

ated

. Dou

ble-

blin

d. O

ther

IBS

med

icat

ions

are

allo

wed

.

Sinn

( 58

) K

orea

, sec

onda

ry

care

A

ny im

prov

emen

t in

abdo

min

al p

ain

mea

sure

d on

a 1

0-po

int L

iker

t sca

le

40 (

65),

Rom

e III

O

ne c

apsu

le c

onta

inin

g L.

aci

doph

ilus

SDC

20

12 a

nd 2

013

(2 ×

10 9

c.f.u

. / ml)

b.i.d

. for

4

wee

ks

Met

hod

of r

ando

miz

atio

n an

d co

ncea

lmen

t of

allo

catio

n ar

e st

ated

. Dou

ble-

blin

d. N

o ot

her

IBS

med

icat

ions

allo

wed

.

Zeng

( 62

) C

hina

, ter

tiary

car

e C

ontin

uous

sca

le fo

r IB

S sy

mpt

oms

29 (

34),

Rom

e II

Ferm

ente

d m

ilk (

200

ml)

cont

aini

ng S

. th

erm

ophi

lus

(1 ×

10 8

c.f.u

. / ml),

L.

bulg

ari-

cus

(1 ×

10 7

c.f.u

. / ml),

L.

acid

ophi

lus

(1 ×

10 7

c.f.u

. / ml),

and

B.

long

um (

1 × 10

7 c.

f.u. / m

l) b.

i.d. f

or 4

wee

ks

Met

hod

of r

ando

miz

atio

n an

d co

ncea

lmen

t of

allo

catio

n ar

e no

t sta

ted.

Pat

ient

-blin

ded.

No

othe

r IB

S m

edic

atio

ns a

llow

ed.

Agr

awal

( 29

) U

K, t

ertia

ry c

are

Con

tinuo

us s

cale

for

IBS

sym

ptom

s 34

(10

0), R

ome

III

Ferm

ente

d m

ilk (

125

g) c

onta

inin

g B

. an

imal

is D

N17

3 01

0 (1

.25 ×

10 10

c.f.

u. / 1

25 g

) S

. th

erm

ophi

lus

(1.2

× 10

9 c.

f.u. / 1

25 g

) an

d L.

bul

gari

cus

(1.2

× 10

9 c.

f.u. / 1

25 g

) b.

i.d. f

or

4 w

eeks

Met

hod

of r

ando

miz

atio

n an

d co

ncea

lmen

t of

allo

catio

n ar

e no

t sta

ted.

Dou

ble-

blin

d. O

ther

IBS

med

icat

ions

are

allo

wed

.

Enck

( 38

) G

erm

any,

prim

ary

care

50

% Im

prov

emen

t in

IBS

glob

al

sym

ptom

s 29

8 (5

6), K

ruis

sco

re

E.

coli

DSM

1725

2 (1

.5 – 4

.5 ×

10 7

c.f.u

. / ml)

0.75

ml d

rops

t.i.d

. for

1 w

eek,

then

1.5

ml

t.i.d

. for

wee

ks 2

– 8

Met

hod

of r

ando

miz

atio

n an

d co

ncea

lmen

t of

allo

catio

n ar

e no

t sta

ted.

Dou

ble-

blin

d. O

ther

IBS

med

icat

ions

are

allo

wed

(no

t ant

ispa

smod

ics)

.

Hon

g ( 4

3 )

Kor

ea, t

ertia

ry c

are

50 %

Impr

ovem

ent i

n IB

S gl

obal

sy

mpt

oms

70 (

33),

Rom

e III

O

ne s

ache

t con

tain

ing

B.

bifi d

um B

GN

4, B

. la

ctis

AD

011,

L.

acid

ophi

lus

AD

031,

and

L.

case

i IB

S041

(20

bill

ion

bact

eria

/ sac

het)

b.i.

d.

for

8 w

eeks

Met

hod

of r

ando

miz

atio

n an

d co

ncea

lmen

t of

allo

catio

n ar

e st

ated

. Dou

ble-

blin

d. N

o ot

her

IBS

med

icat

ions

allo

wed

.

Will

iam

s ( 6

1 )

UK

, ter

tiary

car

e C

ontin

uous

sca

le fo

r IB

S sy

mpt

oms

52 (

87),

Rom

e II

One

cap

sule

con

tain

ing

L. a

cido

philu

s C

UL-

60 N

CIM

B 3

0157

and

CU

L-21

NC

IMB

301

56,

B.

bifi d

um C

UL-

20 N

CIM

B 3

0153

, and

B

. la

ctis

CU

L-34

NC

IMB

301

72 (

2.5 ×

10 10

c.

f.u. / c

apsu

le)

o.d.

for

8 w

eeks

Met

hod

of r

ando

miz

atio

n an

d co

ncea

lmen

t of

allo

catio

n ar

e no

t sta

ted.

Dou

ble-

blin

d. N

o ot

her

IBS

med

icat

ions

allo

wed

.

Sim

ren

( 57 )

Sw

eden

, ter

tiary

car

e A

dequ

ate

relie

f of g

loba

l IB

S sy

mp-

tom

s fo

r at

leas

t 50 %

of w

eeks

, and

co

ntin

uous

sca

le fo

r IB

S sy

mpt

oms

74 (

70),

Rom

e II

Ferm

ente

d m

ilk (

200

ml)

cont

aini

ng L

. pa

raca

sei s

sp p

arac

asei

F19

, L.

acid

ophi

lus

La5,

and

B.

lact

is B

b12

(5 ×

10 7

c.f.u

. / ml)

b.i.d

. for

8 w

eeks

Met

hod

of r

ando

miz

atio

n an

d co

ncea

lmen

t of

allo

catio

n ar

e st

ated

. Dou

ble-

blin

d. O

ther

IBS

med

icat

ions

are

allo

wed

.

Cho

i ( 32

) K

orea

, ter

tiary

car

e C

ontin

uous

sca

le fo

r IB

S sy

mpt

oms

90 (

51),

Rom

e II

Two

caps

ules

con

tain

ing

Sac

char

omyc

es b

ou-

lard

ii (2

× 10

11 li

ve c

ells

) b.

i.d. f

or 4

wee

ks

Met

hod

of r

ando

miz

atio

n is

sta

ted.

Met

hod

of c

on-

ceal

men

t of a

lloca

tion

is n

ot s

tate

d. D

oubl

e-bl

ind.

N

o ot

her

IBS

med

icat

ions

allo

wed

.

Gug

lielm

etti

( 41 )

G

erm

any,

not

sta

ted

Impr

ovem

ent i

n av

erag

e w

eekl

y gl

o-ba

l IB

S sy

mpt

om s

core

of 1

or

mor

e fo

r 50

% o

f wee

ks

122

(67)

, Rom

e III

O

ne c

apsu

le c

onta

inin

g B

. bi

fi dum

MIM

Bb7

5 (1

× 10

9 c.

f.u. / c

apsu

le)

o.d.

for

4 w

eeks

M

etho

d of

ran

dom

izat

ion

and

conc

ealm

ent o

f al

loca

tion

are

stat

ed. D

oubl

e-bl

ind.

No

othe

r IB

S m

edic

atio

ns a

llow

ed.

Tabl

e co

ntin

ued

on fo

llow

ing

page

© 2014 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

1553

RE

VIE

W

Prebiotics, probiotics, and synbiotics in IBS and CIC

Tabl

e 1

. C

onti

nued

Stu

dy

Cou

ntry

and

re

crui

tmen

t C

rite

ria

used

to

defi n

e sy

mpt

om

impr

ovem

ent

follo

win

g th

erap

y S

ampl

e si

ze (

% f

emal

e) a

nd

diag

nost

ic c

rite

ria

for

IBS

P

robi

otic

use

d an

d du

rati

on o

f th

erap

y M

etho

dolo

gy

Mic

hail

( 50 )

U

SA, t

ertia

ry c

are

Con

tinuo

us s

cale

for

IBS

sym

ptom

s 24

(67

), R

ome

III

VSL #

3 (

900

billi

on b

acte

ria / d

ay)

for

8 w

eeks

M

etho

d of

ran

dom

izat

ion

and

conc

ealm

ent o

f al

loca

tion

are

stat

ed. D

oubl

e-bl

ind.

Unc

lear

if o

ther

IB

S m

edic

atio

ns a

re a

llow

ed.

Rin

gel-K

ulka

( 54

) U

SA, p

opul

atio

n ba

sed

50-p

oint

dec

reas

e in

IBS

sym

ptom

se

verit

y sc

ore

33, R

ome

III

One

pill

con

tain

ing

L. a

cido

philu

s N

CFM

and

B

. la

ctis

Bi-0

7 (1

× 10

11 c

.f.u.

/ pill

) b.

i.d. f

or 8

w

eeks

Met

hod

of r

ando

miz

atio

n is

not

sta

ted.

Met

hod

of

conc

ealm

ent o

f allo

catio

n is

sta

ted.

Dou

ble-

blin

d.

Oth

er IB

S m

edic

atio

ns a

re a

llow

ed.

Sond

erga

ard

( 59 )

D

enm

ark

and

Swed

en, p

rimar

y an

d se

cond

ary

care

Ade

quat

e re

lief o

f glo

bal I

BS

sym

p-to

ms,

and

con

tinuo

us s

cale

for

IBS

sym

ptom

s

64 (

75),

Rom

e II

Ferm

ente

d m

ilk (

250

ml)

cont

aini

ng L

. pa

raca

sei s

sp p

arac

asei

F19

, L.

acid

ophi

lus

La5,

and

B.

lact

is B

b12

(5 ×

10 7

c.f.u

. / ml)

b.i.d

. for

8 w

eeks

Met

hod

of r

ando

miz

atio

n an

d co

ncea

lmen

t of

allo

catio

n ar

e st

ated

. Dou

ble-

blin

d. U

ncle

ar if

ot

her

IBS

med

icat

ions

are

allo

wed

.

Cha

( 31

) K

orea

, ter

tiary

car

e A

dequ

ate

relie

f of g

loba

l IB

S sy

mp-

tom

s fo

r at

leas

t 50 %

of w

eeks

, and

co

ntin

uous

sca

le fo

r IB

S sy

mpt

oms

50 (

48),

Rom

e III

O

ne c

apsu

le c

onta

inin

g L.

aci

doph

ilus

KC

TC11

906B

P, L

. pl

anta

rum

KC

TC11

867B

P,

L. r

ham

nosu

s K

CTC

1186

8BP,

B.

brev

e K

CTC

1185

8BP,

B.

lact

is K

CTC

1190

3BP,

B.

long

um K

CTC

1186

0BP,

and

S.

ther

mop

hilu

s K

CTC

1187

0BP

(5

billi

on b

acte

ria / c

apsu

le)

b.i.d

. for

8 w

eeks

Met

hod

of r

ando

miz

atio

n is

sta

ted.

Met

hod

of

conc

ealm

ent o

f allo

catio

n is

not

sta

ted.

Dou

ble-

blin

d. N

o ot

her

IBS

med

icat

ions

allo

wed

.

Cui

( 33

) C

hina

, ter

tiary

car

e Im

prov

emen

t in

abdo

min

al p

ain

freq

uenc

y 60

(70

), R

ome

III

Two

caps

ules

con

tain

ing

B.

long

um a

nd L

. ac

idop

hilu

s t.i

.d. f

or 4

wee

ks

Met

hod

of r

ando

miz

atio

n an

d co

ncea

lmen

t of

allo

catio

n ar

e no

t sta

ted.

Dou

ble-

blin

d. N

o ot

her

IBS

med

icat

ions

allo

wed

.

Dap

oign

y ( 3

4 )

Fran

ce, t

ertia

ry c

are

Red

uctio

n in

IBS

sym

ptom

sev

erity

sc

ore

of 5

0 % o

r m

ore

52 (

70),

Rom

e III

Th

ree

caps

ules

con

tain

ing

L. c

asei

rha

mno

-su

s LC

R35

(2 ×

10 8

c.f.u

. / cap

sule

) o.

d. fo

r 4

wee

ks

Met

hod

of r

ando

miz

atio

n an

d co

ncea

lmen

t of

allo

catio

n ar

e no

t sta

ted.

Dou

ble-

blin

d. N

o ot

her

IBS

med

icat

ions

allo

wed

.

Duc

rotte

( 36

) In

dia,

prim

ary

care

P

atie

nts

rate

d tr

eatm

ent e

ffi ca

cy a

s ex

celle

nt, a

nd c

ontin

uous

sca

le fo

r IB

S sy

mpt

oms

214

(29)

, Rom

e III

O

ne c

apsu

le c

onta

inin

g L.

pla

ntar

um L

P29

9V

DSM

984

3 (1

0 bi

llion

c.f.

u. / c

apsu

le)

o.d.

for

4 w

eeks

Met

hod

of r

ando

miz

atio

n an

d co

ncea

lmen

t of

allo

catio

n ar

e st

ated

. Dou

ble-

blin

d. U

ncle

ar if

ot

her

IBS

med

icat

ions

are

allo

wed

.

Faru

p ( 3

9 )

Nor

way

, sec

onda

ry

care

Sa

tisfa

ctor

y re

lief o

f sym

ptom

s (d

ata

obta

ined

from

the

auth

ors)

, and

con

-tin

uous

sca

le fo

r IB

S sy

mpt

oms

16 (

69),

Rom

e II

One

cap

sule

con

tain

ing

L. p

lant

arum

MF1

298

(10 10

c.f.

u. / c

apsu

le)

o.d.

for

3 w

eeks

M

etho

d of

ran

dom

izat

ion

and

conc

ealm

ent o

f al

loca

tion

are

stat

ed. D

oubl

e-bl

ind.

Unc

lear

if

othe

r IB

S m

edic

atio

ns a

re a

llow

ed.

Kru

is (

49 )

Ger

man

y, te

rtia

ry c

are

Pat

ient

s re

port

ed v

ery

muc

h sa

tisfi e

d or

a li

ttle

satis

fi ed

with

trea

tmen

t 12

0 (7

7), R

ome

II O

ne c

apsu

le c

onta

inin

g E

. co

li N

issl

e 19

17

(2.5

-25 ×

10 9

c.f.u

. / cap

sule

) o.

d. fo

r 4

days

th

en b

.i.d.

for

12 w

eeks

Met

hod

of r

ando

miz

atio

n an

d co

ncea

lmen

t of a

llo-

catio

n ar

e st

ated

. Dou

ble-

blin

d. O

ther

IBS

med

ica-

tions

are

allo

wed

(no

t lax

ativ

es o

r an

ti-di

arrh

eals

).

Beg

trup

( 30

) D

enm

ark,

prim

ary

care

A

dequ

ate

relie

f of g

loba

l IB

S sy

mpt

oms

for

at le

ast 5

0 % o

f the

tim

e, a

nd c

ontin

uous

sca

le fo

r IB

S sy

mpt

oms

131

(74)

, Rom

e III

Fo

ur c

apsu

les

cont

aini

ng L

. pa

raca

sei s

sp

para

case

i F19

, L.

acid

ophi

lus

La5,

and

B.

lact

is B

b12

(1.3

× 10

10 c

.f.u.

/ cap

sule

) o.

d. fo

r 6

mon

ths

Met

hod

of r

ando

miz

atio

n an

d co

ncea

lmen

t of

allo

catio

n ar

e st

ated

. Dou

ble-

blin

d. U

ncle

ar if

ot

her

IBS

med

icat

ions

are

allo

wed

.

Rob

erts

( 55

) En

glan

d, p

rimar

y ca

re

Ade

quat

e re

lief o

f glo

bal I

BS

sym

ptom

s 18

4 (8

3), R

ome

III

One

pot

con

tain

ing

B. l

actis

I-24

94 (

prev

ious

ly

know

n as

DN

173

010)

(1.

25 ×

10 10

c.f.

u. / p

ot),

S

. th

erm

ophi

lus

I-16

30 (

1.2 ×

10 9

c.f.u

. / pot

),

and

L. b

ulga

ricu

s I-

1632

and

I-15

19 (

1.2 ×

10 9

c.f.u

. / pot

) b.

i.d. f

or 1

2 w

eeks

Met

hod

of r

ando

miz

atio

n an

d co

ncea

lmen

t of

allo

catio

n ar

e st

ated

. Dou

ble-

blin

d. O

ther

IBS

med

icat

ions

are

allo

wed

.

ATCC, Am

eric

an T

ype

Cul

ture

Col

lect

ion;

c.f

.u, co

lony

-for

min

g un

its;

IB

S, irrita

ble

bow

el s

yndr

ome;

o.d

., o

nce

daily

; VA

S, vi

sual

ana

log

scal

e. a D

oes

not

mee

t Fo

od a

nd A

gric

ultu

ral O

rgan

izat

ion

defi n

itio

n of

a p

robi

otic

.

The American Journal of GASTROENTEROLOGY VOLUME 109 | OCTOBER 2014 www.amjgastro.com

1554R

EV

IEW

Ford et al.

Lactobacillus was used in six trials (422 patients) ( 34,36,39,51,

53,58 ), with no clear benefi t detected over placebo (RR = 0.75; 95 %

CI 0.54 – 1.04), again with signifi cant heterogeneity between studies

( I 2 = 75 % , P = 0.001). However, when only the three RCTs that used

L. plantarum DSM 9843 were considered in the analysis ( 36,51,53 ),

which contained 314 subjects, the RR of symptoms persisting was

signifi cantly lower with active therapy (0.67; 95 % CI 0.51 – 0.87),

although the signifi cant heterogeneity observed persisted ( I 2 = 63 % ,

P = 0.07). Bifi dobacterium was studied in two RCTs (484 patients)

( 41,60 ), with no benefi t over placebo (RR = 0.71; 95 % CI 0.44 –

1.16). Escherichia was assessed in two trials (418 patients) ( 38,49 ),

with a benefi t detected compared with placebo (RR = 0.86; 95 % CI

0.79 – 0.93), although only signifi cantly so in the trial of E. coli DSM

17252 ( 38 ). Finally, S. faecium was used in one trial recruiting 54

patients, and appeared to be superior to placebo (RR = 0.72; 95 %

CI 0.53 – 0.99 ( 40 )).

Effi cacy of probiotics in the treatment of IBS: effect on Global IBS or abdominal pain scores Th ere were 24 separate trials ( 19,29 – 32,35,36,39,41,42,44 – 48,

50,52,53,56,57,59 – 62 ), making 25 comparisons, comprising 2001

patients that reported the eff ect of probiotics on global IBS or

abdominal pain scores. Th ere was a statistically signifi cant eff ect

of probiotics in reducing global symptoms or abdominal pain

(SMD = − 0.25; 95 % CI − 0.36 to − 0.14) with no signifi cant

heterogeneity ( I 2 = 27 % , P = 0.11; Figure 3 ). Th ere were six trials

1.1.1 Combination

Kim, 2003 8 12 8 13 2.6% 1.08 [0.60, 1.95] 2003Kajander, 2005 21 52 34 51 4.1% 0.61 [0.41, 0.89] 2005Enck, 2008 47 149 92 148 5.3% 0.51 [0.39, 0.66] 2008Drouault-Holowacz, 2008 33 53 31 53 4.9% 1.06 [0.78, 1.45] 2008Hong, 2009 16 36 17 34 3.1% 0.89 [0.54, 1.46] 2009Simren, 2010 23 37 27 37 4.8% 0.85 [0.62, 1.17] 2010Ringel-Kulka, 2011 11 17 9 16 2.7% 1.15 [0.66, 2.01] 2011Sondergaard, 2011 25 32 23 32 5.1% 1.09 [0.82, 1.44] 2011Cha, 2012 13 25 22 25 3.9% 0.59 [0.39, 0.88] 2012Cui, 2012 13 37 16 23 3.0% 0.51 [0.30, 0.84] 2012Roberts, 2013 70 92 67 92 6.4% 1.04 [0.88, 1.24] 2013Begtrup, 2013 32 67 38 64 4.7% 0.80 [0.58, 1.11] 2013Subtotal (95% Cl) 609 588 50.6% 0.81 [0.67, 0.98]Total events 312 384

Test for overall effect: Z = 2.15 (P = 0.03)

Nobaek, 2000 21 30 25 30 5.1% 0.84 [0.63, 1.12] 2000Niedzielin, 2001 11 20 17 20 3.6% 0.65 [0.42, 1.00] 2001Sinn, 2008 4 20 13 20 1.3% 0.31 [0.12, 0.78] 2008Dapoigny, 2012 19 26 16 26 4.1% 1.19 [0.81, 1.74] 2012Ducrotte, 2012 61 108 105 106 6.4% 0.57 [0.48, 0.67] 2012Farup, 2012 6 9 3 7 1.2% 1.56 [0.59, 4.11] 2012

?

Subtotal, (95% Cl) 213 209 21.7% 0.75 [0.54, 1.04]

Total events 122 179

Whorwell, 2006 143 270 54 92 6.0% 0.90 [0.74, 1.11] 2006 Guglielmetti, 2011 26 60 49 62 4.8% 0.55 [0.40, 0.75] 2011Subtotal (95% Cl) 330 154 10.8% 0.71 [0.44, 1.16]Total events 169 103

1.1.4 Escherichia

Probiotics Control Risk ratio Risk ratioYearStudy or subgroup Events EventsTotal Total Weight M-H, random, 95% Cl M-H, random, 95% Cl

Heterogeneity: τ2 = 0.07; χ2 = 39.53, df = 11 (P < 0.0001); I2 = 72%

1.1.2 Lactobacillus

Heterogeneity: τ2 = 0.10; χ2 = 20.20, df = 5 (P = 0.001); I2 = 75%Test for overall effect: Z = 1.72 (P = 0.08)

1.1.3 Bifidobacterium

Heterogeneity: τ2 = 0.11; χ2 = 6.72, df = 1 (P = 0.010); I2 = 85%

Test for overall effect: Z = 1.35 (P = 0.18)

Enck, 2009 121 148 143 150 7.1% 0.86 [0.79, 0.93] 2009Kruis, 2012 33 60 37 60 4.9% 0.89 [0.66, 1.21] 2012

Total events 154 180

Subtotal (95% Cl) 208 210 12.1% 0.86 [0.79, 0.93]

Test for overall effect: Z = 3.65 (P = 0.0003)

Gade, 1989 20 32 19 22 4.8% 0.72 [0.53, 0.99] 1989Subtotal (95% Cl) 32 22 4.8% 0.72 [0.53, 0.99]Total events 20 19Heterogeneity: Not applicableTest for overall effect: Z = 2.01 (P = 0.04)

Total (95% Cl) 1392 1183 100.0% 0.79 [0.70, 0.89]Total events 777 865

Heterogeneity: τ2 = 0.00; χ2 = 0.08, df = 1 (P = 0.78); I2 = 0%

1.1.5 Streptococcus

Heterogeneity: τ2 = 0.05; χ2 = 78.60, df = 22 (P < 0.00001); I2 = 72%Test for overall effect: Z = 3.95 (P < 0.0001)

Favors probiotics

0.1 0.2 0.5 1 2 5 10

Favors controlTest for subqroup differences: χ2 = 2.16, df = 4 (P = 0.71), I2 = 0%

Figure 2 . Forest plot of randomized controlled trials of probiotics vs. placebo in irritable bowel syndrome (IBS): effect on persistence of symptoms.

© 2014 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

1555

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W

Prebiotics, probiotics, and synbiotics in IBS and CIC

Th ere were 15 trials ( 29 – 31,35,42,44 – 48,50,57,59,61,62 ), evalu-

ating 1,038 patients, using combinations of probiotics that did sug-

gest a signifi cant improvement in IBS symptom scores with active

treatment (SMD – 0.24; 95 % CI − 0.37 to − 0.12; Figure 3 ). When

specifi c combinations were studied, three trials used VSL # 3 in 93

patients, with no signifi cant benefi t over placebo (SMD – 0.32;

95 % CI – 0.73 to 0.10) ( 46,47,50 ); three trials used a combination

of L. paracasei ssp paracasei F19, L. acidophilus La5, and B. lactis

Bb12 in 217 patients with no benefi t over placebo (SMD = – 0.07;

95 % CI – 0.34 to 0.20) ( 30,57,59 ); and two trials used a combina-

tion of B. lactis DN-173 010, S. thermophilus , and L. bulgaricus

(420 patients) that evaluated Lactobacillus ( 19,36,39,52,53,56 ),

and three trials (501 patients) that investigated Bifi dobacterium

( 19,41,60 ), and neither were statistically signifi cantly more effi ca-

cious than placebo ( Figure 3 ), although there was a trend toward

a benefi t for the latter (SMD − 0.46; 95 % CI − 0.92 to 0, P = 0.05).

When only the three trials that used L. plantarum DSM 9843 were

considered in the analysis, there was no benefi t in 314 patients

(SMD = − 0.18; 95 % CI – 0.60 to 0.25) ( 36,53,56 ). Similarly, when

only the two trials that used B. infantis 35624 were included in the

analysis there was no benefi t in 379 patients (SMD = – 0.33; 95 %

CI – 0.90 to 0.24) ( 9,60 ).

Probiotics Control

YearStudy or subgroup Mean s.d. Total Mean s.d. Total Weight IV, random, 95% Cl IV, random, 95% Cl

Std. mean differenceStd. mean difference

Kajander, 2005

Kim, 2005

20.4

101.8

13.88

79.72 11

41 26.8

99.72 86.81

13.88 40

10

4.6%

1.5%

–0.46 [–0.90, –0.02]

0.02 [–0.83, 0.88]

2005

2005

Kim, 2005 102.4 47.03 24 125.3 52.79 24 3.1% –0.45 [–1.02, 0.12] 2005

Kim, 2006 1.6 1.6 17 1.8 2.1 17 2.4% –0.10 [–0.78, 0.57] 2006

Guyonnet, 2007 5.07 1.14 135 5.22 1.26 132 9.3% –0.12 [–0.36, 0.12] 2007

Zeng, 2008 7.64 1.24 14 9.18 1.48 15 1.8% –1.09 [–1.88, –0.30] 2008

Drouault–Holowacz, 2008 2.71 2.16 48 3.34 2.24 52 5.4% –0.28 [–0.68, 0.11] 2008

Kajander, 2008 24 16.73 43 30 18.01 43 4.8% –0.34 [–0.77, 0.08] 2008

Williams, 2009 150.23 101.96 28 172 99.51 24 3.3% –0.21 [–0.76, 0.33] 2009

Agrawal, 2009 2.9 0.9 17 3.7 0.9 15 2.0% –0.87 [–1.60, –0.14] 2009

Simren, 2010 206 113 33 228 125 34 4.1% –0.18 [–0.66, 0.30] 2010

Sondergaard, 2011 176 138 27 206 124 25 3.3% –0.22 [–0.77, 0.32] 2011

Michail, 2011 1.5 0.3 15 1.7 0.8 9 1.6% –0.36 [–1.19, 0.48] 2011

Cha, 2012 1.56 1.21 24 1.97 1.65 23 3.1% –0.28 [–0.85, 0.30] 2012

Begtrup, 2013 2.9 1.1 54 2.8 1 44 5.3% 0.09 [–0.30, 0.49] 2013

Subtotal (95% Cl) 531 507 55.8% –0.24 [–0.37, –0.12]

Heterogeneity: τ2 = 0.00; χ2 = 13.30, df = 14 (P = 0.50); l2 = 0%

Test for overall effect: Z = 3.90 (P < 0.0001)

1.2.2 Lactobacillus

Nobaek, 2000 3.9 1 25 4.26 1.67 27 3.3% –0.26 [–0.80, 0.29] 2000

Niv, 2005 270 139 21 230 139 18 2.6% 0.28 [–0.35, 0.91] 2005

O'Mahony, 2005 5.25 2.8 26 5.68 2.8 25 3.3% –0.15 [–0.70, 0.40] 2005

Simren, 2006 279 129 29 245 118 29 3.6% 0.27 [–0.25, 0.79] 2006Farup, 2012 6.18 1.83 9 5.61 1.31 7 1.2% 0.33 [–0.67, 1.33] 2012

Ducrotte, 2012 0.68 0.53 105 0.92 0.57 99 8.2% –0.43 [–0.71, –0.16] 2012Subtotal (95% Cl) 215 205 22.2% –0.08 [–0.38, 0.21]

Heterogeneity: τ2 = 0.06; χ2 = 9.30, df = 5 (P =0.10); l2 = 46%

Test for overall effect: Z = 0.54 (P = 0.59)

1.2.3 BifidobacteriumO'Mahony, 2005 3.7 2.88 24 5.68 2.8 25 3.0% –0.69 [–1.26,– 0.11] 2005

Whorwell, 2006 2.01 0.82 250 2.09 0.89 80 9.0% –0.10 [–0.35, 0.16] 2006

Guglielmetti, 2011 2.07 0.85 60 2.63 0.74 62 5.9% –0.70 [–1.07, –0.33] 2011Subtotal (95% Cl)

Heterogeneity: τ2 = 0.12; χ2 = 8.70, df = 2 (P = 0.01); l2 = 77%

Test for overall effect: Z = 1.97 (P = 0.05)

1.2.4 Saccharomyces

Choi, 2011

Subtotal (95% Cl)

Heterogeneity: Not applicable

Test for overall effect: Z = 0.51 (P = 0.61)

Heterogeneity: τ2 = 0.02; χ2 = 32.74, df = 24 (P = 0.11); l2 = 27%Test for overall effect: Z = 4.44 (P < 0.00001)

Test for subgroup difference: χ2 = 2.18 , df = 3 (P = 0.54), l2 = 0%

334

34

1114

34

0.81.2 1.3 0.8

167

33

33

912

18.0%

4.1%

4.1%

100.0%

–0.46 [–0.92, –0.00]

–0.12 [–0.60, 0.36]

–4 –2

Favors probiotics Favors control

0 2 4

–0.12 [–0.60, 0.36]

–0.25 [–0.36, –0.14]

2011

1.2.1 Combination

Total (95% Cl)

Figure 3 . Forest plot of randomized controlled trials of probiotics vs. placebo in irritable bowel syndrome (IBS): effect on global symptom or abdominal pain scores.

The American Journal of GASTROENTEROLOGY VOLUME 109 | OCTOBER 2014 www.amjgastro.com

1556R

EV

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Ford et al.

in 299 patients, again with no signifi cant benefi t over placebo

(SMD = – 0.41; 95 % CI – 1.12 to 0.30) ( 29,42 ).

Effi cacy of probiotics in the treatment of IBS: effect on individual symptom scores Th ere were 17 separate trials ( 19,29 – 32,41,42,44,46 – 48,50,57,

59 – 62 ), making 18 comparisons, and containing 1,446 patients,

that reported the eff ect of probiotics on bloating symptom

scores. Overall, bloating scores were signifi cantly reduced with

probiotics (SMD = − 0.15; 95 % CI − 0.27 to − 0.03; Figure 4 ),

with no signifi cant heterogeneity between individual study results

( I 2 = 16 % , P = 0.26).

Ten trials reported continuous data for the eff ect of probiotics

on fl atulence symptom scores in 741 patients ( 29,31,32,44,

46 – 48,53,60,62 ). Flatulence scores were signifi cantly lower with

probiotics compared with placebo (SMD = − 0.23; 95 % CI − 0.38

to − 0.07; Figure 5 ), with no signifi cant heterogeneity detected

( I 2 = 0 % , P = 0.63).

Finally, six RCTs reported the eff ect of probiotics on urgency

symptom scores in 635 patients ( 31,32,41,46,47,60 ). Th ere was

no apparent benefi t detected for probiotics, in terms of eff ect on

symptoms of urgency (SMD = − 0.10; 95 % CI − 0.30 to 0.10), with

no signifi cant heterogeneity detected ( I 2 = 20 % , P = 0.28).

Adverse events with probiotics Total adverse events were reported by 24 RCTs ( 30 – 32,34,36 – 38,

40 – 47,49 – 53,57,58,61,62 ), containing 2,407 patients. Overall,

201 (16.5 % ) of 1,215 patients allocated to probiotics experienced

any adverse event, compared with 164 (13.8 % ) of 1,192 patients

assigned to placebo. Th e RR of experiencing any adverse event

Probiotics Control Std. mean differenceStudy or Subgroup Mean s.d. Total Mean s.d. Total Weight IV, random, 95% Cl Year1.3.1 Combination

Kim, 2003 22.32 21.93 11 27.3 24.42 10 1.9% –0.21 [–1.07, 0.65] 2003Kim, 2005 32.24 18.05 24 35.8 15.27 24 4.1% –0.21 [–0.78, 0.36] 2005Kajander, 2005 5.1 4.25 41 6.7 4.19 40 6.3% –0.38 [–0.82, 0.06] 2005Kim, 2006 2.2 1.44 17 2.58 0.86 17 3.0% –0.31 [–0.99, 0.36] 2006Guyonnet, 2007 3.13 1.12 135 3.06 1.17 132 15.1% 0.06 [–0.18, 0.30] 2007Zeng, 2008 32.1 4.53 14 29.67 3.91 15 2.5% 0.56 [–0.18, 1.30] 2008Williams, 2009 25.88 25.05 28 32.05 29.64 24 4.4% –0.22 [–0.77, 0.32] 2009Agrawal, 2009 3.2 1.2 17 3.9 0.9 15 2.7% –0.64 [–1.35, 0.08] 2009Simren, 2010 41 33 33 43 30 34 5.5% –0.06 [–0.54, 0.42] 2010Sondergaard, 2011 33.3 33.3 27 41.1 30.2 25 4.4% –0.24 [–0.79, 0.30] 2011Michail, 2011 1.6 0.3 15 1.5 0.9 9 2.0% 0.16 [–0.67, 0.99] 2011Cha, 2012 1.91 1.48 24 2.41 2.2 23 4.0% –0.26 [–0.84, 0.31] 2012Begtrup, 2013 3.7 1.4 54 3.5 1.3 44 7.4% 0.15 [–0.25, 0.54] 2013

Subtotal (95% Cl) 440 412 63.3% –0.08 [–0.21, 0.06]Heterogeneity: τ2 =0.00; χ2 = 11.53, df = 12 (P = 048); l 2 = 0%Test for overall effect: Z = 1.11 (P = 0.27)

1.3.2 Lactobacillus

O'Mahony, 2005 15.32 12.44 26 17.04 15.7 25 4.3% –0.12 [–0.67, 0.43] 2005Subtotal (95% Cl) 26 25 4.3% –0.12 [–0.67, 0.43]

Heterogeneity: Not applicableTest for overall effect: Z = 0.43 (P = 0.67)

Test for overall effect: Z = 1.53 (P = 0.13)

1.3.3 BifidobacteriunO'Mahony, 2005

Whorwell, 2006

Guglielmetti, 2011Subtotal (95% Cl)

Heterogeneity: τ2 = 0.08; χ2 = 6.29, df = 2 (P = 0.04); l 2 = 68%

1.3.4 Saccharomyces

Choi, 2011 Subtotal (95% Cl)

Heterogeneity: Not applicableTest for overall effect: Z = 1.48 (P = 1.14)

Total (95% Cl)

Heterogeneity: τ2 = 0.01; χ2 = 20.19, df = 17 (P = 0.26); l 2 = 16%Test for overall effect: Z = 2.46 (P = 0.01)Test for subgroup differences: χ2 = 2.22, df = 3 (P = 0.53), l 2 = 0%

11.66

1.94

2.09

1.7 1.3 3434

11.51 24

60

250

834

17.04

1.96

2.61

2.2

15.7

0.89

0.93

1.4

25

62167334

3333

4.1%

14.3%

8.6%27.0%

5.4%5.4%

100.0%637

–0.38 [–0.95, 0.18]

–0.02 [–0.27, 0.23]

–0.57 [–0.93, –0.21]–0.30 [–0.68, 0.09]

–0.37 [–0.85, 0.12]–0.37 [–0.85, 0.12]

–0.15 [–0.27, –0.03]

2005

2006

2011

2011

Std. mean difference

IV, random, 95% Cl

0

Favors probiotics

800.91

0.88

–4 –2 2 4

Favors control

Figure 4 . Forest plot of randomized controlled trials of probiotics vs. placebo in irritable bowel syndrome (IBS): effect on bloating scores.

© 2014 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

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Prebiotics, probiotics, and synbiotics in IBS and CIC

between studies (SMD = − 1.73; 95 % CI − 3.73 to 0.27, I 2 = 96 % ,

P = 0.09; Supplementary Figure 1 online). Adverse events were

reported in both studies, and no signifi cant events occurred in

either treatment arm.

Effi cacy and safety of prebiotics in CIC Th e trial of prebiotics vs. placebo in CIC recruited 60 female

volunteers ( 65 ). Patients were randomized to receive 3 weeks

of a 15 g per day mixture of inulin and partially hydrolyzed

guar gum or placebo. Th e trial was at an unclear risk of bias,

as the methods used to randomize and conceal treatment allo-

cation were not reported. Th ere was no diff erence in satisfac-

tion in relief of constipation in the prebiotic group (9 (32.1 % )

of 28 satisfi ed) vs. the placebo group (10 (31.3 % ) of 32), and the

mean number of bowel movements per week was also not sta-

tistically diff erent (5.95 ± 2.50 in the prebiotic group, compared

with 6.70 ± 3.83 in the control group). Adverse events data were

not reported.

Effi cacy and safety of probiotics in CIC We identifi ed three trials evaluating probiotics in 245 CIC

patients ( 66 – 68 ). Two trials were at an unclear risk of bias ( 66,68 ),

was signifi cantly higher with probiotics (1.21; 95 % CI 1.02 – 1.44).

Th e number needed to harm with probiotics was 35 (95 % CI

16 – 362).

Effi cacy and safety of synbiotics in IBS Th e two RCTs of synbiotics in IBS recruited a total of 198 patients

( 63,64 ). Th e fi rst RCT was a single-blind RCT conducted in Italy,

recruiting 68 patients with Rome II-defi ned IBS, and it used a

combination of L. acidophilus and L . helveticus , with Bifi dobac-

terium species, in a vitamin and phytoextract-enriched medium

for 12 weeks ( 63 ). Th e second RCT, conducted in South Korea,

used B. lactis in combination with acacia fi ber for 8 weeks, in 130

patients who met the Rome III criteria for IBS ( 64 ). Th is double-

blind trial was at an unclear risk of bias owing to failure to report

the method used to conceal treatment allocation. Only one trial

reported dichotomous data. Th ere were 7 (20.6 % ) of 34 patients

assigned to synbiotics with persistent symptoms, compared with

30 (88.2 % ) of 34 patients assigned to control therapy ( P < 0.01)

( 63 ). Both trials assessed IBS symptoms on a continuous scale in

185 patients ( 63,64 ). Th ere was no statistically signifi cant eff ect

of synbiotics in reducing symptoms, even though both trials

were individually positive, owing to signifi cant heterogeneity

Study or subgroupProbiotics Std. mean difference

YearWeightStd. mean differenceIV, random, 95% Cl

1.4.1 Combination

Kim, 2003 27.63 27 11 28.35 28.13 10 3.3% –0.03 [–0.88, 0.83] 2003Kajander, 2005 8.2 4.74 41 9.5 4.68 40 12.4% –0.27 [–0.71, 0.16] 2005Kim, 2005 31.4 17.35 24 39.63 16.2 24 7.2% –0.48 [–1.06, 0.09] 2005Kim, 2006 6 5.36 17 6.6 7.01 17 5.3% –0.09 [–0.77, 0.58] 2006Zeng, 2008 32.5 8.11 14 37.62 7.76 15 4.3% –0.63 [–1.38, 0.12] 2008Agrawal, 2009 3.1 1.1 17 3.4 1.1 15 4.9% –0.27 [–0.96, 0.43] 2009Cha, 2012 2.38 2.25 24 3.02 2.16 23 7.2% –0.29 [–0.86, 0.29] 2012Subtotal (95% Cl) 148 144 44.5% –0.30 [–0.53, –0.07]

Test for overall effect: Z = 2.56 (P = 0.01)

Nobaek, 2000 Subtotal (95% Cl)

Heterogeneity: Not applicableTest for overall effect: Z = 2.38 (P = 0.02)

Test for overall effect: Z = 0.29 (P = 0.78)

Test for overall effect: Z = 1.15 (P = 0.25)

Test for subgroup differences: χ2 = 5.18, df = 3 (P = 0.16), I 2 = 42.1%

Test for overall effect: Z = 2.91 (P = 0.004)Heterogeneity: τ2 = 0.00; χ2 = 7.08, df = 9 (P = 0.63); I 2 = 0%

1.4.3 BifidobacteriumWhorwell, 2006 Subtotal (95% Cl)

Heterogeneity: Not appplicable

1.4.4 Saccharomyces

Choi, 2011

Subtotal (95% Cl)

Heterogeneity: Not appplicable

Total (95% Cl)

3.4 1

1.7 1.4

2525

2.01 0.82 250250

2.04 0.8

34

34

4.48 1.94

1.4

2727

8080

33

33

457 284

7.6%7.6%

37.6%37.6%

10.3%

10.3%

100.0%

2000

2006

2011

–4 –2 0 2 4Favors probiotics Favors control

IV, random, 95% Cl

ControlTotal Totals.d.s.d.Mean Mean

Heterogeneity: τ2 = 0.00; χ2 = 1.90 df = 6 (P = 0.93); I 2 = 0%

1.4.2 Lactobacillus

–0.68 [–1.24, –0.12]–0.68 [–1.24, –0.12]

–0.04 [–0.29, 0.22]–0.04 [–0.29, 0.22]

–0.28 [–0.76, 0.20]

–0.28 [–0.76, 0.20]

–0.23 [–0.38,–0.07]

2.1

Figure 5 . Forest plot of randomized controlled trials of probiotics vs. placebo in irritable bowel syndrome (IBS): effect on fl atulence scores.

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Ford et al.

and one was at a high risk of bias ( 67 ). Detailed trial characteris-

tics are provided in Table 2 . Th ere were two trials that reported

dichotomous outcomes in 110 CIC patients ( 66,67 ). Although

both trials demonstrated a benefi t of probiotics in CIC, in terms

of failure to respond to therapy, when data were pooled the over-

all result was not statistically signifi cant (RR of failure to respond

to therapy = 0.29; 95 % CI 0.07 – 1.12), with signifi cant hetero-

geneity between the two trials ( I 2 = 71 % , P = 0.06; ( Supplemen-

tary Figure 2 ).

Th ere were two trials that reported on mean number of

bowel movements per week in 165 patients ( 67,68 ). Th ere was

a signifi cant increase in the mean number of stools per week

(1.49; 95 % CI = 1.02 – 1.96; Supplementary Figure 3 ). Two

studies reported that there were no adverse events in either arm

( 66,68 ).

Effi cacy and safety of synbiotics in CIC Th e two trials of synbiotics included a total of 166 CIC patients

( 69,70 ). One trial was conducted in Iran and recruited 66 male

patients with Rome III-defi ned CIC, randomizing them to

receive 4 weeks of a synbiotic mixture containing B. longum

NCIMB 30182, B. breve NCIMB 30180, L. casei NCIMB1 30185,

L. rhamnosus NCIMB 30188, L. acidophilus NCIMB 30184,

L. bulgaricus NCIMB 30186, S. thermophilus NCIMB 30189,

and fructo-oligosaccharide twice a day, or an identical-look-

ing placebo ( 70 ). Th e second trial was conducted in Brazil; it

used the Rome III criteria to defi ne CIC and recruited only

women, randomizing them to a synbiotic containing a mixture

of fructo-oligosaccharide, B. lactis HN019, L. paracasei Lpc-37,

L. rhamnosus HN001, and L. acidophilus (NCFM), or placebo

for 30 days, or maltodextrin ( 69 ). Both trials were at a low risk

of bias. Overall, when dichotomous data from these two trials

were pooled, there was a signifi cant benefi t of synbiotics in CIC

(RR of failure to respond to therapy = 0.78; 95 % CI 0.67 – 0.92;

Supplementary Figure 4 ). Th e NNT with synbiotics in CIC was

5 (95 % CI 3 – 14). Only one study reported adverse events, with

none in either arm of the trial ( 70 ).

DISCUSSION Th is systematic review and meta-analysis has demonstrated

that probiotics are eff ective therapies for IBS, in terms of both

improvement in overall symptoms as a dichotomous measure

and improvement in global symptom, abdominal pain, bloating,

and fl atulence scores. Th e NNT to improve one patient ’ s symp-

toms was 7. We found evidence to support the use of combina-

tions of probiotics as a group, although not for any of the diff erent

combinations studied individually , L. plantarum DSM 9843,

E. coli DSM 1752, and S. faecium , although the latter two were

only used in one RCT each. Th ere was also a trend toward a

bene fi cial eff ect of Bifi dobacterium , in terms of improvement of

global IBS symptoms and pain scores, although which particu-

lar strain or species may be of benefi t remains unclear. Adverse

events were rare, but were signifi cantly more common with

probiotics, with a number needed to harm of 35. Th ere were

no trials of prebiotics that were eligible for inclusion. Synbiot-

ics appeared to be of no benefi t in IBS, albeit in only two trials,

and part of the reason for this was heterogeneity between studies

when data were pooled as both RCTs demonstrated a benefi -

cial eff ect on symptom scores. In terms of CIC, prebiotics did

not demonstrate any effi cacy in one RCT. Probiotics were no

more eff ective than placebo when improvement in dichotomous

symptoms was assessed, but they did lead to a signifi cant improve-

ment in the mean number of stools per week, although the risk

Table 2 . Characteristics of randomized controlled trials of probiotics vs. placebo in chronic idiopathic constipation

Study Country and recruit-ment

Criteria used to defi ne symptom improvement following therapy

Sample size ( % female) and diagnostic criteria for CIC

Probiotic used and duration of therapy Methodology

Koebnick ( 66 ) Germany, recruited from a naturopathic practice

Improvement in consti-pation

70 (53), clinical criteria L. casei Shirota (6.5 × 10 9 c.f.u. in a 65 ml bever-age) for 4 weeks

Method of randomization and concealment of allocation are not stated. Double-blind. Unclear if other CIC medications are allowed.

Yang ( 68 ) China, secondary care Mean number of stools per week

135 (100), clinical criteria

B. lactis DN-173010 (1.25 × 10 10 c.f.u. / pot), S. thermophilus and L. bulgaricus (1.2 × 10 9 c.f.u. / pot) b.i.d. for 2 weeks

Randomization and conceal-ment of allocation are not stated. Double-blind. Unclear if other CIC medications are allowed.

Sakai ( 67 ) Belgium, recruited from a drug research unit

< 25 % Of bowel movements Bristol Stool Scale < 3, mean number of stools per week

40 (57.5), Rome III L. casei YIT 9029 FERM BP-1366 (6.5 × 10 9 c.f.u.) for 3 weeks

Randomization and conceal-ment of allocation are not stated. Open study. Unclear if other CIC medications are allowed.

c.f.u., colony-forming units; CIC, chronic idiopathic constipation.

© 2014 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

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Prebiotics, probiotics, and synbiotics in IBS and CIC

suggesting some promise for both probiotics and syn biotics

in the trials we identifi ed that were conducted among CIC

patients, further studies are needed before their benefi t can be

judged with any great certainty. Th e mechanism of action of

individual probiotics in improving symptoms in IBS or CIC

also remains speculative. Th ere have been previous studies

conducted that have suggested that some probiotics have the

ability to modify the expression of pain receptors in the gut

( 72 ), and one of the RCTs we identifi ed measured cytokine

levels in patients and demonstrated that B. infantis 35624 had

the ability to normalize interleukin levels in patients with IBS

( 19 ). However, it is unlikely that this is a class eff ect, and further

research is required to identify species and strains of probiotics

that are consistently benefi cial, as well as to elucidate how these

benefi ts are achieved.

In summary, this meta-analysis has demonstrated little evi-

dence for the use of prebiotics or synbiotics in IBS. Probiotics

were of benefi t, with a NNT of 7 and signifi cant improvements

in terms of global symptom, abdominal pain, bloating, and

fl atulence scores. Combinations of probiotics and L. plantarum

DSM 9843 appeared to have the most evidence supporting their

use. Trials of probiotics and synbiotics in CIC demonstrated

some promising results, in terms of response to therapy or

increase in mean number of stools per week, but more RCTs

are needed before their true effi cacy in treating this condition

is known.

ACKNOWLEDGMENTS We thank Peter Bytzer, Philippe Ducrotte, Paul Enck, Per Farup,

Simone Guglielmetti, Lesley Houghton, Solveig Ligaarden, Julie

Morris, Yehuda Ringel, Magnus Simren, and Bo Sondergaard for

responding to our queries about their papers and, in some instances,

providing us with extra data.

CONFLICT OF INTEREST Guarantor of the article: Alexander C. Ford, MBChB, MD.

Specifi c author contributions: A.C.F., E.M.M.Q., B.E.L. A.J.L.,

Y.A.S., L.R.S., E.E.S., B.M.R.S., and P.M. conceived the study; A.C.F.

and P.M. collected all data; A.C.F. and P.M. analyzed and interpreted

the data; A.C.F. draft ed the manuscript; and all authors commented

on the draft s of the paper and approved the fi nal draft of the manu-

script.

Financial support: Th is work was supported by American College

of Gastroenterology.

Potential competing interests : None.

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of bias of all studies of probiotics in CIC was unclear. Finally,

synbiotics also appeared to be more eff ective than placebo in

CIC, with an NNT of 5, but again there were only two trials study-

ing their effi cacy, although these were both at a low risk of bias.

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A strength of this systematic review and meta-analysis is our

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Th ere remains a paucity of evidence for the effi cacy of

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