1-s2.0-S0021755714001478-main

J Pediatr (Rio J). 2015;91(1):6---21

www.jped.com.br

REVIEW ARTICLE

Probiotics: an update

Yvan Vandenplasa,, Geert Huysb, Georges Daubec

a UZ Brusseb Laboratorc Facult de

Received 14Available on

KEYWOBidobacGastro-inmicrobioLactobacMicrobioProbiotic

Please ci Correspo

E-mail: y

http://dx.d0021-7557/l, Department of Pediatrics, Vrije Universiteit Brussel, Brussels, Belgiumy of Microbiology & BCCM/LMG Bacteria Collection, Faculty of Sciences, Ghent University, Ghent, Belgium

Mdecine Vtrinaire, Dpartement des Sciences des Denres Alimentaires, University of Lige, Lige, Belgium

July 2014; accepted 6 August 2014line 23 October 2014

RDSteria;testinalta;illus;me;

AbstractObjective: Triggered by the growing knowledge on the link between the intestinal microbiomeand human health, the interest in probiotics is ever increasing. The authors aimed to review therecent literature on probiotics, from denitions to clinical benets, with emphasis on children.Sources: Relevant literature from searches of PubMed, CINAHL, and recent consensus state-ments were reviewed.Summary of the ndings: While a balanced microbiome is related to health, an imbalancedmicrobiome or dysbiosis is related to many health problems both within the gastro-intestinaltract, such as diarrhea and inammatory bowel disease, and outside the gastro-intestinal tractsuch as obesity and allergy. In this context, a strict regulation of probiotics with health claims isurgent, because the vast majority of these products are commercialized as food (supplements),claiming health benets that are often not substantiated with clinically relevant evidence.The major indications of probiotics are in the area of the prevention and treatment of gastro-intestinal related disorders, but more data has become available on extra-intestinal indications.At least two published randomized controlled trials with the commercialized probiotic productin the claimed indication are a minimal condition before a claim can be sustained. Today,Lactobacillus rhamnosus GG and Saccharomyces boulardii are the best-studied strains. Althoughadverse effects have sporadically been reported, these probiotics can be considered as safe.Conclusions: Although regulation is improving, more stringent denitions are still required.Evidence of clinical benet is accumulating, although still missing in many areas. Misuse anduse of products that have not been validated constitute potential drawbacks. 2014 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda.

te this article as: Vandenplas Y, Huys G, Daube G. Probiotics: an update. J Pediatr (Rio J). 2015;91:6---21.nding [email protected] (Y. Vandenplas).

oi.org/10.1016/j.jped.2014.08.005 2014 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda.

Este um artigo Open Access sob a licena de CC BY-NC-ND

Este um artigo Open Access sob a licena de CC BY-NC-ND

Probiotics: an update 7

PALAVRAS-CHAVEBidobactrias;Microbiotagastrointestinal;LactobacMicrobioProbitic

Probiticos: informaces atualizadas

ResumoObjetivo: Motivado pelo conhecimento cada vez maior da associaco entre o microbioma

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intestinal e a sade humana, o interautores visaram analisar a ltima literaclnicos com nfase nas criancas.Fontes dos dados: Foi analisada a litedos ltimos consensos.Sntese dos dados: Apesar de um equdesequilbrio no microbioma ou disbiosgastrointestinal, como diarreia e doennal, como obesidade e alergia. Nessealegaces de sade urgente, pois a alimentaco (suplementos), alegandoprovados com evidncias clinicamentefeitas na rea da prevenco e tratamesido disponibilizados a respeito de indicontrolados e randomizados publicadosso a condico mnima antes de uma arhamnosus GG e Saccharomyces boulaadversos terem sido esporadicamente rConcluses: Apesar de a regulamentamais rigorosas. As evidncias de benefem vrias reas. O uso inadequado e a udesvantagens. 2014 Sociedade Brasileira de Pediatr

Este um artigtion

ood and Agriculture Organization (FAO) and Worldanization (WHO) Expert Consultation on evalua-lth and nutritional properties of probiotics in foodowder milk with live lactic acid bacteria denedas: live microorganisms that, when adminis-equate amounts, confer a health benet on the2002, a joint FAO/WHO Working Group2 releasedfor the evaluation of probiotics in food. The min-irements needed for probiotic status include:

nt of strain identity (genus, species, strain level);tests to screen potential probiotics: e.g. resis-

gastric acidity, bile acid, and digestive enzymes,obial activity against potentially pathogenic;sessment: requirements for proof that a probioticsafe and without contamination in its delivery

tudies for substantiation of the health effects int host.

g the FAO/WHO denition, the International Lifestitute (ILSI)3 and the European Food and Feedssociation (EFFCA)4 have released similar deni-probiotic: a live microbial food ingredient that,

when consuts on the cingested orconsumer wdenitions benets fo

The sciein constantdietary supmedicationthrough thvival, but sthe gut. Prthe host thTopical or lview of thethe ability should be better, forshould be pnot with thtributes toinformationliterature of action osystem. It be alivedenition mnos probiticos vem crescendo cada vez mais. Osa respeito dos probiticos, de denices a benefcios

a relevante de pesquisas do PubMed, do CINAHL e

io no microbioma estar relacionado sade, umt relacionado a vrios problemas de sade no tratoamatria intestinal, e fora do trato gastrointesti-exto, a regulamentaco rigorosa dos probiticos ade maioria desses produtos comercializada comoefcios sade que frequentemente no so com-vantes. As principais indicaces de probiticos soe doencas gastrointestinais, porm mais dados tmes extraintestinais. Pelo menos dois ensaios clnicos

o probitico comercializado na indicaco declaradaco poder ser mantida. Atualmente, o Lactobacilluso as melhores cepas estudadas. Apesar de efeitosdos, os probiticos podem ser considerados seguros.star aumentando, ainda so necessrias deniceslnicos esto aumentando, apesar de ainda ausentesaco de produtos no validados constituem possveis

ublicado por Elsevier Editora Ltda. n Access sob a licena de CC BY-NC-NDmed in adequate amounts, confers health bene-onsumers and live microorganisms that, when

locally applied in sufcient numbers, provide theith one or more proven health benets. Thesede facto imply that probiotic ingestion providesr host health.nce related to probiotics is recent, and is thus

evolution. Probiotics used in food, supplied asplement, or as active components of a registered, should not only be capable of surviving passagee digestive tract by exhibiting acid and bile sur-hould also have the capability to proliferate inobiotics must be able to exert their benets onrough growth and/or activity in the human body.ocal application of probiotics is also proposed in

recent evolution of scientic data. Therefore,to remain viable and effective at the target sitestudied and conrmed for each strain, or even

each commercialized product. Clinical studieserformed with the commercialized product and

e isolated strain. However, lack of protection con- the fact that some companies refuse to deliver

on the specic strains in their product.5 Recenthas demonstrated that one of the mechanismsf probiotics involves stimulation of the immuneis questionable whether the probiotics need to

to induce immune-modulation. Therefore, theay have to be revised in the future.

8 Vandenplas Y et al.

According to the European Union (EU), health claimsshould only be authorized for use in the EU after a scien-tic assessment of the highest possible standard has beencarried out by the Panel on Dietetic Products, Nutrition, andAllergies (NDA) of the European Food Safety Authority (EFSA)[Regulationaddressed

- Is the foorized?

- Is the claecial ph

- Have pertiate the

The EFSward in tryand medicaered side-wsupplemendevice, fhard scienments on qbetween focation in a

Ofcial to ensure cusing unauproblem, ping methodofcial connies are imstrains and

In theirFood, the following iprobiotic p

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Suggestedose of p

Health c Proper s Corporat

In mostrently allowWorking Grfoods shouwhenever specic hein promotioing that a rotavirus dthe consumhealth. Thturer shoul

third party review by scientic experts in order to establishthe truthfulness of the health claims.

In line with the suggestions of the FAO/WHO WorkingGroup,2 on December 20, 2006, the European Parliamentand the Council published a new regulation (No. 1924/2006)

ing gulag tocludh clad het cong, s traued

tion

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tic p con (EC) N 1924/2006].6 The key questions that wereby the EFSA NDA panel are:

d/constituent sufciently dened and characte-

imed effect sufciently dened, and is it a ben-ysiological effect?tinent human studies been presented to substan-

claim?

A recommendations are an important step for-ing to bring claims for probiotic food supplementstion closer together. However, companies discov-ays to avoid EFSA restrictions. Some of the food

ts are in the process of registration as medicalor which claims can be made without providingtic evidence. Moreover, production require-uality control and safety still differ substantiallyod supplements and medication, putting medi-

disadvantageous situation.controls by national authorities are performedompliance with food law. Apart from the risk ofthorized strains, product mislabeling is a knownartly due to the use of phenotyping or genotyp-s that lack discriminative power.7 In addition totrols, private controls by food producing compa-portant in the context of protection of patented

industrial property rights. Guidelines for the Evaluation of Probiotics inFAO/WHO Working Group2 recommends that thenformation should be described on the label ofroducts:

pecies, and strain designation. Strain designationot mislead consumers regarding the functionalityrain;

viable numbers of each probiotic strain at thee shelf-life;d serving size, which must deliver the effectiverobiotics related to the health claim;laim(s);torage conditions;e contact details for consumer information.

countries, only general health claims are cur-ed on foods containing probiotics. The FAO/WHO

oup2 recommended that specic health claims onld be allowed relating to the use of probiotics,sufcient scientic evidence is available. Suchalth claims should be permitted on the label andnal material. For example, a specic claim stat-

probiotic reduces the incidence and severity ofiarrhea in infants would be more informative toer than a general claim that states improves gute recommendation is that the product manufac-d be responsible for conducting an independent

regardThis rerelatinthus ina healttion anprotec(labeliwell aconstr

Func

The dwhen benetionalithis deiologicIn addmust bcic realso imthrougsite fodelivecoccusas a pdoes n

Whtionedbroad the prouse oftract, and itsulationand imvidualof potties arperfecprobiotheir ipathogproper

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Targe

ProbiologicalNutrition and Health Claims Made on Foods.6

tion applies to all nutritional and health claims all types of food intended for nal consumers;ing probiotic products brought to the market withim. The regulation aims to consolidate the nutri-alth claims at European level in order to betternsumers, including commercial communicationspresentation, and promotional campaigns), asdemarks and other brand names that could beas nutrition or health claims.

al effects of probiotics

ion probiotics are live microorganisms whichinistered in adequate amounts confer a health

the host only generalizes the probiotic func- conferring a health benet to the host. Hence,ion entails that there must be a measurable phys-net to the host who uses the probiotic product., it is not specied that the probiotic strainovided through oral delivery, nor are there spe-ements regarding the mode of action. The latters that survival of the probiotic microorganisms

the gastrointestinal (GI) tract is not a prerequi-ognition of probiotic effects. For example, the

lactase through administration of live Strepto-mophilus to the small intestine can be consideredtic activity, although the bacterial strain itselfrvive the digestive tract.8

nsidering probiotic functionality, the abovemen-nition of probiotics is to be interpreted in a very

This broad functionality denition complicates of functional characterization of probiotics. Theiotics may target several body sites (mouth, GIiratory tract, urinary tract, skin, vagina, etc),lication can also target specic human subpop-ealthy individuals, children, elderly, ill subjects,ecompromised and genetically predisposed indi-ong others. There is an extremely diverse rangel biological effects, and new functional activi-nstantly being explored. While some models areuited for studying the colonization potency of

other models need to be applied for assessingne-modulating potential, their resilience againstvasion of the GI tract, or their anti-inammatory

al characterization of probiotics

es

roducts have been developed to improve physio-ditions at different body sites. While the GI tract


is the most important target for the majority of probioticapplications, other body sites, such as the mouth, the uro-genital tract, and the skin, are also considered. Probioticsmay play an important in oral medicine and dentistry.9,10

Probiotics are also considered for controlling and pre-venting infRegarding orally to ieffects, e.matologicabeen usedtions. Lacttract infecagainst GIstrains andget site. Ssuch as decsynthesis, intolerancemodulatory

Delivery

In order torequire a spalong the been formumore optimwith convemethods inventional pin more speand cookiecommerciaor to integfruit juices

Besidesucts, probioften targsupplemenication (e.standard inare many iand allevia

L. lactitory Yersinin mouse msidered forin head/nehuman trefof the theactivities othe interacular signaltargets in p

Finally, pharmaceumulated. Sdeveloped;in mattress

an optimized hygienic control. The latter illustrates theneed to broaden the control on claims larger than foodsupplements and food. If the EU installs authorities, suchas the EFSA, to control claims for foods and food supple-ments, health-claims for non-food related products should

ally

sur

y casstraind irganatic,tly, nt frce o

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fun to dlt hyiety cterimizeropoowethercolon ec

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it hnmenant ng b, reseredandtic imustilabmusttem.ith re

thrivucohobightfon beections of the reproductive and urinary tract.11---14

skin applications, probiotics may be consumednduce an immune response that has systemicg., for controlling skin inammation15 and der-l diseases in general.16 Probiotics have also

as protection against respiratory tract infec-obacillus (L.) rhamnosus GG prevents respiratorytions in addition to the conventional protection

infections.17 There is a plethora of probiotic applications available with the GI tract as tar-uch applications aim at several health benets,reasing pathogen colonization, improving vitaminoptimizing intestinal transit, alleviating lactose, reducing bloating, and promoting immune-

effects, among others.

mode

provide health benets, probiotic strains oftenecic matrix to guarantee optimal strain survival

GI tract. For instance, probiotics have recentlylated in a chocolate matrix, which resulted in aal survival of the probiotic strains in comparisonntional probiotic formulation methods.18 Otherclude the introduction of probiotics in more con-roducts such as milk,19 ker,20 and yoghurts, orcic matrices such as cereals, cheese, sausages,s. Obviously, many probiotics are introduced forl reasons, to obtain a better product placementrate the probiotic market (common examples are, ice creams, candies, granola bars, etc).

the incorporation of probiotics in food prod-otic strains are also provided as food supplement,eting specic health problems. Probiotic foodts (e.g. L. rhamnosus GG, L. reuteri) and med-g. Saccharomyces boulardii) have almost become

the treatment of pediatric gastroenteritis. Therenfant formulas with probiotics, both to preventte diarrhea.s strains that secrete IL-10 or immunomodula-ia LcrV protein were developed to treat colitisodels.21,22 Such approach is currently being con-

the treatment of oral mucositis (high incidenceck cancer patients receiving radiotherapy) with aoil factor 1-secreting L. lactis. A molecular basisrapeutic applications and the chemopreventivef certain probiotic metabolites, with emphasis ontion between these metabolites and the molec-ing cascades, are considered to be epigeneticreventing colon cancer.23

probiotic delivery not only pertains the food ortical environment in which the probiotic is for-pecic ointments and nasal sprays have been24 currently, even the introduction of probioticses and cleaning agents is gaining momentum for

be equ

Strain

In manbiotic state amicrooenzym

Firsronmepresenproleinitial biotic longermay exfor a loselectenew mprobio

A ssalts thmicrooticularabilityBile sarin moless bato optbeen pcould l

Anoity to into aFirstly,and ducolon,envirosignicreachichymeconsidbiota, probiostrain for avabiotic ecosyse.g. wto andlium. Mhydropa straision cacontrolled.

vival

es, health benets are only obtained when a pro-n reaches the target site in a metabolically activen sufcient numbers. For oral delivery, probioticisms must survive the different physicochemical,

and microbial stresses throughout the GI transit.microorganisms have to cross the acidic envi-om the stomach. In addition, the absence orf a food matrix signicantly determines the pHhich the probiotic strain is subjected. While theuffering effect from food may subject the pro-n to initially less stringent acidic conditions, astion time in the stomach under fed conditions

part of the dosed probiotic to acidic conditionsr time. Many probiotic microorganisms have beenr their higher resilience in such conditions, anddologies are available to allow encapsulation oftrains in that purpose.25

d stress component is the presence of bilelicit membrane-compromising properties towardsisms, due to their amphiphilic character. A par-ctional characteristic of microorganisms is theireal with bile salt stress via bile salt hydrolase.drolase bacteria typically cleave the glycin or tau-from conjugated bile salts, rendering the latteriostatic. This feature is of particular importance

strain survival during intestinal transit and hassed as a mechanism to explain how probioticsr serum cholesterol levels.26

feature of probiotic strain survival is the abil-nize the GI tract. This property can be dividedological component and a mucosal component.e a probiotic organism has survived gastric acidnal bile salts and thus reaches the ileum andas the possibility to develop in a less stringentt. Yet, it reaches an environment with a highlymicrobial background --- the ileum and colon

acterial concentrations of 107 and 1011 cells/mLpectively. Obviously, a probiotic strain can be

as foreign to the residing endogenous micro- unless specic nutrients are provided for then the product formulation (e.g. synbiotic), the

compete with the residing microbial communityle substrates. In ecological terms, the dosed pro-

occupy a functional niche in the gut microbial Secondly, an important property for probiotics,spect to pathogen control, is its ability to adheree in the mucus surface that covers the gut epithe-sal adhesion can rely on cell wall properties. Thec nature of microbial strains can be assessed withrward BATH assay,27 while a specic mucus adhe-

measured using short term adhesion assays with


gut-derived mucins (mostly from animal origin).27,28 How-ever, the aspecic adhesion of gut microorganisms to gutmucins is only sufcient for microcolony formation, and doesnot guarantee a prolonged colonization of the mucus layer. Ithas been well described that specic microorganisms modu-late their gthe mucosapathogens,as L. rhamnspecic pil

Human ta

Probiotic pof health cindividualscurative nadisease or associated or metabol

With ththe intakeprimarily psized that is a probiobe performParticularlypopulationdegree of biotic applthat can behave shownsuch as minfants, old

For exaShirota poshuman subthe effectson infectiocenters,32

1 was givenrisk of infe

In case region is ditional nichof dysbiosimouth assoated with the effectFor examplas L. rhamchildren;35

during orthmicrobial dterial vagirhamnosusused to treapplied orthe gut enjects have

L. gasseri OLL2716 (LG21),41 while specic Bidobacteriumstrains display anti-Helicobacter effects through the pro-duction of antimicrobial peptides.42 However, there is proofthat dysbiosis occurs in Crohns disease (either as causeor consequence), but probiotic supplementation has always

to pis speildrereaseis de

of t

althtremsigh

biol

timatics n a blonit invailabnal

unityecosbioti

micccupenouthogrefegetsucu

of an(oppe ection(e.g.

andtowawhictericxygereacro-en

ion

c miuteitamns, s, canivitieeredene expression following their incorporation intol surface. This has not only been described for

28,29 but also for probiotic microorganisms, suchosus GG, which may upregulate the formation ofi in the mucosal environment.30

rget groups

roducts have been developed for a wide varietylaims. Probiotics can target both healthy and ill. The expected effects can be of a preventive orture. The goal can be to ght the cause of themetabolic alterations, or to lessen the symptomswith the occurrence or progression of a diseaseic alteration.e aim of improving health in the human body,

of a probiotic strain by healthy subjects hasreventive objectives. Yet, it must be empha-the introduction of a foreign strain --- even if ittic --- must be approached with care and musted after a well-considered evaluation process., the gut environment from sensitive human sub-s, such as infants and toddlers, undergoes a highdevelopment or transition. Many studies on pro-ications reported a positive outcome in markers

of relevance for human health. Probiotic studies benecial effects in all age-related subgroups,

other-infant pairs, preterm infants, newborns,er children, and elderly people.

mple, fermented milk drinks with L. casei strainitively stimulate the immune system in healthyjects.31 With respect to different age groups,

from long term consumption of probiotic milkns was evaluated in children attending day carewhile L. delbrueckii subsp. bulgaricus OLL1073R-

to elderly persons with the aim of reducing thection.33

the microbial community from a specic bodysturbed, leading to the so-called dysbiosis, func-es become available in the ecosystem. Exampless are the changes in microbial ecosystem in theciated with dental caries, or dysbiosis associ-

bacterial vaginosis. Twetman recently revieweds from probiotics on oral health in children.34

e, long-term application of probiotic strains suchnosus GG lowered the risk of dental caries inthe importance of probiotic supplementationodontic therapy was also reported.36 Similarly,ysbiosis in the urogenital tract, particularly bac-nosis, can also be treated with probiotics.37 L.

GG and specic L. acidophilus strains have beenat bacterial vaginosis.38,39 Probiotics may also beally to reduce health risks that originate fromvironment. Helicobacter pylori-colonized sub-

been treated with L. casei milk drinks40 and

failed there for chan incwhich

Basis

The heare exnew in

Micro

The ulprobiostasis iand coagainsthe avfunctiocommin the

Prorestoremay oendogtic) paoften ily tar(e.g. mmore lower into thproducacids the pHacids ocins, or bactive ohighly in mic

Nutrit

Specicontribfrom vvitamiamineof actconsidrevent relapse, except in pouchitis. In addition,cic attention for developing probiotic conceptsn under modied risks. Preterm infants displayd risk for developing necrotizing enterocolitis,creased by the application of oral probiotics.43

he biological effect of probiotics

benets from probiotic products and applicationsely diverse and are continuously expanded withts and scientic developments.

ogical functionality

te goals of microbiological interventions throughmay be to stabilize or improve microbial homeo-ody environment and to lower pathogen invasionzation. The resilience of a microbial communityasion by exogenous strains largely depends onility of non-occupied functional niches. If not allniches are occupied by the endogenous microbial, there is an increased risk for pathogen invasionystem, colonization, and subsequent infection.c microorganisms can be used to improve orrobial homeostasis in two scenarios. Firstly, theyy functional niches that are left open by thes community, thereby preventing (opportunis-ens from occupying that niche. Such process isrred to as competitive exclusion, and primar-

the competition for nutrients, physical sitess adhesion) or receptors. The second scenario is

antagonistic nature as probiotics may activelyortunistic) pathogen invasion or developmentosystem. Such approach primarily targets: i) the

of short chain fatty acids and other organic lactic acid) by probiotics, thereby lowering

increasing the bacteriostatic effect of organicrds pathogens; ii) the production of bacteri-h are small microbial peptides with bacteriostaticidal activity; and iii) the production of reac-

n species, such as hydrogen peroxide, that aretive and increase oxidative stress for pathogensvironments.

al functionality

crobial groups produce vitamins and may thereby to vitamin availability to the human host. Apartin K,44 vitamin B12,45 and pyridoxine,46 otheruch as biotin, folate, nicotinic acid, and thi-

be produced by gut microorganisms. This types may affect host health and may therefore be

as potential probiotic effects.


Lactase deciency causes lactose intolerance, whichresults in abdominal cramping, nausea, and bloating. Probio-tic strains that are lactase-positive have been successfullyapplied to relieve discomfort from lactose intolerance.47

Other nutritional functionalities may include the pro-duction ofpotency orival or evronment hproduce nhealth-modhealth-proing probiohealth-proreported f1551,51 ansion of phby supplemfuture propreviously soy-derivedsemiers etprobiotic pvert hop is

Physiolog

Probiotic mGI transit.tionality fopersons.54

the reductthe enhanccells55 andof serum cprobiotics.

Lowering

Probiotic mhealth riskexposure tfrom an endominant sexposed toduced fromparticular;residues fchain; or ition proceof meat). lower the roften relatbial biomawhich has strains.58 Acation of tof fumoniscorn leave

resembles the abovementioned probiotic modulation of gutmicroenvironment, where (food) pathogens produce toxins.For example, the production of organic acids by probio-tic microorganisms was reported to negatively affect theproduction of Shiga-toxin 2 from enterohemorrhagic E. coli

7.

nolo

munion tionmatose to

otic

llowiew od as incethorn.

inf

tics te inRCT)

signe proi andevenized

partventrobi

lact reualony in rheafectitiona (ee ofpital7938l incion.70

ool cstion

usee cogastrosus) anmend health-promoting compounds. The metabolicf gut microorganisms is enormous and mayen exceed that of the liver.48 The gut envi-arbors several small chemical factories thatumerous chemical components with putativeulating effects.49 Isolated strains that produce

moting products may also be considered as hav-tic potential. For instance, the production ofmoting conjugated linoleic acids (CLA) has beenor Bidobacterium strains,50 L. plantarum JCMd specic L. acidophilus strains. Also, conver-ytoestrogen precursors to bioactive metabolitesented microorganisms is a potential pathway forbiotic applications. For example, Decroos et al.isolated a microbial consortium that converts

daidzein into the bioactive equol,52 while Pos- al. performed an in vitro investigation of theotential of Eubacterium limosum strains to con-oxanthohumol into 8-prenylnaringenin.53

ical functionality

icroorganisms have been reported to enhance Hamilton-Miller previously reviewed such func-r the application of probiotic products in elderlyOther potential physiological effects may includeion by probiotics of bloating or gas production,ement of ion absorption by intestinal epithelial

the decrease of bile salt toxicity or the decreaseholesterol levels by bile salt hydrolase positive56,57

health detrimental components in the gut

icroorganisms are also applied to reduce thes from hazardous components. For example, oralo contaminants, either from a food matrix orvironmental matrix (soil, dust, water) is the mostcenario by which the human body gets internally

contaminants. These can be: i) mycotoxins, pro- fungi on a wide variety of crops, cereals in

ii) xenobiotics with toxic properties as unwantedrom environmental contamination of the foodii) hazardous compounds from the food produc-ss as such (e.g. PAH production during grillingThe mode of action by which these probioticsisk derived from ingested hazardous componentses to the sorption of the compound to micro-ss. This is the case for aatoxin B1, for example,been shown in vitro to be bound by probioticnother mode of action may be direct detoxi-he hazardous compound, such as the breakdownin by Pediococcus pentosaecus L006 isolated froms. A nal mode of action is more indirect and

O157:H

Immu

The imactivatproducinamrespon

Probi

The foovervistudietion, sthe auchildre

Acute

Probioof acutrials (ticallyof somreuterthe prrandomferentfor premain psubsp.and L.either efcacof diartory inprevendiarrhecentagIn hosDSM 1overalinfectipreschbe que

Themay bacute rhamndationrecomgical functionality

ological benets of probiotics can be due toof local macrophages and modulation of IgA

locally and systemically, to changes in pro/anti-ry cytokine proles, or to the modulation ofwards food antigens.59,60

products in prevention and treatment

ng paragraphs does not aim to provide a completef all indications in which probiotics have beenpossible preventive and/or therapeutic interven-

new manuscripts are published weekly. Rather,s focused on the most relevant indications for

ectious diarrhea

have been largely studied for the preventionfectious diarrhea. Large, randomized controlled

provide evidence of a very modest effect (statis-icant, but of questionable clinical importance)biotic strains (L. rhamnosus GG, and strains of L.

Bidobacterium (B.) animalis subsp. lactis) ontion of community-acquired diarrhea.61---69 Many

and placebo-controlled trials conducted in dif-s of the world have assessed the use of probioticsion of diarrhea acquired in day-care centers. Theotics tested were L. rhamnosus GG, B. animalisis alone or in combination with S. thermophilus,teri, L. rhamnosus (not GG), and L. acidophiluse or in a comparative study. The evidence of theirthese settings is only modest for the prevention

and sometimes also for preventing upper respira-ons.66 However, the protective effect on diarrhea

becomes far less signicant if the incidence ofpisodes per patient-month) rather than the per-

patients with diarrhea is taken into account.68

ized children, the administration of L. reuteri compared with placebo had no effect on thedence of nosocomial diarrhea, including rotavirusAlthough the same strain prevented diarrhea inhildren,71 the clinical impact of such ndings caned.72

of the following probiotics (in alphabetical order)nsidered in the management of children withoenteritis in addition to rehydration therapy: L.

GG (low quality of evidence; strong recommen-d S. boulardii (low quality of evidence; strongation). Less compelling evidence is available for


L. reuteri DSM 17938 (very low quality of evidence; weakrecommendation) and heat-inactivated L. acidophilus LB(very low quality of evidence; weak recommendation).73 Thelatter, although traditionally discussed with other probio-tics, does not t in the denition of probiotics. A numberof RCTs have evaluated the effect of Enterococcus fae-cium SF68Cochrane E. faeciumfour days 0.52).73 Hothe E. faecomycin rein vivo cosafety issuhave strentreatment strains or evidence otures of diSince in tzinc is noimpact of pConsideringtaneously will in greaused.78,79

Antibiotic

The pooledincluded 11icant associn AAD (relI(2), 54%; [NNT 13; 9concluded analysis, pchildren.82

tion of therhamnosus0.07-0.6), 0.95).82 Forhea whiledevelop AAwas reportRecently, aS. boulardment of AAmany studany (othercile infecA new metreduce the95% CI: 0.3cile infectiboulardii (GG (RR = 0.strains.87 Iwith antibi

Travelers diarrhea

Travelers diarrhea is a frequent condition of great socio-economic impact. In this topic, there are more reviewsthan origin

erfotionus an.89---9

ant cal dded nos

cacyelerded ea.94

tmes is t

le B

is suadul

frommenptom6

CT od ov, althinal osusf bored ting.lacebith aoverGI dnce in onos

acebeek

of Vl as ssineant re arebioiotic

coma coormumenith ted i

gainther 73.73 A sub-group analysis performed within areview (search date: July of 2010) found that

SF68 reduced the risk of diarrhea lasting (four RCTs, n = 333; RR: 0.21; 95% CI: 0.08 towever, in vitro studies have documented that

cium SF68 strain is a possible recipient of van-sistance genes.74 Considering that the risk for

njugation cannot be discarded, probiotics withes should not be used.73 Recent publicationsgthened the evidence for L. reuteri in theof diarrhea in hospitalized children.75,76 Othercombinations of strains have been tested, butf their efcacy is weak or preliminary. Mix-

fferent strains do not necessarily score better.77

ropical countries with zinc-decient regions,w added to oral rehydration salts (ORS), therobiotics above its efcacy should be studied.77

that an acute gastroenteritis will heal spon-in almost every child, the cost/benet impactt part determine whether probiotics should be

-associated diarrhea (AAD)

relative risk in a meta-analysis of 63 RCTs, which,811 participants, indicated a statistically signif-iation of probiotic administration with reductionative risk, 0.58; 95% CI, 0.50 to 0.68; p < 0.001;[risk difference, -0.07; 95% CI, -0.10 to -0.05],5% CI, 10.3 to 19.1])80 Another meta-analysisthe NNT was 8.81 According to a recent meta-robiotics signicantly reduce the risk of AAD inPreplanned subgroup analysis showed that reduc-

risk of AAD was associated with the use of L. GG (95% CI: 0.15 to 0.6), S. boulardii (95% CI:or B. lactis and S. thermophilus (95% CI: 0.3 tor every seven patients that would develop diar-

being treated with antibiotics, one fewer willD if also receiving probiotics82 Only S. boulardiied to be effective in C. difcile disease.83---85

large single-center study showed in elderly thatii was not effective in preventing the develop-D or in prevention of C. difcile infection.86 In

ies, there is no evidence to support the use of) probiotic to prevent the recurrence of C. dif-tion or to treat existing C. difcile diarrhea.64

a-analysis concluded that probiotics signicantly incidence of pediatric AAD (22 trials; RR = 0.42;3-0.53) and the incidence of pediatric C. dif-on (ve trials; RR = 0.35; 95% CI: 0.13-0.92).85 S.RR = 0.43; 95% CI: 0.32-0.60) and L. rhamnosus36; 95% CI: 0.19-0.69) are the two best studiedn most studies, the probiotic is started togetherotic treatment.88

been pprevendophilresultssignicgraphiconcluL. rhamno efin travconcludiarrhor treastudie

Irritab

There IBS in reviewsuppleon sym2.21).9

A Rshoweadultsabdomrhamntion ocompaity teswith pated win the tional differeinal paL. rhamand pltwo-weffectas weling/gasignic

Thewith pa prebrior GIformulfree fimpairized wobservweightbe fural research studies published. Different RCTs havermed evaluating the efcacy of probiotics in the

of travelers diarrhea. One trial with L. aci-d two with L. rhamnosus GG observed negative

1 One trial with S. boulardii reported a small butpreventive effect in a subgroup, suggesting geo-ifferences in efcacy.92 In a review, McFarlandthat there is comparable evidence for efcacy forus GG, L. casei DN-114001, and S. boulardii, and

for L. acidophilus.93 Since the number of studiess diarrhea is very limited, a recent meta-analysisthat probiotics are not efcient for travelersThere are no data on prebiotics and preventionnt of travelers diarrhea. Overall, the number ofoo small to allow for recommendations.95

owel Syndrome (IBS)

bstantial literature on the effect of probiotics onts, but data in children are limited. A Cochrane

2009 failed to demonstrate an effect of berts and recorded a limited effect of lactobacillis compared to placebo (OR: 1.17; 95% CI: 0.62,

f six weeks with L. rhamnosus GG versus placeboerall negative results in 50 children and youngough there was a lower incidence of perceiveddistension in the L. rhamnosus GG group.97 L.

GG, but not placebo, caused a signicant reduc-th frequency and severity of abdominal painto baseline, and inuenced intestinal permeabil-98 A meta-analysis demonstrated that, comparedo, L. rhamnosus GG supplementation was associ-

signicantly higher rate of treatment respondersall population with abdominal pain-related func-isorders and in the IBS subgroup.99 However, nowas observed in children with functional abdom-r functional dyspepsia who received placebo orus GG. A randomized cross-over trial with VSL#3o, comprising 59 patients for six weeks, with awashout period in-between, showed a superiorSL#3 compared to placebo in symptom relief,in abdominal pain/discomfort, abdominal bloat-ss, and family assessment of life disruption.99 Nodifference was found in the stool pattern.100

re no data on prevention or treatment of IBStics. Data from one trial suggest that, in infants,-containing whey-based formula provides supe-fort than a control formula.101 A peptide-basedntaining ber was as well-tolerated as a ber-la in a small population of children with GIts.102 Extremes of stool consistency were normal-he ber formula. No signicant differences weren vomiting, abdominal pain, feeding intakes, or

between the two formulas.103 Synbiotics shouldinvestigated in this indication.103 Probiotics are


more effective than placebo in the treatment of patientswith abdominal pain-related functional gastro-intestinal dis-orders, especially with respect to patients with IBS.104

Helicobac

The use ofgastric inSpecic stin vitro barelease ofand/or inhtive effecttrials are vbe reprodurial load aclinical triaicate H. pthereby mstomach; iprobiotics adverse efa moderatwhen probpump inhibimprove erreduce theregimens.1

apy for H.eradicationdiarrhea, i

Constipat

Constipatiopre- and pintestinal and frequetory. In anstool frequFurthermostool consinence episopen trial,Pro BioticsB. longum,positive efsus Lcr35 constipatioconstipatioin infants even whenand episodstudy showquency witwith B. lodairy prod010 increarable with

currently not sufcient evidence to recommend fermenteddairy products containing strain DN-173 010 in this cate-gory of patients.117 No evidence for any effect was foundfor uid supplements, prebiotics, probiotics, or behavioralintervention.118 Probiotics have not proven effective for

n wile, t

cond

tizi

izingpecipmeologhilus20 Thdayshe of u.121

acilli dev

to ang mranepleme ane evetic me NNer, t

haan oay b

whto a

to biotpretece sd to

and be

be s12 sssocledhyla

,500 humere

advritioncient

to dagincacs of ers, ter pylori

probiotics in H. pylori-colonized subjects withammation is supported by many observations.rains of Lactobacillus and Bidobacerium exertctericidal effects against H. pylori through the

bacteriocins or production of organic acids,ibit its adhesion to epithelial cells. Such protec-s have been conrmed in animal models. Clinicalery important, since in vitro results cannot alwaysced in patients. Probiotics decrease the bacte-nd improve the immune response.105 Results ofls indicate that probiotics generally do not erad-

ylori, but decrease the density of colonization,aintaining lower levels of this pathogen in then association with antibiotic treatments, someincreased eradication rates and/or decreasedfects due to the antibiotics. Many studies showe higher eradication rate (10%) of H. pyloriiotics are added to the antibiotics and protonitor.106 Although L. rhamnosus GG appears not toadication,107 most probiotic bacteria and yeasts

adverse effects of standard H. pylori eradication08,109 Probiotics supplementation in triple ther-

pylori infection may have benecial effects on and therapy-related side effects, particularlyn children.110

ion

n is a frequent problem in childhood in whichrobiotics could have a positive inuence on themicrobiota with an effect on stool consistencyncy. Unfortunately, study results are contradic-

open trial, B. breve was effective in increasingency in children with functional constipation.111

re, it had a positive effect regarding improvingstency, decreasing the number of fecal inconti-odes, and reducing abdominal pain.111 In another

a probiotic mixture (Ecologic Relief, Winclove, Netherlands) containing B. bidum, B. infantis,

L. casei, L. plantarum, and L. rhamnosus showedfects on constipation symptoms.112 L. rhamno-was effective in treating children with chronicn.113 B. lactis was reported to be non effective forn.94,114 L. reuteri DSM 17938 had a positive effectwith chronic constipation on bowel frequency,

there was no improvement in stool consistencyes of inconsolable crying episodes.115 A Brazilianed a positive inuence of yoghurt on stool fre-h an additional effect of yoghurt supplementedngum.116 In constipated children, a fermenteduct containing B. animalis subsp. lactis DN-173se stool frequency, but this increase was compa-

that observed in the control group.117 There is

childreavailabpation

Necro

Necrotring esdeveloble etiacidop1999.1

seven with tdence infantslactobtion inshownin youA Cochtic supor moradversprobioals, thHowevformedEuropetion mNEC, incult comesof proity in evidenneedeinfantsdose toshouldThe 20gical Aacknowof propthan 2use ofble. Thor slowof nutinsufbioticsencourthe efstanceto othth functional constipation.104 Until more data arehe use of probiotics for the treatment of consti-ition should be considered investigational.119

ng enterocolitis

enterocolitis (NEC) is a severe condition occur-ally in preterm infants. Abnormal GI microbiotant has been hypothesized as one of the possi-ic factors. The rst publication reporting that L.

and B. infantis reduced NEC dates back fromis was followed by a negative study showing that

of L. rhamnosus GG supplementation startingrst feed was not effective in reducing the inci-rinary tract infection, NEC and sepsis in pretermThen, several randomized trials with different

and bidobacteria showed a signicant reduc-elopment of NEC.122,123 Although S. boulardii wasmeliorate hypoxia/reoxygenation-induced NECsice,124 it did not protect for NEC in infants.125

review concluded in 2008 that enteral probio-entation reduced the incidence of NEC stage IId mortality.126 No systemic infections or seriousnts were directly attributed to the administeredicroorganism.126 According to the published tri-T to prevent one case of NEC is 21 and 27.126

he centers in which these trails have been per-ve a much higher incidence of NEC than mostr North American centers. The recommenda-e different in centers with a high incidence ofich other measurements to decrease NEC are dif-pply. The updated Cochrane review from 2011different conclusions: enteral supplementationics prevents severe NEC and all cause mortal-rm infants.127 The updated review of availableupports a change in practice. More studies are

assess efcacy in extremely low birth weight to assess the most effective formulation andused.127 The debate regarding whether probioticsystematically given to preterms is still ongoing.ystematic review of the American Pediatric Sur-iation Outcomes and Clinical Trials Committeeges that recent Cochrane reviews support the usectic probiotics in preterm infants weighing less

g to reduce the incidence of NEC, as well as thean breast milk rather than formula when possi-is no clear evidence to support delayed initiationancement of feeds.128 However, an expert groupists and neonatologists concluded that there is

evidence to recommend the routine use of pro-ecrease NEC.129 According to this group, there isg data to justify further investigation regardingy and safety of specic probiotics in circum-high local incidence of severe NEC.129 Accordingavailable evidence is still too limited in order to


recommend probiotics to reduce NEC.130 A third group sug-gests that it may become unethical not to give probiotics topreterm babies to decrease NEC.131 Enteral supplementationof probiotics prevents severe NEC and all cause mortality inpreterm infants.132

Colic

Colic is a are desperof L. reutinfants.133---

given the sgiven placeprobiotic scontaining mophilus, Bsubsp. bulgeffective ipared to pl

Allergy an

Simultaneofour strainfour weeksshowed nodiseases atbut tendeda signicanHowever, Tallergy prementation atopic derassociated receiving scluded thathe additioallergic diswas a reduwas not conin view of studies.142

reduce atoon the moof probiotinancy. Probcumulativesensitizatioadministraatopic ecza mixture developmethey contareported elife, persistHN019 hadistration aHowever, t

then again contradicted in the meta-analysis by Pelucchiet al., supporting a moderate role of probiotics in theprevention of atopic dermatitis and IgE-associated atopicdermatitis in infants, regardless of the time of probiotic use(pregnancy or early life) or the subject(s) receiving probio-

othe neentra

detety ando

and samweree pla

pre samnatioone som

bened frL. paadjuogresed.1

ive in suggy of

of a dihile

is, thion fderating

-inte

iatrs of aons .88,15

inteslactoon inme id thaitiesdidions ant al sttics ion e caiedcatered tytasfrequent problem in infants and often parentsate for a solution. In this indication, the effecteri has been exhaustively studied in breastfed135 However, recent data suggested that infantsame probiotic cry for 50 minutes more than thosebo.136 Dupont et al. reported efcacy of anothertrain in formula fed infants.137 A synbiotic sachet1 billion CFU of L. casei, L. rhamnosus, S. ther-. breve, L. acidophilus, B.infantis, L. delbrueckiiaricus, and fructooligosacharide was shown to ben reducing colic in breastfed infants when com-acebo.138

d atopic dermatitis

us pro- and prebiotic treatment (a mixture ofs and GOS) given to pregnant women for two to

before delivery and to the infants for six months effect on the cumulative incidence of allergic

the age of 2 years when compared with placebo, to reduce IgE-associated (atopic) diseases sincet reduction of (atopic) eczema was noticed.139

aylor et al challenged the role of probiotics invention, observing that early probiotic supple-with L. acidophilus did not reduce the risk ofmatitis (AD) in high-risk infants, and was evenwith increased allergen sensitization in infants

upplements.140 A Cochrane review from 2007 con-t there was insufcient evidence to recommendn of probiotics to infant feeds for prevention ofease or food hypersensitivity.141 Although therection in clinical eczema in infants, this effectsistent between studies, and caution was advisedmethodological concerns regarding the includedHowever, the efcacy of probiotic intervention topic dermatitis and/or allergic disease may dependment of intervention. Preventive administrationcs may be only effective if given during preg-iotics given to unselected mothers reduced the

incidence of AD, but had no effect on atopicn.142 A recent meta-analysis showed that thetion of lactobacilli during pregnancy preventedema in children aged 2 to 7 years.143 However,of various bacterial strains does not affect thent of atopic eczema, independent of whetherin lactobacilli or not.143 L. rhamnosus HN001 wasffective against eczema in the rst two years ofing to age 4 years, while B. animalis subsp. lactis

no effect.144 Therefore, not only timing of admin-ppears to important, but also strain specicity.iming of administration and strain specicity were

tics (mallergyhow cohave a

Ninwere rM-16 Vor theThere and thbioticsAt thecombiotic alWhile show areporttis or as an the probserveffectresultsefcacrevieweczemworthwanalysan optfor mosuppor

Extra

No pedeffectinfectimediaextra-some infectiThe sashowemorbid

Caninfectisignichospitprobioonizatinvasiv

Purpseudocompagal phr, child, or both).145 The data on probiotics andd further clarication, because data are some-dictory. Geographical or genetic differences mayrimental role, especially for atopic dermatitis.infants with atopic dermatitis, age < 7 months,mized to receive an infant formula with B. breve

a mixture of short chain GOS and long chain FOS,e formula without synbiotics during 12 weeks.146

no signicant differences between the synbioticcebo group.146 The same group showed that syn-vent asthma-like symptoms in infants with AD.147

e time, another group reported that a synbioticn of L. salivarius plus FOS is superior to the prebi-for treating moderate to severe childhood AD.148

e studies with probiotics as a treatment for ADet,149 most studies are negative. No benet wasom supplementation with B. animalis subsp. lac-racasei in the treatment of eczema, when givennct to basic topical treatment, and no effect onsion of allergic disease from age 1 to 3 years was

50 Most reviews conclude that probiotics are not reducing atopic dermatitis. These contradictoryest strain specicity or a genetic inuence on the

probiotics in children with atopic dermatitis. A13 studies of probiotics for treating establishedd not show convincing evidence of a clinically

benet.151 However, according to a recent meta-e overall result suggests that probiotics could beor the treatment of atopic dermatitis, especiallyte to severe cases, and no evidence was found

the benecial role of probiotics in infants.152

stinal infections and other effects

ic studies have demonstrated denite benecialdministering probiotics to treat extra-intestinalsuch as respiratory tract infections or otitis

3 There is no evidence that probiotics decreasetinal infections. There is some evidence thatbacilli might prevent recurrent urinary tract

women. However, data in children are lacking.s true for recurrent vulvovaginitis. Sazawal et al.t prebiotic and probiotic fortied milk prevented

among children in a community-based RCT.154

asis accounts for 10% to 20% of bloodstreamin pediatric intensive care units (PICUs) and aincrease in morbidity, mortality, and length ofay.155 A few studies have demonstrated thatare able to prevent Candida outgrowth and col-in neonates, whereas their role in preventingndidiasis in such patients is still unclear.155

phytases from B. longum subsp. infantis and B.nulatum reduced the contents of phytate wheno control samples (untreated or treated with fun-e), and led to increased levels of myo-inositol


triphosphate.156 This is the rst example of the applica-tion of puried bidobacterial phytases in food processing,demonstrating the potential of these enzymes to be usedin products for human consumption.156 Lactic acid bacteriaimprove the synthesis of vitamins B2, B11 and B12 and havethe potentin cereals-leading tofoods.157

Pandemoped and dselectivelyin favor of studies withave been The admin2 diabetic pceral and sAndreasentration of sensitivity.microbiotamass indexgain duringup).160 So applicationadiposity.

Fecal mic

A new apptransplantacult to tfecal micrwarrant caoption.162 Tto intestinthe intestiapproach. positive remicrobiotaBacteremiaHowever, microbiotastudies shofailure.

Safety an

Probiotics primarily tExperiencemore limitlarly in theProbiotics in ambulatscale epideuse is endtemic infec

during pregnancy and early infancy is considered safe.169

Probiotic compounds may contain hidden allergens of foodand may not be safe for subjects with allergy to cowsmilk or hens eggs.170 Documented invasive infections havebeen primarily noted to occur in immunocompromised

butely obaical

infanocomlli hly, p

to bantince,bactnto is pol, anregance th cormsidets of

devtic th

lusi

tics h-intef th

meevenrs,

nal ispirath cionsd. Cudieta oicall

andnsti

icts

andaceunic

enc

od anzatiotion ial strategies to increase B-group vitamin contentbased products.157 Vitamin-producing L. has been

the elaboration of novel fermented functional

ic obesity is now a matter of interest in all devel-eveloping countries. Treatment with probiotics

changes the composition of the gut microbiotaspecic genus and even strains. Few interventionh probiotics in overweight or obese individualspublished until now, and mostly focus on L. or B.istration of a strain of L. gasseri in obese and typeatients has been shown to decrease fat mass (vis-

ubcutaneous) and body mass index.158 In addition, et al. have demonstrated that the adminis-Lactobacillus spp. positively impact on insulin159 Compelling evidence suggests that early gut

modulation with probiotics reduces the body in young children by restraining excessive weight

the rst years of life (from 0 to 10 years of follow-far, only few data are available on the possible

of lactobacilli or bidobacteria to counteract

robiota transplantation

roach in microbial therapeutic applications istion of intestinal microbiota, especially in dif-reat conditions in which it is known that theobiota is abnormal.161,162 Observed side effectsution in the ongoing pursuit of this treatmenthere is evidence that many diseases are related

al dysbiosis. As a consequence, manipulation ofnal microbiota is a very attractive therapeuticHowever, results are often negative,162 althoughsults have been reported.163 The transplanted

should be carefully screened for pathogens.164

has been reported as an adverse event.165

the rst cure of early onset colitis after fecal transplantation has been reported.166 Furtheruld now focus on the reasons for success and

d side effects

have a long record of safety, which relateso the use of lactobacilli and bidobacteria.167

with other microorganisms used as probiotic ised. There is no such thing as zero risk, particu-

context of certain forms of host susceptibility.167

are generally regarded as safe, and side effectsory care have almost not been reported. Largemiological studies in countries where probioticemic demonstrate (in adults) low rates of sys-tion, between 0.05 and 0.40%.168 Administration

adults,extremto Lactcal clinin an immuntobaciRecentshownunder resistaother tract iThere generatainty resistalow wiother fbe conbenerisk ofprobio

Conc

Probiogastroment oof thethe prdisordeintestiand reals wiindicatmendebest-sttive dasporadMisusemay co

Con

Yvan VPharmtial co

Refer

1. Fonita invasive infections in infants and children arerare.171---173 Two cases of bacteremia attributablecillus supplementation with genotypically identi-

and supplement isolates were recently reportedt and a child without underlying GI disease orpromised status.174 Sepsis with probiotic lac-

as been reported in children with short gut.lasmid transfer of antibiotic resistance has beene clinically possible. Long-term use of probioticsbiotic selection pressure could cause antibiotic

and the resistance gene could be transferred toeria.175 Translocation from the gastro-intestinalthe systemic circulation has not been reported.or public understanding of the concept of risk, ind risk/benet analysis, in particular.168 Uncer-rding the potential for transfer of antibiotic

with probiotics persists, but the risk appears to beurrently available probiotic products.168 As withs of therapeutics, the safety of probiotics shouldred on a strain-by-strain basis.168 The potential

supplementation should be weighed against theelopment of an invasive infection resulting fromerapy.

on

ave entered the mainstream of healthcare. Thestinal microbiota is fundamental for the develop-e immune system. Although the main indicationsdical use of probiotics is still in the area oftion and treatment of gastro-intestinal relatedgradually more evidence is collected on extra-ndications, such as vaginitis, atopic dermatitis,tory tract infections. Randomized controlled tri-ommercially available products in the claimed

are mandatory before their use can be recom-urrently, L. rhamnosus GG and S. boulardii are thed strains, while recent literature provides posi-n L. reuteri. Although adverse effects have beeny reported, probiotics can be considered safe.

use of products that have not been validatedtute potential drawbacks.

of interest

enplas is consultant for Biocodex and Unitedticals. The co-authors did not report any poten-ts of interest.

es

d Agriculture Organization (FAO). World Health Orga-n (WHO). Report of a joint FAO/WHO expert consul-on evaluation of health and nutritional properties


of probiotics in food including powder milk with live lac-tic acid bacteria. 1-4 October 2001, Crdoba, Argentina.[cited 18 Aug 2014]. Available from: http://www.who.int/foodsafety/publications/fs management/en/probiotics.pdf

2. Food anizatioon drafood. A18 Augfood/w

3. Ashweltional

4. Europeinition2003.

5. Vandenby spe860.

6. Europe1924/2cil of made oL 404, 18. [citupload

7. Huys GGoossecommenutritio

8. SanderNutr Re

9. Stamatmouth.

10. Meurmand de

11. Hoesl Ctreatm

12. Barronterial g2008;3

13. Reid Gbacter2003;1

14. Falagaprevena reviestudies

15. Hacini-S, Kaisacting 2009;4

16. CaramDerma

17. HojsakKolacecomialPediatr

18. PossemBacterbiotic d

19. Pereg The efrhea in2005;3

20. MagalhL, Teix

whey-based beverage using ker grains as starter culture:evaluation of morphological and microbial variations. Biore-sour Technol. 2010;101:8843---50.

21. Steidler L, Hans W, Schotte L, Neirynck S, Obermeier F, Falk, et acretilignet B, ccusoteinmar

et aevensein

. Evarns. ok M

icroey. J Cmar mar othe12;2n derbek

the otechacfarne G05;9assaota ary bobeersowssus Gteracicrobgao rmenirotaosci takk

et a infeind, akinoii N.etaryueck8---10etmfectsse L

et alriumd carant

conj06;7id Gctobal va---41.ssi Aamnnd Agriculture Organization (FAO). World Health Orga-n (WHO). Report of a Joint FAO/WHO working groupfting guidelines for the evaluation of probiotics inpril 30, May 1; London Ontario, Canada; 2002. [cited

2014]. Available from: ftp://ftp.fao.org/es/esn/greport2.pdf.l M. Concepts of functional foods. Brussels. Interna-Life Sciences Institute (ILSI) Europe. 2002.an Food and Feed Cultures Association (EFFCA). Def-

of microbial food culture (MFC). Brussels: EFFCA;

plas Y. Authors reply: Identication of probioticscic strain name. Aliment Pharmacol Ther. 2012;35:

an Parliament and Council. Regulation (EC) No006 of the European Parliament and of the Coun-20 December 2006 on nutrition and health claimsn foods. Ofcial Journal of the European Union. OJ30.12. 2006. Corrigendum OJ L 12, 18.1.2007, p. 3-ed 18 Aug 2014]. Available from: ttps://www.fsai.ie/edFiles/Cor Reg1924 2006.pdf., Vancanneyt M, DHaene K, Vankerckhoven V,

ns H, Swings J. Accuracy of species identity ofrcial bacterial cultures intended for probiotic ornal use. Res Microbiol. 2006;157:803---10.s ME. Probiotics: considerations for human health.v. 2003;61:91---9.ova I, Meurman JH. Probiotics: health benets in the

Am J Dent. 2009;22:329---38.an JH. Probiotics: do they have a role in oral medicinentistry? Eur J Oral Sci. 2005;113:188---96.E, Altwein JE. The probiotic approach: an alternativeent option in urology. Eur Urol. 2005;47:288---96.s R, Tassone D. Use of Lactobacillus probiotics for bac-enitourinary infections in women: a review. Clin Ther.0:453---68., Bocking A. The potential for probiotics to prevential vaginosis and preterm labor. Am J Obstet Gynecol.89:1202---8.s ME, Betsi GI, Tokas T, Athanasiou S. Probiotics fortion of recurrent urinary tract infections in women:w of the evidence from microbiological and clinical. Drugs. 2006;66:1253---61.Rachinel F1, Gheit H, Le Luduec JB, Dif F, Nanceyerlian D. Oral probiotic control skin inammation byon both effector and regulatory T cells. PLoS One.:e4903.ia G1, Atzei A, Fanos V. Probiotics and the skin. Clintol. 2008;26:4---11.

I, Abdovic S, Szajewska H, Milosevic M, Krznaric Z,k S. Lactobacillus G.G. in the prevention of noso-

gastrointestinal and respiratory tract infections.ics. 2010;125:e1171---7.iers S, Marzorati M, Verstraete W, Van de Wiele T.ia and chocolate: a successful combination for pro-elivery. Int J Food Microbiol. 2010;141:97---103.

D, Kimhi O, Tirosh A, Orr N, Kayouf R, Lishner M.fect of fermented yogurt on the prevention of diar-

a healthy adult population. Am J Infect Control.3:122---5.es KT, Pereira MA, Nicolau A, Dragone G, Domingueseira JA, et al. Production of fermented cheese

Wse

22. FoPocopr

23. KuR,pr

24. HuMBu

25. CoMer

26. KuKubi20

27. VaVeofBi

28. Mla20

29. Chbito

30. LeOsnoinM

31. NafeShBi

32. HaL,onbl

33. MOrdibr99

34. Twef

35. NT,tean

36. Sain20

37. ReLam37

38. Rorhl. Treatment of murine colitis by Lactococcus lactisng interleukin-10. Science. 2000;289:1352---5.

B, Dessein R, Marceau M, Poiret S, Chamaillard M,et al. Prevention and treatment of colitis with Lacto-

lactis secreting the immunomodulatory Yersinia LcrV. Gastroenterology. 2007;133:862---74.M, Nagpal R, Verma V, Kumar A, Kaur N, Hemalathal. Probiotic metabolites as epigenetic targets in thetion of colon cancer. Nutr Rev. 2013;71:23---34.i HF, Rahimzadeh G, Fazeli MR, Mehrazma M, Salehiluation of wound healing activities of ker products.2012;38:719---23.T, Tzortzis G, Charalampopoulos D, Khutoryanskiy VV.ncapsulation of probiotics for gastrointestinal deliv-ontrol Release. 2012;162:56---67.M, Nagpal R, Kumar R, Hemalatha R, Verma V,A, et al. Cholesterol-lowering probiotics as potentialrapeutics for metabolic diseases. Exp Diabetes Res.012:902917.n Abbeele P, Grootaert C, Possemiers S, Verstraete W,en K, et al. In vitro model to study the modulationmucin-adhered bacterial community. Appl Microbiolnol. 2009;83:349---59.lane S, Furrie E, Kennedy A, Cummings JH, Macfar-T. Mucosal bacteria in ulcerative colitis. Br J Nutr.3:S67---72.ing B, Darfeuille-Michaud A. The commensal micro-nd enteropathogens in the pathogenesis of inamma-wel diseases. Gastroenterology. 2011;140:1720---8.

S, Claes I, Tytgat HL, Verhoeven TL, Marien E, vonki I, et al. Functional analysis of Lactobacillus rham-G pili in relation to adhesion and immunomodulatorytions with intestinal epithelial cells. Appl Environiol. 2012;78:185---93.F, Nakayama M, Muto T, Okumura K. Effects of ated milk drink containing Lactobacillus casei strain

on the immune system in healthy human subjects.Biotechnol Biochem. 2000;64:2706---8.a K, Savilahti E, Pnk A, Meurman JH, Poussa T, Nsel. Effect of long term consumption of probiotic milkctions in children attending day care centres: doublerandomised trial. BMJ. 2001;322:1327.

S, Ikegami S, Kume A, Horiuchi H, Sasaki H, Reducing the risk of infection in the elderly by

intake of yoghurt fermented with Lactobacillus del-ii ssp. bulgaricus OLL1073R-1. Br J Nutr. 2010;104:06.an S, Stecksn-Blicks C. Probiotics and oral health

in children. Int J Paediatr Dent. 2008;18:3---10., Hatakka K, Savilahti E, Saxelin M, Pnk A, Poussa. Effect of long-term consumption of a probiotic bac-

Lactobacillus rhamnosus GG, in milk on dental cariesries risk in children. Caries Res. 2001;35:412---20.os SR. The importance of probiotic supplementationunction with orthodontic therapy. J N J Dent Assoc.7:10---3., Beuerman D, Heinemann C, Bruce AW. Probioticacillus dose required to restore and maintain a nor-ginal ora. FEMS Immunol Med Microbiol. 2001;32:

, Rossi T, Bertini M, Caccia G. The use of Lactobacillusosus in the therapy of bacterial vaginosis Evaluation


of clinical efcacy in a population of 40 women treated for24 months. Arch Gynecol Obstet. 2010;281:1065---9.

39. Andreeva P, Dimitrov A. The probiotic Lactobacillus aci-dophilus --- an alternative treatment of bacterial vaginosis.Akush

40. Cats AGraulsa Lactter py2003;1

41. UshiyaT, et aclarithGastro

42. ColladFerrsthe anagainst2005;2

43. Alfalehrisk ofanalys

44. Webersome c2012;2

45. SantosSesma gene c2008;1

46. FabianInuenof vitaMetab.

47. de VreSchrezcienc

48. Sousa B, Basthe bi1---25.

49. FischbCurr O

50. GorisseF, De acid adobact2257---6

51. Ando Aricinol2003;8

52. DecrooW. Isomixed its acti2005;1

53. PossemGonzlisoxanpotentintesti

54. HamiltPostgra

55. BorthaHecht stimulaintesti

56. De Boever P, Wouters R, Verschaeve L, Berckmans P,Schoeters G, Verstraete W. Protective effect of the bile salthydrolase-active Lactobacillus reuteri against bile salt cyto-toxicity. Appl Microbiol Biotechnol. 2000;53:709---14.

Smegs th

J Nuatz S-Nezacter04;7beer

Mecbactmunult vadim, Schnomood mcts. Iaved. Fes thearrho46---9ajewkoaj

nos1---5.streara A

the pstroajew

gastrd e06;4ustinkito

diarildreandaarrheajewith acouraula sfant oenteibaunsumriumute tr. 2ankeuterien: aPediatierr

mene et s re14;1ndenr theGinekol (Soia). 2002;41:29---31., Kuipers EJ, Bosschaert MA, Pot RG, Vandenbroucke-

CM, Kusters JG. Effect of frequent consumption ofobacillus casei-containing milk drink in Helicobac-lori-colonized subjects. Aliment Pharmacol Ther.7:429---35.ma A, Tanaka K, Aiba Y, Shiba T, Takagi A, Minel. Lactobacillus gasseri OLL2716 as a probiotic inromycin-resistant Helicobacter pylori infection. Jenterol Hepatol. 2003;18:986---91.o MC, Gonzlez A, Gonzlez R, Hernndez M,

MA, Sanz Y. Antimicrobial peptides are amongtagonistic metabolites produced by Bidobacterium

Helicobacter pylori. Int J Antimicrob Agents.5:385---91.

K, Anabrees J, Bassler D. Probiotics reduce the necrotizing enterocolitis in preterm infants: a meta-is. Neonatology. 2010;97:93---9.

TK, Polanco I. Gastrointestinal microbiota andhildren diseases: a review. Gastroenterol Res Pract.012:676585.

F, Vera JL, van der Heijden R, Valdez G, de Vos WM,F, et al. The complete coenzyme B12 biosynthesisluster of Lactobacillus reuteri CRL1098. Microbiology.54:81---93.

E, Majchrzak D, Dieminger B, Meyer E, Elmadfa I.ce of probiotic and conventional yoghurt on the statusmins B1 B2 and B6 in young healthy women. Ann Nutr

2008;52:29---36.se M, Stegelmann A, Richter B, Fenselau S, Laue C,enmeir J. Probiotics ---compensation for lactase insuf-y. Am J Clin Nutr. 2001;73:421S---9S.T, Paterson R, Moore V, Carlsson A, Abrahamssonit AW. The gastrointestinal microbiota as a site forotransformation of drugs. Int J Pharm. 2008;363:

ach MA. Antibiotics from microbes: converging to kill.pin Microbiol. 2009;12:520---7.n L, Raes K, Weckx S, Dannenberger D, LeroyVuyst L, et al. Production of conjugated linoleicnd conjugated linolenic acid isomers by Bi-erium species. Appl Microbiol Biotechnol. 2010;87:6., Ogawa J, Kishino S, Shimizu S. CLA production fromeic acid by lactic acid bacteria. J Am Oil Chem Soc.0:889---94.s K, Vanhemmens S, Cattoir S, Boon N, Verstraetelation and characterisation of an equol-producingmicrobial culture from a human faecal sample andvity under gastrointestinal conditions. Arch Microbiol.83:45---55.iers S, Rabot S, Espn JC, Bruneau A, Philippe C,ez-Sarras A, et al. Eubacterium limosum activatesthohumol from hops (Humuluslupulus L.) into the

phytoestrogen 8-prenylnaringenin in vitro and in ratne. J Nutr. 2008;138:1310---6.on-Miller JM. Probiotics and prebiotics in the elderly.d Med J. 2004;80:447---51.kur A, Gill RK, Tyagi S, Koutsouris A, Alrefai WA,GA, et al. The probiotic Lactobacillus acidophilustes chloride/hydroxyl exchange activity in human

nal epithelial cells. J Nutr. 2008;138:1355---9.

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58. GrElba20

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60. GhKJgeblje

61. SaRHcudi10

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66. Gudi

67. Szw

68. Chmintr

69. ThcoteacNu

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72. Vafot I, De Boever P, Verstraete W. Cholesterol lowering inrough enhanced bacterial bile salt hydrolase activity.tr. 1998;79:185---94., Mykknen H, Ouwehand AC, Juvonen R, Salminen S,mi H. Intestinal mucus alters the ability of probiotic

ia to bind aatoxin B1 in vitro. Appl Environ Microbiol.0:6306---8.doss J, Devi RS, Mary RR, Prabhavathi D, Vidyahenro J, et al. Effect of yoghurt containing Bi-erium lactis Bb12 on faecal excretion of secretoryoglobulin A and human beta-defensin 2 in healthyolunteers. Nutr J. 2011;10:138.i D, Flster-Holst R, de Vrese M, Winkler P, Hellerrezenmeir J. Effects of probiotic bacteria and theiric DNA on TH1/TH2-cytokineproduction by peripheralononuclear cells (PBMCs) of healthy and allergic sub-mmunobiology. 2008;213:677---92.ra JM, Bauman NA, Oung I, Perman JA, Yolkeneding of Bidobacterium bidum and Streptococ-rmophilus to infants in hospital for prevention ofea and shedding of rotavirus. Lancet. 1994;344:.ska H, Kotowska M, Mrukowicz JZ, Armanska M,czyk W. Efcacy of Lactobacillus GG in preventionocomial diarrhea in infants. J Pediatr. 2001;138:

tta E, Longo P, Laccisaglia A, Balbo L, Russo R, Mazza-, et al. Effect of Lactobacillus GG and breast-feedingrevention of rotavirus nosocomial infection. J Pediatrenterol Nutr. 2002;35:527---31.ska H, Setty M, Mrukowicz J, Guandalini S. Probioticsrointestinal diseases in children: hard and not-so-vidence of efcacy. J Pediatr Gastroenterol Nutr.2:454---75.a R, Kok FJ, van de Rest O, Fahmida U, Firmansyah A,W, et al. Randomized trial of probiotics and calciumrhea and respiratory tract infections in Indonesiann. Pediatrics. 2012;129:e1155---64.lini S. Probiotics for prevention and treatment ofa. J Clin Gastroenterol. 2011;45:S149---53.ska H, Mrukowicz JZ. Use of probiotics in childrenute diarrhea. Paediatr Drugs. 2005;7:111---22.qui JP, Van Egroo LD, Fichot MC. Acidied milk for-upplemented with Bidobacterium lactis: impact ondiarrhea in residential care settings. J Pediatr Gas-rol Nutr. 2004;38:288---92.lt H, Aubert-Jacquin C, Goulet O. Effects of long-termption of a fermented infant formula (with Bidobac-

breve c50 and Streptococcus thermophilus 065) ondiarrhea in healthy infants. J Pediatr Gastroenterol004;39:147---52.

M, Szajewska H. Lack of an effect of Lactobacillus DSM 17938 in preventing nosocomial diarrhea in chil-

randomized, double-blind, placebo-controlled trial.tr. 2012;161:40---3.ez-Castrellon P, Lopez-Velazquez G, Diaz-Garcia L,z-Gutierrez C, Mancilla-Ramirez J, Estevez-Jimenezal. Diarrhea in preschool children and Lactobacil-uteri: a randomized controlled trial. Pediatrics.33:e904---9.plas Y. Lactobacillus reuteri is an effective option

prevention of diarrhoea in preschool children but


may not be cost-effective in all settings. Evid Based Med.2014.

73. Szajewska H, Guarino A, Hojsak I, Indrio F, Kolacek S, ShamirR, et al. Use of probiotics for management of acute gas-troenteritis: a position paper by the ESPGHAN Working Groupfor Pro2014;5

74. Lund Bpossibl2001;3

75. Dinleyibacilluof acu2014;1

76. SzajewShamir17938 (gastroe

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86. PozzonE, Rothe prhospitablind, 2012;1

87. McFarlassociawith p2013;1

88. BraeggMorenobioticsby the terol N

89. Katelaris PH, Salam I, Farthing MJ. Lactobacilli to preventtravelers diarrhea? N Engl J Med. 1995;333:1360---1.

90. Hilton E, Kolakowski P, Singer C, Smith M. Efcacy of Lacto-bacillus GG as a diarrheal preventive in travelers. J TravelMed. 1997;4:41---3.

sanermis

trav90;2llariarm c89;5cFarl10;5nou-Znt paom twoperPontg LKse f09;1ertaetaryd irrtabausseitablmizeanca

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Nev galadobtr Mrteri, Decstroialysing Ylicobtestiildreajewe effbiotics and Prebiotics. J Pediatr Gastroenterol Nutr.8:531---9., Edlund C. Probiotic Enterococcus faecium strain is ae recipient of the vanA gene cluster. Clin Infect Dis.2:1384---5.ci EC, PROBAGE Study Group. Vandenplas Y. Lacto-s reuteri DSM 17938 effectively reduces the durationte diarrhoea in hospitalised children. Acta Paediatr.03:e300---5.ska H, Urbanska M, Chmielewska A, Weizman Z,

R. Meta-analysis: Lactobacillus reuteri strain DSMand the original strain ATCC 55730) for treating acutenteritis in children. Benef Microbes. 2014;5:285---93.B, Waspada IM, Gunardi H, Vandenplas Y. A doubleandomized trial showing probiotics to be ineffectivee diarrhea in Indonesian children. Indian J Pediatr.pub ahead of print].plas Y, De Hert S. Probiotical study group Cost/benetiotics in acute infectious gastroenteritis: spend toenef Microbes. 2012;3:189---94.itr N, Puwdee P, Tantibhaedhyangkul R. Cost-benets of the probiotic treatment of children hospitalizedte diarrhea in Bangkok. Thailand Southeast Asian Jed Public Health. 2013;44:1065---71.l S, Newberry SJ, Maher AR, Wang Z, Miles JN, Shan-, et al. Probiotics for the prevention and treatmentbiotic-associated diarrhea: a systematic review andnalysis. JAMA. 2012;307:1959---69.k EJ, Cremonini F, Meta-analysis:. probiotics intic-associated diarrhoea. Aliment Pharmacol Ther.5:1355---69.l S, Hiremath G, Dhingra U, Malik P, Deb S, Blackcacy of probiotics in prevention of acute diarrhoea:-analysis of masked, randomised, placebo-controlledLancet Infect Dis. 2006;6:374---82.and LV. Meta-analysis of probiotics for the preven-

antibiotic associated diarrhea and the treatmentstridium difcile disease. Am J Gastroenterol.01:812---22.on BC, Goldenberg JZ, Vandvik PO, Sun X, Guy-H. Probiotics for the prevention of pediatrictic-associated diarrhea. Cochrane Database Syst Rev.1):CD004827., Dolovich LR, Lee CH. Prevention of Clostridium dif-

nfection with Saccharomyces boulardii: a systematic. Can J Gastroenterol. 2009;23:817---21.i P, Riva A, Bellatorre AG, Amigoni M, Redaellinchetti A, et al. Saccharomyces boulardii forevention of antibiotic-associated diarrhea in adultlized patients: a single-center, randomized, double-placebo-controlled trial. Am J Gastroenterol.

07:922---31.and LV, Goh S. Preventing pediatric antibiotic-ted diarrhea and Clostridium difcile infectionsrobiotics: a meta-analysis. World J Meta-Anal.:102---20.er C, Chmielewska A, Decsi T, Kolacek S, Mihatsch W,

L, et al. Supplementation of infant formula with pro- and/or prebiotics: a systematic review and commentESPGHAN committee on nutrition. J Pediatr Gastroen-utr. 2011;52:238---50.

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106. Szthn PJ, Salminen S, Saxelin M, Hmlinen P, Ihantola-to A, Muurasniemi-Isoviita L, et al. Preventionellers diarrhoea by Lactobacillus GG. Ann Med.2:53---6.tsch H. Travellers diarrhea among Austrian tourists tolimate countries: II Clinical features. Eur J Epidemiol.:355---62.and LV. Probiotics and diarrhea. Ann Nutr Metab.7:10---1.ekri N, Blum S, Schiffrin EJ, von der Weid T. Diver-tterns of colonization and immune response elicitedo intestinal Lactobacillus strains that display similar

ties in vitro. Infect Immun. 2003;71:428---36. HL, Ericsson CD, Farthing MJ, Gorbach S, Picker-, Rombo L, et al. Expert review of the evidenceor prevention of travelers diarrhea. J Travel Med.6:149---60.s-Ceballos AA, Logan S, Bennett C, Macarthur C.

interventions for recurrent abdominal pain (RAP)itable bowel syndrome (IBS) in childhood. Cochranese Syst Rev. 2009;(1):CD003019.rman M, Michail S. The use of Lactobacillus GG ine bowel syndrome in children: a double-blind ran-d control trial. J Pediatr. 2005;147:197---201.villa R, Miniello V, Magist AM, De Canio A, Bucciliardi F, et al. A randomized controlled trial of Lac-lus GG in children with functional abdominal pain.ics. 2010;126:e1445---52.h A, Dziechciarz P, Szajewska H. Meta-analysis:acillus rhamnosus GG for abdominal pain-relatednal gastrointestinal disorders in childhood. Alimentcol Ther. 2011;33:1302---10.lini S, Magazz G, Chiaro A, La Balestra V, Di Nardoalan S, et al. VSL#3 improves symptoms in childrenritable bowel syndrome: a multicenter, randomized,o-controlled, double-blind, crossover study. J Pediatrenterol Nutr. 2010;51:24---30.kin B, Mahayosnond A, Theamboonlers A, Steenhoutnus NJ. Effect of a whey-predominant starter for-ontaining LCPUFAs and oligosaccharides (FOS/GOS)trointestinal comfort in infants. Asia Pac J Clin Nutr.9:473---80.o V, Sun SS, Storm H. Tolerance of an enteral for-ith insoluble and prebiotic ber in children withmised gastrointestinal function. J Am Diet Assoc.10:1728---33.n L, Kekkonen RA, Kajander K, Ahlroos T, Tynkkynen

ala R, et al. In school-aged children a combinationcto-oligosaccharides and Lactobacillus GG increasesacteria more than Lactobacillus GG on its own. Annetab. 2008;52:204---8.nk JJ, Ockeloen L, Benninga MA, Tabbers MM, Hilbinkkers-Kocken JM. Probiotics for childhood functionalntestinal disorders: a systematic review and meta-s. Acta Paediatr. 2014;103:365---72.J, Sheu BS. Probiotics-containing yogurts suppressacter pylori load and modify immune response and

nal microbiota in the Helicobacter pylori-infectedn. Helicobacter. 2012;17:297---304.ska H, Horvath A, Piwowarczyk A. Meta-analysis:ects of Saccharomyces boulardii supplementation on


Helicobacter pyl

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