Probiotic, Prebiotic, and Brain Development

19 Pages·2017·0.72 MB·English

nutrients
Review
Probiotic, Prebiotic, and Brain Development
TomásCerdó1,2,AliciaRuíz2,3,AntonioSuárez3andCristinaCampoy1,2,4,5,* ID
1 DepartmentofPaediatrics,SchoolofMedicine,UniversityofGranada,18016Granada,Spain;[email protected]
2 EURISTIKOSExcellenceCentreforPaediatricResearch,BiomedicalResearchCentre,UniversityofGranada,
18016Granada,Spain;[email protected]
3 DepartmentofBiochemistryandMolecularBiology2,BiomedicalResearchCentre,UniversityofGranada,
18016Granada,Spain;[email protected]
4 SpanishNetworkofBiomedicalResearchinEpidemiologyandPublicHealth(CIBERESP),
CarlosIIIInstitute,18016Granada,Spain
5 DepartmentofPaediatrics,FacultyofMedicine,UniversityofGranada,Av.delaInvestigación,11,
18016Granada,Spain
* Correspondence:[email protected];Tel.:[phone]
Received:8September2017;Accepted:10November2017;Published:14November2017
Abstract: Recently, a number of studies have demonstrated the existence of a link between the
emotional and cognitive centres of the brain and peripheral functions through the bi-directional
interactionbetweenthecentralnervoussystemandtheentericnervoussystem. Therefore,theuseof
bacteriaastherapeuticshasattractedmuchinterest. Recentresearchhasfoundthatthereareavariety
ofmechanismsbywhichbacteriacansignaltothebrainandinfluenceseveralprocessesinrelationto
neurotransmission,neurogenesis,andbehaviour. Dataderivedfrombothinvitroexperimentsand
invivoclinicaltrialshavesupportedsomeofthesenewhealthimplications. Whilerecentmolecular
advancementhasprovidedstrongindicationstosupportandjustifytheroleofthegutmicrobiota
onthegut–brainaxis,itisstillnotclearwhethermanipulationsthroughprobioticsandprebiotics
administrationcouldbebeneficialinthetreatmentofneurologicalproblems. Theunderstandingof
thegutmicrobiotaanditsactivitiesisessentialforthegenerationoffuturepersonalizedhealthcare
strategies.Here,weexploreandsummarizethepotentialbeneficialeffectsofprobioticsandprebiotics
intheneurodevelopmentalprocessandinthepreventionandtreatmentofcertainneurologicalhuman
diseases,highlightingcurrentandfutureperspectivesinthistopic.
Keywords: microbiota;prebiotics;probiotics;health;disease
1. Introduction
Themicro-organismsthatinhabitthehumangastrointestinaltract(GI)havebeenimplicatedin
the development and functioning of a number of basic physiological processes, such as digestion,
immunity,andthemaintenanceofhomeostasis. TheGImicrobiotamayalsoplayaroleinmultiple
diseases, rangingfrominflammationtoobesity[1,2]. Recently, manystudieshaveshownthatgut
microbiotaplayaveryimportantroleinthedevelopmentandfunctionofthecentralnervoussystem
(CNS) through specific channels, such as metabolic, neuroendocrine, and immune pathways [3].
Inparticular,theseresearchershavefoundbi-directionalcommunicationbetweenthebrainandthe
gutmicrobiota,denominatedthemicrobiota–gut–brainaxis[4–6].
Althoughthemolecularmechanismsbywhichthegutmicrobiotacommunicatewiththebrain
arenotyetclear,thelinkbetweenbothcomponentsiscurrentlyattributedtoimmunesignalsand
thevagusnerve. Cellularcomponentsproducedbygutmicrobiota,suchaslipopolysaccharide(LPS),
peptidoglycan,andflagellin,arerecognizedbypattern-recognitionreceptors(PRRs),suchasToll-like
receptors(TLRs),NOD-likereceptors(NLRs),orRIG-1-likereceptors(RLRs),onepithelialandimmune
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Nutrients2017,9,1247 2of19
cells,producingcytokines,hormones,andothermolecularsignals,whichwillactasneurotransmitters
withintheCNS[7]. Severalstudieshavefoundthat,inthedenselyinnervatedgut,thevagusnerveis
involvedinthebi-directionalcommunicationofthemicrobiota–gut–brainaxis[8,9],whileothershave
shownvagus-independenteffects[10,11]. Eitherway,asupplementingnutritiontherapywithspecific
probioticcommensalsandprebioticscanaltertheexcitabilityofentericnervoussystem(ENS)sensory
neurons [12–14]. Prebiotics-induced growth of probiotic members within the Bifidobacterium and
Lactobacillusgenerashowmultiplebeneficialeffectsonhostimmunityandphysiology[15]. Moreover,
strongeffectsofBifidobacteriumandLactobacillusspp. onthebrain–gutaxishavebeenreported[16].
This review summarizes current knowledge on the influence of the establishment of the gut
microbiotaincriticalneurodevelopmentalwindows,anddiscussesrecentfindingsontheinteractions
betweenthegutmicrobiotaandthehost’sbrain–gutaxiscommunications.Inaddition,currentresearch
ontheeffectsoftheadministrationofprobioticsandprebioticsinspecificneurologicaldisordersis
reviewed. Finally,recommendationsforfutureresearchonthistopicarealsodiscussed.
2. EstablishmentofIntestinalMicrobiotaduringEarlyNeurodevelopmentalWindows
Gutmicrobiotaestablishabeneficialcohabitationwiththehostthatwillprimeforhealthlaterin
life[17].Theassemblyofthegutmicrobiotaoccursduringthefirstthreeyearsoflife,startingfrombirth,
wherethereisarapidrateofcolonizationandexpansionofgutbacteriadominatedbyActinobacteria
and Proteobacteria that shifts towards one dominated by Firmicutes and Bacteroidetes, increasing
compositional diversity and stability while maturing into an adult-like state [18]. This process
coincides in time with the intense synaptogenesis and pruning in the cerebral cortex during early
life [18–20], ending in adolescence [21]. Therefore, perturbations of gut microbiota colonization
andmaturationbyenvironmentalfactorsmayinfluencebraindevelopment. Thedynamicsofthe
microbialecosystem’smaturationduringthiscriticalperiodofCNSdevelopmentisinfluencedby
severalenvironmentalfactors,suchasmother-to-childbacterialtransfer,modeofdelivery,andtypeof
feeding. Themother-to-childtransferofcommensalbacteriaintheuterushasbeenshowntoinfluence
aninfant’simmunesystemdevelopment[22,23]. Untilrecently,theideathatfoetusesweresterilein
theuterusandthatthemicrobialcolonizationofthenew-bornstartedduringandafterbirthhadbeen
widelyaccepted[24]. However,nowadays,thisbeliefhasbeenchallengedbyevidenceofmicrobes
inplacentaandothertissuessurroundingthefoetus,suchasumbilicalcordbloodaftervaginaland
caesareanbirth[25–27]. Severalstudieshaveanalysedthemeconiumofnew-bornbabiesandshowed
the presence of bacterial populations, including Enterococcus, Lactococcus, Escherichia, Leuconostoc,
andStreptococcus,thoughatlowlevels,concludingthatgutcolonizationoccursmainlyafterbirth[28].
Basedonthesefindings,prenatalprobioticinterventionhasbeenshowntomodulatetheexpression
of TLR-related genes in the placenta and foetal GI tract and to reduce atopic dermatitis [29,30].
Thus,prenatalandpostnatalmaternaloralprobiotictherapymayrepresentaneffectivemethodof
interventiontopreventpathologiessuchasallergy[31],atopicdiseases[32],andneurodevelopmental
disorders,reviewedbelow. Still,theoriginofthemicrobiotacolonizingtheplacentaisunknownand
resultshavetobecarefullyinterpreted,because,insampleswithlowmicrobialbiomass,suchasthose
fromplacenta,theriskofcontaminationishighwhenusinghigh-throughputsequencingmethods
basedonDNAamplification[29]. Furtherstudiesareneededtodiscernwhetherfoetuseshavecontact
withbacteriabeforebirthorarecolonizedduringandafterparturition.
Regardlessofmother-to-childtransmissionwithintheintrauterineenvironment,twodifferent
modesofmaternal–infanttransmissionduringdeliveryhavebeenproposed: (a)horizontal,inwhich
microbesaretakenupfromtheenvironmentforinfantsbornbycaesareansection;and(b)vertical,
in which vaginal microbes are transferred during parturition to the infants [33]. Infants delivered
byCaesareansectionaremorelikelytosufferseveraldiseases,suchasasthma,obesity,orallergies,
in adulthood [34]. Interestingly, a study carried out by Jasarevic et al. using a mouse model of
early prenatal stress found that changes in the vaginal microbiome were associated with shifts
in the abundance of Lactobacillus in the expression of maternal stress proteins related to vaginal
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immunity,inoffspringmetabolicprofilesrelatedtoenergybalance,andintheaminoacidprofilesof
thedevelopingbrain[35].
Thethirdstrongenvironmentalfactorthatinfluencesaninfant’sgutmicrobialdevelopmentas
wellasneurodevelopmentisthetypeoffeeding. Inrecentyears,severalstudieshavereportedthat
breastfeedingandparticularlyfullbreastfeedinghasbeneficialeffectsonchildneuropsychological
development[36]. Humanmilkistheoptimalfeedingsource,sinceitprovidesallthenutritionfactors
thataninfantneedsforhealthydevelopment. Humanmilkisnotsterile,and,duringbreastfeeding,
bacteriafrommother’sskinandmammaryglandviamaternaldendriticcellsandmacrophages[37]
aretransferredtothebaby[38]. Breast-fedinfantstendtocontainamoreuniformpopulationofgut
microbes dominated by Bifidobacterium and Lactobacillus [39], whereas formula-fed infants exhibit
higher proportions of Bacteroides, Clostridium, Streptococcus, Enterobacteria, and Veillonella spp. [21].
Bacteria belonging to the Bifidobacterium genus present in human milk are early colonizers that
characterize the gut microbial composition of healthy breast-fed new-born’s [40] with beneficial
functionsforthehost,suchastheaccelerationofthematurationoftheimmuneresponse,thelimitation
ofexcessiveinflammation,theimprovementoftheintestinalpermeability,andanincreaseofacetate
production[41]. Inmice,B.infantisproducesantidepressant-likeeffectsandnormalizesperipheral
pro-inflammatorycytokineandtryptophanconcentrations,bothofwhichhavebeenimplicatedin
depression[42–44]. Moreover,breastfeedinghasanadditionalroleintheestablishmentofaninfant’s
gutmicrobiota, sinceitcontainsbioactivemoleculesthatareincreasinglyrecognizedasdriversof
microbiotadevelopmentandoverallguthealth[45]. Amongthenutrientspresentinhumanmilk,
oligosaccharidesconstitutethethird-mostabundantclassofmoleculesintermsofconcentrationafter
lactoseandlipids. Nowadays,morethan200differentstructureshavebeenidentifiedashumanmilk
oligosaccharides(HMOs)[35]. HMOscanactasprebiotics,stimulatingthegrowthofspecificbacterial
groupssuchasStaphylococci[46]andBifidobacteria[47].
Theseresultssuggestthatpostnatalneurodevelopmentandgutmicrobiotaestablishmentco-occur,
suggesting the intriguing possibility of a bi-directional regulation of each other’s maturation [48].
Furtherstudiesareneededinordertoclarifywhetherthosedifferencesinbacterialacquisitionduring
earlylifeleadtoneurodevelopmentaldifferencesininfants.
3. GutMicrobiota–BrainAxis
The brain and the gut reciprocally influence each other by constant communication
(Figure 1). The brain–gut–microbiota axis includes the CNS, the endocrine-immune system,
thehypothalamus–pituitary–adrenal(HPA)axis,theautonomicnervoussystem,theENS,andthe
gutmicrobiota[49]. Thisbi-directionalcommunicationenablessignallingfromthebraintoinfluence
motor,sensory,andsecretorymodalitiesoftheGItract,andconversely,signallingfromtheguttoaffect
brainfunction,mostnotablythehypothalamusandamygdalathatareimplicatedinstress[50–52].
Though communication between brain and gut was realized in the middle of the nineteenth
century [53], gut microorganisms had not been considered important for the development and
functionoftheCNSorforbraindiseasesuntilrecently,expandingthetermtomicrobiome–gut–brain
axis[54]. Inhumans,evidenceofmicrobiome–gut–brainaxisinteractionshavebeenobtainedfromthe
associationofshiftsingutmicrobiotacompositionwithcentralnervousdisorders(i.e.,autismspectrum
disorder(ASD)andanxietyanddepressivebehaviours)andfunctionalgastrointestinaldisorders[54].
Mostofthedatademonstratingtheroleofthemicrobiotainthegut–brainaxishavebeenobtainedfrom
germ-freeanimals[55]. Micefedwithprebioticsshoweddiminishedstressor-inducedanxiety-like
behavior [56]. In a mouse model of ASD, Buffington et al. showed that a maternal high-fat diet
reducedthenumberofoxytocinimmunoreactiveneuronsinthehypothalamusandinduceddysbiosis
thatwasrestoredbyacommensalLactobacillusreuteristrain[57]. InamousemodelofParkinson’s
disease,Sampsonetal. highlightedanegativeinteractioninthemicrobiome–gut–brainaxisbecause
the absence of gut bacteria decreased aggregated misfolded α-synuclein levels and reduced the
severity of the animals’ abnormal movements. The authors showed that short chain fatty acids
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(SCFA), such as acetate, propionate, and butyrate, the end products of anaerobic fermentation of
dietaryfibreandstarch,promotedamicroglia-mediatedimmuneresponseandincreasedα-synuclein
aggregation,causingmovementabnormalities[58]. Butyratecancrosstheblood-brainbarrier(BBB)
andproduceadose-dependentincreaseinneuronalandglialnuclearhistoneH3acetylationinmice
duetoitspotentialtoinhibithistonedeacetylation[59]. Anothermetabolitewhoselevelsinthehost
are influenced by gut microbiota is tryptophan, the amino acid precursor of the neurotransmitter
serotonin,andkynurenine,themainbreakdownproductoftryptophancatabolism[60]. Kynurenine
intakeduringgestationandpostnataldevelopment,atimeframeinwhichthematernalandoffspring
microbiotaundergomajorcompositionalandfunctionalremodelling,producedneurochemicaland
cognitivedeficitslaterinadulthood[61]. Theprenatalinhibitionofkynureninesynthesismodified
hippocampal neuron morphology and changed neocortical and cerebellar protein expression that
persistedintoadulthood.Ingerm-freeandinantibiotic-inducedmicrobiota-depletedmice,despite
increased circulating tryptophan levels, serotonin and kynurenin availabilities were decreased,
suggestingthatgutmicrobiotamodulatedkynureninmetabolism[62].Distinctgutmicrobialspecies
affecthostphysiology,producingdiverseneuromoleculesinvolvedinmoodregulation. Lactobacillus
andBifidobacteriumspp.generategamma-aminobutyricacid(GABA).Candida,Streptococcus,Escherichia,
andEnterococcusspp. synthesiseserotoninwhileBacillusspp. producesdopamine[63].
Gut microbiota also influence the regulation of BBB integrity. The BBB is an active interface
betweensystemiccirculationandtheCNSthatmaintainsbrainhomeostasisbypreventingtheentry
ofpotentiallytoxicorharmfulsubstancesandregulatesthetransportofnutrientsandtheremoval
ofmetabolites[64]. Branisteetal. (2014)[65]showedthatthetransplantationofgutmicrobiotainto
germ-freemicenormalizedBBBpermeabilityandupregulatedtheexpressionoftightjunctionproteins.
Therefore,gutmicrobiotahaveakeyroleinregulatingBBBpermeability,suggestingthatthematernal
gutmicrobiomeinfluencesanoffspring’sBBBintegrity. Togetherwiththeresultsdiscussedinthe
previoussection,thesefindingsopenanintriguingquestiononthemechanismbywhichamother’s
gutmicrobiotacooperateinregulatingBBBintegrityandultimatelybrainfunctiondevelopment.
Gutmicrobiotahavedirecteffectsontheimmunesystem, whichconstitutesanotherrouteof
communicationbetweengutmicrobesandthebrain. Thesignallingmoleculesoftheimmunesystem,
cytokinesandchemokines,accessthebrainfromtheperipheryviathevagusnerveordirectlyvia
thecircumventricularorgans[66]. Theadministrationofrifaximin(anon-systemic,broad-spectrum
antibiotic)tostressedratsincreasedtheabundanceofLactobacillusintheileumandtheexpressionof
thetightjunctionproteinoccludinwhiledecreasingtheexpressionofpro-inflammatoryinterleukin17,
interleukin6,andtumournecrosisfactorαmRNA[67].
Since many of the above effects have been observed during early life, it is plausible that
anenvironmentallyinduceddysbiosisofinfants’microbiota(e.g.,modeofbirth,maternaltransmission
of a suboptimal microbiota, antibiotics) may generate altered patterns of microbial metabolites
withdetrimentaleffectsinhumanCNSdevelopment. Furtherresearchisneededtounravelthese
mechanismsanddevelopprobioticsorprebioticstherapiesthatshapegutmicrobialcompositionand
metabolismtoultimatelymodulateCNSdevelopment.
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Nutrients 2017, 9, 1247 5 of 18

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4. Probiotics
4. Probiotics
In 2001, the Food and Agriculture Organization of the United Nations and the World Health
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(SNacAchFaLrDom),yaclelteersg hyavdeis beeaesnes s,uagngdeastsetdh mtoa p.lTahye ay raollseo inp rfoigmhotitnegp hroutmecatnio dnisaegaasienss, tsautcohp aics dniosne-aaslecoinhothliec
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baloswo erleddiusecea stehse( IdBuDrsa)t,icoenl iaocf dainsteiabsieo,timc etthaebroalpicy,s yannddr ormedeuacne dsydmiabpetotems [s7e2v,7e3r]i.ty in immune-related
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idniarbeecetenst [y7e2a,7rs3](.T able1). Psychobioticsaredefinedasliveorganismsthat,wheningestedinadequate
amouTnhtes, pseroardcuhc efobre nperfiocbiaiolthiecas ltthhaetff eccatns toafpfeactite ncotsgsnuitfifverei nfgunfrcotmionpss,y ckhnioawtrinc iallsn epsssy[7ch4]o.bDioetpicres,s shioans
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min oaoddeqouraltoes samofoiunntetsr,e sptraondducaen bxeienteyfiacfifael chtienaglthap epffeetcittes aton dpastlieeenpts. Msueffsesraionugd firoemta pl.s[y7c5h,7ia6t]rrice pilolnrteesds
a[74d]o. uDbleep-brelisnsdio,np laisc ebcuo-rcroennttlryo llae d,mraajnodr ompsiyzcehdiasttruicd ydwishoredreera min uldtiesvpeelcoipeesdp rcoobuionttirciecso, ntaanindi nigs
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weto aml. e[n75f,o7r63] 0redpaoyrst.eTdh ais dtoreuabtlme-ebnlitnrdes, uplltaecdebino-acodnetcrroelalesed,i nratnhdeogmloibzaelds csoturedsyo wfthheereh oas mpiutalltiasnpxecieietys
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(aHdmSCinLi-s9t0e)reddu teot ohetahlethdye cwreoamseeno ffothr e30su dba-sycso. rTeshios ftsreoamtmateiznat tiroensu,ldteedp riens saio dne,carnedasea nigne rth–he ogsltoilbitayl
sscpohreerse so.f Itnhea hcooshpoitratl oafnx1i2e4tyh aenadlt hdyephruemssiaonns ,scBaelen t(oHnAeDtsa) l.anredp tohrete gdlotbhaalt stehveercitoyn siundmepxt ioofn thoef
LHaocptokbiancsil lsuysmcapsteoi-mcos ncthaienciknlgisty o(HguSrCtLi-m90p)r odvueed ttoh ethsee lfd-erecpreoarstee dofm tohoed soufb-tshcoosreesw ohfo sseommaotoizdatwioans,
depression, and anger–hostility spheres. In a cohort of 124 healthy humans, Benton et al. reported
that the consumption of Lactobacillus casei-containing yogurt improved the self-reported mood of
Nutrients2017,9,1247 6of19
initially poor [77]. Similarly, Steenbergen et al. reported a significantly reduced overall cognitive
reactivitytodepression,inparticularaggressiveandruminativethoughts,infortyhealthyyoungadults
thatconsumedeitheraprobioticsupplementorplacebofor4weeks[78]. Recently,Akkashehetal.
showed that the consumption of a probiotic supplement significantly decreased Beck Depression
Inventory (BDI) scores, indicating overall improved symptoms, including mood, in 40 patients
diagnosed with depression [79]. Conversely, Marcos et al. reported that probiotics decreased,
respectively,levelsofstressandanxietyassessedusingthestate-traitanxietyinventory(STAI)that
remainedunchangedinsubjectsunderacademicexaminationstress[80]. Inarecentstudycarried
outbyRomijnetal.[81],administeringamultispeciesprobioticcontainingL.helveticusandB.longum
in79participantsthatwerenottakingpsychotropicmedicationsatthatmomentandwithatleast
moderatescoresonself-reportmoodmeasures,foundnoevidencethattheprobioticformulationwas
effective in treating low mood or in moderating the levels of inflammatory and other biomarkers.
Improvedcognitivefunction(neuropsychologicalandcognitivefatigue)wasreportedbyChungetal.,
whichtestedaL.helveticus-fermentedmilkinhealthy60–75yearolds,thoughnoeffectsonstressor
geriatricdepressionsymptomswereobserved[82].
Probiotics affect mood by their ability to modulate pain in the gut. A recent study reported
thattheadministrationofLactobacillusreuteriDSM17938inthetreatmentofchildrenwithfunctional
abdominal pain (FAP) and irritable bowel syndrome (IBS) is associated with a possible reduction
of the intensity of pain [83]. In 35 patients suffering from chronic fatigue syndrome, Rao et al.
showed that while the consumption of the probiotic improved anxiety scores, it had no effect
on depressive symptoms [84]. Giannetti et al. also reported that a probiotic mixture of B. infantis
M-63,B.breveM-16V,andBlongumBB536wasassociatedwithimprovementinchildrenwithIBS,
butnotinchildrenwithfunctionaldyspepsia(FD)[85]. Inhealthywomenwithoutgastrointestinal
orpsychiatricsymptoms,theconsumptionofafermentedmilkproductcontainingB.animalissubsp.
lactis,Streptococcusthermophilus,Lactobacillusbulgaricus,andL.lactissubsp. lactisresultedinrobust
alterationsinactivityinthebrainregionsthatcontrolthecentralprocessingofemotionsandsensations,
asobservedbyfunctionalmagneticresonanceimaging[86].
Nutrients2017,9,1247 7of19
Table1.Studiesevaluatingprobioticssupplementationoncentralnervoussystem(CNS)disorders.
Study(Reference) CohortPopulation ProbioticUsed KeyFindings
55healthyhumanvolunteersplus25subjectswith
Beneficialeffectsonanxietyanddepressionrelatedbehaviors
urinaryfreecortisol(UFC)levelslessthan LactobacillushelveticusR0052andBifidobacteriumlongum
Messaoudietal.(2011)[75,76] inhealthyhumanvolunteersandvolunteerswithlowerlevels
50ng/mL(lessstressedsubjects),10subjects R0175(PF)
ofcortisol
receivedtheprobioticand15placebo.
124healthyadultsvolunteerswererandomly Theconsumptionofaprobiotic-containingyoghurtimproved
Bentonetal.(2007)[77] allocatedtoagroupthatconsumed,onadailybasis, LactobacilluscaseiShirota themoodofthosewhosemoodwasinitiallypoor.However,
aprobiotic-containingmilkdrinkoraplacebo therewasnotanincreasedfrequencyofdefaecation.
40healthyyoungadultswererandomlyassignedto BifidobacteriumbifidumW23,BifidobacteriumlactisW52, Participantswhoreceivedmultispeciesprobioticsshowed
receivea4-weekinterventionofeitherplaceboor LactobacillusacidophilusW37,LactobacillusbrevisW63, asignificantlyreducedoverallcognitivereactivitytosadmood,
Steenbergenetal.(2015)[78]
multispeciesprobioticsinatriple-blindintervention LactobacilluscaseiW56,LactobacillussalivariusW24, whichwaslargelyaccountedforbyreducedruminationand
assessmentdesign. andLactococcuslactis(W19andW58) aggressivethoughts.
40patientswithadiagnosisofmajordepressive
Lactobacillusacidophilus,Lactobacilluscasei, Patientswhoreceivedprobioticsupplementshadsignificantly
Akkashehetal.(2016)[79] disorder(MDD)whoseagerangedbetween20and
andBifidobacteriumbifidum. decreasedBeckDepressionInventorytotalscores
55yearswererandomized.
Lactobacillusdelbrueckiisubsp.bulgaricusand
Marcosetal.(2004)[80] 136universitystudentswererandomized. Streptococcussalivariussubsp.thermophilusplus Therewasnosignificanttreatmenteffectonanxiety.
LactobacilluscaseiDN-114001
79participantsnotcurrentlytakingpsychotropic
medicationswithatleastmoderatescoreson
Nosignificantdifferencewasfoundbetweentheprobioticand
Romijnetal.(2017)[81] self-reportmoodmeasures.Participantswere LactobacillushelveticusandBifidobacteriumlongum
placebogroupsonanypsychologicaloutcomemeasured.
randomlyallocatedtoreceiveaprobiotic
preparationorplacebo.
55childrenwithagebetween4and18yearsold,
AdministrationofL.reuteriDSM17938wasassociatedwith
diagnosedasfunctionalabdominalpain(FAP)or
Jadrešinetal.(2017)[83] LactobacillusreuteriDSM17938 apossiblereductionoftheintensityofpainandsignificantly
irritablebowelsyndrome(IBS)were
moredayswithoutpaininchildrenwithFAPandIBS
randomlyallocated.
48childrenwithIBSagedbetween8and17.9years
BifidobacteriuminfantisM-63,breveM-16V, InchildrenwithIBSamixtureofBifidobacteriaisassociatedwith
Giannettietal.(2016)[85] and25withfunctionaldyspepsia(FD)withage
andlongumBB536 improvementinabdominalpain(AP)andqualityoflife(QoL).
between8and16.6yearswererandomized.
Theprobioticsupplementationlettoasignificantdecreasein
Kałuz˙na-Czaplin´skaetal. D-arabinitol(DA)andtheratioofD-/L-arabinitol(DA/LA)
22autisticchildren. Lactobacillusacidophilus
(2012)[87] andtoasignificantimprovementinabilityofconcentration
andcarryingoutorders
88%reportedadecreaseintotalautismtreatmentevaluation
Delpro®(Lactocillusacidophilus,Lactobacilluscasei, checklist(ATEC)score,animprovementofASDsymptoms.
Westetal.(2013)[88] 33ASDchildren. Lactobacillusdelbruecki,Bifidobacterialongum, ParticipantsalsohadsignificantimprovementsinallATEC
Bifidobacteriabifidum) domains(speech/language/communication,sociability,
sensory/cognitiveawareness,andhealth/physical/behavior)
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Table1.Cont.
Study(Reference) CohortPopulation ProbioticUsed KeyFindings
Probioticdietsupplementationnormalizedthe
“ChildrenDophilus”containingthreestrainsof Bacteroidetes/Firmicutesratio,Desulfovibriospp.andtheamount
10childrenwithautism,9siblingsand
Tomovaetal.(2015)[89] Lactobacillus(60%),twostrainsofBifidobacterium(25%), ofBifidobacteriumspp.infecesofautisticchildren.
10healthychildren.
andonestrainofStreptococcus(15%) Nosignificantdifferencewasfoundtoreducesymptom
severityinpatientswithautism.
“Vivomixx®”(onestrainofStreptococcusthermophilus
100preschoolerswithASDonthebasisof DSM24731,threestrainsofBifidobacterium
asymptomseverityindexspecificto (BifidobacteriumbreveDSM24732,B.longumDSM24736,
Santocchietal.(2016)[90] gastrointestinal(GI)disorders.Patientswithand B.infantisDSM24737),andfourstrainsofLactobacillus Ongoingstudy
withoutGIdisorderswereblindrandomizedto (LactobacillusacidophilusDSM24735,Lactobacillus
regulardietwithprobioticsorwithplacebo plantarumDSM24730,LactobacillusparacaseiDSM24733,
Lactobacillusdelbrueckiisubsp.bulgaricusDSM24734))
Nosignificantdifferencewasfoundtoreducesymptom
32patientshealthyand33patientswith
Dickersonetal.(2014)[91]and LactobacillusrhamnosusstrainGGandBifidobacterium severityinpatientswithschizophrenia.Probioticregulate
schizophreniameetingDSM-IVcriteriaandwithat
Tomasiketal.(2015)[92] animalissubsp.lactisstrainBb12 immuneandintestinalepithelialcellsthroughtheIL-17family
leastmoderatelyseverepsychoticsymptoms
ofcytokines
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Probioticshavebeentestedtonormalizegutmicrobialcompositionandmetabolism,enhance
gut barrier, and relieve patients suffering from ASD. In 2012, Kaluzna-Czaplinska and Blaszczyk
reportedthattheadministrationofLactobacillusacidophilusin22ASDsubjectsdecreasedD-arabinitol
concentration and the ratio of D-arabinitol to L-arabinitol in urine, and improved their ability
to follow directions, as demonstrated through a comparison with data collected before the
treatment [87]. Another study reported that a combination of Lactobacillus acidophilus, L. casei,
Lactobacillusdelbrueckii,B.longumandBifidobacteriumbifidum,formulatedwiththeimunomodulator
Del-Immune V (Lactobacillus rhamnosus V lysate), decreased the severity of ASD symptoms and
improved GI symptoms in 33 children [88]. Moreover, a recent study of “Children Dophilus”
(a combination of three species of Lactobacillus, two species of Bifidobacterium and one strain of
Streptococcus)in10ASDchildrenshowedhigherGIdysfunctioninASDchildrenandsiblingsand
averystrongassociationoftheamountofDesulfovibriospp. withtheseverityofautism. Afterthe
intervention,theBacteroidetes/Firmicutesratio,Desulfovibriospp.,andtheamountofBifidobacterium
spp. were normalized in faeces of autistic children [89]. However, the effects of treatments with
probioticsonchildrenwithASDneedtobeevaluatedthroughrigorous,controlledtrials. Inarecent
clinicalstudycurrentlyinprogress,Santocchietal. areprovidingamultispeciesprobiotic(onestrain
of S. thermophilus DSM 24731, three strains of Bifidobacterium (B. breve DSM 24732, B. longum
DSM24736,andB.infantisDSM24737),andfourstrainsofLactobacillus(L.acidophilusDSM24735,
LactobacillusplantarumDSM24730,LactobacillusparacaseiDSM24733,andL.delbrueckiisubsp. bulgaricus
DSM24734)toagroupof100pre-schoolerswithASD.Thisstudywilltrytoprovidenewinsightsto
clinicalandneurophysiologicalpatternsinresponsetoaprobioticmixtureinASDpatients[90].
Probioticsarealsotestedinthetreatmentofschizophreniaandbipolardisorder. Oneofthefirst
trialsofprobioticcompoundsinschizophreniausedacombinedprobioticofL.rhammosusstrainGG
andB.animalssubsp. LactisstrainBb12. Theresultsshowednosignificantdifferenceinpsychiatric
symptom severity between probiotic and placebo supplementation [91]. However, other studies
havefoundthatprobioticsupplementationsignificantlyaltersthelevelsofseveralserumproteins,
includingthevonWillebrandfactorandthebrain-derivedneurotrophicfactor,andloweredthelevel
ofantibodiestothefungusCandidaalbicans[92,93].
Despitethatthemajorityofthestudiesfoundpositiveresultsonsymptomsintheseneurological
disorders,futurestudiesareneededtoidentifypotentialprobioticsfortheeffectivemodulationof
thesedisordersaswellastodefineprobioticsriskintherapeuticinterventions. Gutmicrobialstudies
thatuse16SrRNAgenesequencingtocharacterizebacteriamustconsiderthathighlysimilarbacteria
(higherthan97%sequenceidentity)canhavelargedifferencesingenomicsequencesandprofound
differencesingrowthandmetabolism. Hence,itisimportanttocharacterizeprobioticstothestrain
level and apply next-generation sequencing techniques to analyse the functions encoded by their
genome[94]. Therefore,theeffectsofoneprobioticstrainshouldnotbegeneralizedtootherswithout
confirmationinseparatestudies.
5. Prebiotics
Althoughtheconceptofaprebioticwasfirstdefinedin1995byGibson,thecurrentdefinitionof
aprebioticistheoneproposedbytheInternationalScientificAssociationforProbioticsandPrebiotics
(ISAPP):asubstratethatisselectivelyutilizedbyhostmicro-organismsandconfersahealthbenefit[95].
The group of substances recognized for their ability to influence gastrointestinal health comprise
certainnon-digestibleoligosaccharides(NDOs),solublefermentablefibres,andHMOs. NDOsare
low molecular weight carbohydrates in nature that are intermediates between simple sugars and
polysaccharides. TheuseofNDOsasprebioticshasrapidlyincreasedbecausetheenrichmentofadiet
withNDOsprovidestheopportunitytoimprovethegutmicrobialecosystem, includingbacterial
populations, biochemical profiles, and physiological effects [96]. Fibre influences satiety by the
followingtwomechanisms. Oneisbyincreasingthechewingtimeoffibre-richfoods,whichpromotes
salivaandgastricacidproductionandincreasesgastricdistension,triggeringafferentvagalsignalsof
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fullnesscontributingtothisend. Theothermechanismisbyslowinggastricemptyinganddecreasing
therateofglucoseabsorptioninthesmallintestine. Consequently,theinsulinresponsemayalsobe
attenuated;thisissometimescorrelatedwithsatiationandsatiety[97]. Varioushormones(i.e.,ghrelin,
thepolypeptideYY,andtheglucagon-likepeptide)havebeenrelatedtosatiety,andaresenttothe
brain,wheretheyregulatefoodintakeandoverallenergybalance[98].
Though prebiotic therapies potentially could be beneficial for children with a genetic
pre-dispositiontodevelopASDorattentiondeficithyperactivitydisorderbecauseoftheirselective
enhancementofLactobacilliandBifidobacteriagrowth[99],asmallnumberofstudieshasexamined
theeffectoftheseprebioticsondisordersrelatedtoCNS(Table2). Inductiveevidencethatprebiotics
modulated emotional satisfaction was provided by Hume et al., who investigated the effect of
oligofructose-enriched inulin/d administration versus a placebo (maltodextrin) in a randomized,
double-blind,placebo-controlledtrialwith42children(whowereaged7–12andwereoverweightand
obese)[100]. Prebioticsupplementationimprovedsubjectiveappetiteratings,reducingenergyintake
inolderbutnotinyoungerchildren.
In a cohort of healthy male and female subjects (n = 45), Schmidt et al. tested the intake of
fructo-oligosaccharides(FOS)andBimuno®-galactooligosaccharides(B-GOS),andreportedthatonly
B-GOSreducedthewaking-cortisolresponse[101]. Exaggeratedwakingcortisolisabiomarkerof
emotionaldisturbances,suchasdepression[102]. Besidesthis,thesubjectsalsoprovidedmeasures
of vigilance, or attention to negative stimuli, which is also a behavioral marker of anxiety and
depression[103]. B-GOSattenuatedvigilance,suggestingareductioninanxietyanddepression[104].
Vandenbergetal. foundnoevidencethattheuseofshort-chaingalacto-oligosaccharides/long-chain
fructo-oligosaccharides/pectin-derived acidic oligosaccharides in preterm infants at 24 months
improves neurodevelopmental outcomes [105]. LeCouffe et al. studied the effect of an enteral
supplementationofaprebioticmixture(neutralandacidicoligosaccharides)intheneonatalperiod
andfoundnoeffectonneurodevelopment[106],thoughlowerBifidobacteriacountsareassociatedwith
seriousneonatalinfectionsandlowerneurodevelopmentaloutcomes.
More studies are required to determine whether prebiotics exert a beneficial effect on
neurodevelopmentaldisordersininfants,andtounderstandthemechanismofaction,bystimulating
certainbacterialtaxaorbacterialactivitieswithingutmicrobiota. Efficacy,safety,anddosingschedules
shouldbeestablishedforeachprebioticproductinlong-termfollow-upstudies.