Immunomodulatorydietarypolysaccharidesa systematicreviewoftheliterature JaneERamberg ErikaDNelsonRobertASinnott Abstract Background Alargebodyofliteraturesuggeststhatcertainpolysaccharidesaffect ID: 399880
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REVIEWOpenAccess Immunomodulatorydietarypolysaccharides:a systematicreviewoftheliterature JaneERamberg * ,ErikaDNelson,RobertASinnott Abstract Background: Alargebodyofliteraturesuggeststhatcertainpolysaccharidesaffectimmunesystemfunction.Much ofthisliterature,however,consistsof invitro studiesorstudiesinwhichpolysaccharideswereinjected.Their immunologiceffectsfollowingoraladministrationislessclear.Thepurposeofthissystematicreviewwasto consolidateandevaluatetheavailabledataregardingthespecificimmunologiceffectsofdietarypolysaccharides. Methods: StudieswereidentifiedbyconductingPubMedandGoogleScholarelectronicsearchesandthrough reviewsofpolysaccharidearticlebibliographies.OnlyarticlespublishedinEnglishwereincludedinthisreview.Two Subsequentsearcheswereconductedtogatherinformationaboutpolysaccharidesafety,structureand composition,anddisposition. Results: Wefound62publicationsreportingstatisticallysignificanteffectsoforallyingestedglucans,pectins, heteroglycans,glucomannans,fucoidans,galactomannans,arabinogalactansandmixedpolysaccharideproductsin rodents.Fifteencontrolledhumanstudiesreportedthatoralglucans,arabinogalactans,heteroglycans,and fucoidansexertedsignificanteffects.Althoughsomestudiesinvestigatedanti-inflammatoryeffects,moststudies investigatedtheabilityoforalpolysaccharidestostimulatetheimmunesystem.Thesestudies,aswellassafetyand toxicitystudies,suggestthatthesepolysaccharideproductsappeartobelargelywell-tolerated. Conclusions: Takenasawhole,theoralpolysaccharideliteratureishighlyheterogenousandisnotsufficientto supportbroadproductstructure/functiongeneralizations.Numerousdietarypolysaccharides,particularlyglucans, appeartoelicitdiverseimmunomodulatoryeffectsinnumerousanimaltissues,includingtheblood,GItractand spleen.Glucanextractsfromthe Trametesversicolor mushroomimprovedsurvivalandimmunefunctioninhuman RCTsofcancerpatients;glucans,arabinogalactansandfucoidanselicitedimmunomodulatoryeffectsincontrolled studiesofhealthyadultsandpatientswithcankersoresandseasonalallergies.Thisreviewprovidesafoundation thatcanservetoguidefutureresearchonimmunemodulationbywell-characterizedpolysaccharidecompounds. Background Polysaccharide-richfungiandplantshavebeen employedforcenturiesbyculturesaroundtheworldfor theirdietaryandmedicinalbenefits[1-5].Oftenthought tomerelysupportnormalbowelfunctionandblood glucoseandlipidlevels[6-8 ],certainpolysaccharides toexertmarkedeffectsonimmunesystemfunction, inflammationandcancers[9-11].Manyofthesechemi- callyandstructurallydiverse,non-topoorly-digestible polysaccharideshavebeenshowntobeneficiallyaffect oneormoretargetedcellularfunctions invitro [11-16], butmuchofthe invivo literatureconsistsofstudiesin whichpolysaccharideswereinjected[1,2].Forclinicians andscientistsinterestedinimmunologiceffectsfollow- ingdietaryintake,thevalueofsuchstudiesisuncertain. Polysaccharidesthateliciteffects invitro orbyinjection maybeineffectiveorhavedifferenteffectswhentaken orally[17].Wethusdecidedtoconductasystematic reviewtoevaluatethespecificimmunologiceffectsof dietarypolysaccharideproductsonrodentsandhuman subjects. *Correspondence:jramberg@mannatech.com Mannatech ,Incorporated,600S.RoyalLane,Suite200,Coppell,TX75019 USA Ramberg etal . NutritionJournal 2010, 9 :54 http://www.nutritionj.com/content/9/1/54 ©2010Rambergetal;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and reproductioninanymedium,providedtheoriginalworkisproperlycited. MethodsLiteraturereviewStudieswereidentifiedbyconductingelectronicsearchesofPubMedandGoogleScholarfromtheirinceptiontotheendofOctober2009.Thereferencelistsoftheselectedarticleswerecheckedforadditionalstudiesthatwerenotoriginallyfoundinthesearch.StudyselectionanddataextractionThefollowingsearchtermswerecombinedwiththetermpolysaccharide:dietaryANDimmune,ororalANDimmune,ordietaryANDinflammation,ororalANDinflammation.Whenspecificpolysaccharidesorpolysaccharide-richplantsandfungiwereidentified,furthersearcheswereconductedusingtheirnameswiththesamesearchterms.Studieswereselectedbasedonthefollowinginclusioncriteria:1.Rodentorhumanstudies2.Thepresenceoftestgroupandcontrolgroup(usingeitherplacebo,crossover,sham,ornormalcare)3.Studiesreportingstatisticallysignificantimmuno-modulatoryeffects4.Englishlanguage5.StudiespublisheduptoOctober2009.Tworesearchers(JER,EDN)reviewedthelistofuniquearticlesforstudiesthatfittheinclusioncriteria.Uncertaintiesoverstudyinclusionwerediscussedbetweentheresearchersandresolvedthroughconsen-sus.Searcheswerethenconductedtoobtainspecificpolysaccharideproductinformation:safety(usingthesearchterms:toxicity,NOAEL,LD),compositionandstructure,anddisposition.QualityassessmentEachstudywasassessedastowhetherornotitreportedasignificantoutcomemeasureforthepolysaccharideinterventiongroup.ResultsAtotalof62rodentpublications(Tables1,2and3)and15humanpublications(Table4)weredeemedappropri-ateforinclusioninthisreview.AvailablestructuralandcompositionalinformationfortheseimmunomodulatorypolysaccharidesareprovidedinTable5andsafetyinfor-mationisprovidedinTable6.Themajorityofanimalstudiesexploredmodelsinwhichanimalswereinjectedorimplantedwithcancercellsortumors,werehealthy,orwereexposedtocarcinogens.Otherstudiesinvesti-gatedimmunodeficient,exercise-stressed,agedanimals,oranimalsexposedtoinflammatoryagents,viruses,bac-terialpathogens,pathogenicprotozoa,radiationormutagens.Humanstudiesassessedimmunomodulatoryeffectsinhealthysubjects,orpatientswithcancers,sea-sonalallergicrhinitisoraphthousstomatitis.Becauseofthelimitednumberofhumanstudies,weincludedsomepromisingopen-labelcontrolledtrials.Humanstudydurationsrangedfromfourdaystosevenyears;dailydosesrangingfrom100-5,400mgwerereportedtobeAnumberofstudiesinhealthyhumanadultsdemon-stratedimmunestimulatingeffectsoforalpolysacchar-ides.ArabinogalactansfromLarixoccidentalis(Westernlarch)wereshowninRCTstoincreaselymphocytepro-liferationandthenumberofCD8+lymphocytes[18]andtoincreasetheIgGsubtyperesponsetopneumo-coccalvaccination[19].Afuranoseextractfromquiquefolium(NorthAmericanginseng)wasshowninanRCTofhealthyolderadultstodecreasetheincidenceofacuterespiratoryillnessandsymptomduration[20].Finally,anRCTofhealthyadultsconsumingUndariapinnatifida(wakame)fucoidansfoundbothimmunesti-mulatingandsuppressingeffects,includingincreasedstromal-derivedfactor-1,IFN-g,CD34+cellsandCXCR4-expressingCD34+cellsanddecreasedbloodleukocytesandlymphocytes[21].StudiesinhealthyanimalsshowedanumberofimmunestimulatingeffectsofvariousglucanproductsfromAgaricussubrufescens(A.blazei)(aqueousextracts[22],aqueousextractswithstandardized-glucans[23],-1,6and-1,4glucans[24],andwholeplantpowders[25]);Lentinulaedodes(shiitake)(lentinan[26]andglucans[27]);Saccharomycescerevisiae[27,28]);Laminariadigitata(laminarin[29]);Sclerotiumrofsii(glucanphosphate[29]);Sclerotiniasclerotiorum(SSG[30]);andPhellinuslinteus(powder[31]andaqu-eous,alcohol-precipitatedextract[32]).AfuranoseextractfromP.quiquefoliumandpectinsfromBuplerumfalcatumand(apple)spp.havealsobeenshowntoenhanceimmunefunctioninhealthyyounganimals[33-35].Cyamopsistetragonolobusgalac-tomannan(guargum)orhighlymethoxylatedpectinfeedingexertednumerousstimulatingeffectsonanti-bodyproductioninolderanimals[36].Evidencefortheeffectivenessoforalpolysaccharidesagainstinfectionandimmunechallengeshasbeenmainlydemonstratedinanimals.Immunestimulatingeffectshavebeenshowninrestingandexercise-stressedanimalswiththioglycollate,clodronate,orHSV-1injec-tionsfedAvena(oat)spp.solubleglucans[37-41];ani-malsinjectedwithorfedE.vermiformisandfedspp.particulateglucans[42,43];animalswithE.coliinjectionsfedL.digitataglucans(laminarin)[44];ani-malswithHSVinjectionsfedU.pinnatifidafucoidans[45];animalswithStaphylococcusaureusCandidaetalNutritionJournalhttp://www.nutritionj.com/content/9/1/54Page2of22 Table1ImmunomodulatoryGlucanExtracts:OralAnimalStudiesSourceExtractAnimalDose/dayDurationofstudyTreatmentEffectsReferenceA.blazeisubrufescens-1,6andHemice(5/100mg/kgIGevery31monthHealthyanimals#ssplenicTlymphocytes(Thy1.2,CD4+andCD8+)CD8+)Aqueous7-9-weekBalb/cByJmice1ml0.45N,0.6N,or3N2monthsAlldosesserumIgGlevels,CD3+TcellpopulationsandPMLphagocyticactivityactivity7-9-weekmaleBalb/cByJmice1ml0.45N,0.6N,or3N10weeksIPinjectionofOVAat40.6Nand3NlevelsofOVA-specificserumIgG28dayspost-immunization;alldoseshypersensitivityandTNF-secretedfromsplenocytesat10weeks;0.6Nproliferationat10weeks5-6-weekmice(8/group×2)One200extractday1,orogastric1weekInjectedIPfecalsolutiondayCFUinbloodofmicewithsevereperitonitis&improvedoverallsurvivalrateinallperitonitisgroupsgroups6-weekBALB/cnu/numice(7/2.5mgextractdays41daysInjectedSCSp-2myelomacellsday1tumorsize&weightafter21daystreatmenttreatmentAqueous,acidtreatedC57BL/6mice20,100or9daysInjectedIPhumanovariancancercellsday1tumorweight[66]20,100or3weeksInjectedIVmurinelungcancer(3LL)cells100&500metastatictumorswith200BALB/cmice200ngdays3weeksInjectedMethAtumorcellsday1tumorsize&weight[23]2weeksInjectedMethAtumorcellscytotoxicTlymphocyteactivity&spleencellIFN-300mg5daysHealthyanimalssplenicNKcellactivity(particulate)6-7-weekC57BL/6mice3mgevery48h,days1monthOralE.vermiformisday10E.vermiformisfecaloocyte#s;increasedintestinalanti-merozoiteIgA;#ofIL-4-secretingMLNcellscells3mgondays,days22daysInjectedIPday10E.vermiformisfecaloocyteanti-merozoiteintestinalintestinalb-glucans(soluble)4-weekCD-1mice(24/0.6mg/ml1monthRestingorexercise-stressed(days8-10)animalsadministeredHSV-1INday10morbidityinrestingandexercise-stressedanimals;mortalityinexercise-stressedanimals;pre-infection,anti-viralresistanceinrestingandexercise-stressedanimalsanimals~3.5mgRestingorexercise-stressed(days5-10)animalsadministeredHSV-1INday10Pre-infection,MøantiviralresistanceinrestinganimalsanimalsRambergetalNutritionJournalhttp://www.nutritionj.com/content/9/1/54Page3of22 Table1ImmunomodulatoryGlucanExtracts:OralAnimalStudiesmice(10/0.6mg/ml10daysRestinganimalsoranimalsexposedtoaboutoffatiguingexercisedays8-10ormoderateexercisedays5-10,injectedIPwiththioglycollateonday10neutrophilmobilizationinresting&moderatelyexercisedanimals;neutrophilrespiratoryburstactivityinrestingandfatiguingexercisedanimalsanimals4-weekCD-1mice(19-30/0.8mg/mlglucan,days1monthRestingorexercise-stressed(days8-10)animalsadministeredINclodronate-filledliposomestodepleteMødays8&14&infectedINwithHSV-1day10morbidity,mortality,symptomseverityinexercise-stressedanimals,withoutMødepletiondepletion4-weekCD-1mice(20/Restingorexercise-stressed(days8-10)animalsadministeredHSV-1INdaymorbidityinexercise-stressed&restinganimals;mortalityinexercise-stressedssedGanodermaAqueous7-weekmice(26/5%ofdiet5monthsInjectedIMDMHonceaweek,weeks1-10aberrantcryptfocipercolon,tumorsize,cellproliferation,nuclearstainingstaining4-8-weekBALB/cmice50,100or200mg/kg,10daysInjectedSDSarcoma180oftumorweightwasdosedependent:27.7,55.8,66.7%,respectivelyyGanodermaAqueous7-weekF344/DuCrjrats(16/group)1.25%or2.5%ofdiet6monthsInjectedSCAOMonceaweek,weeks2-5Bothdosesadenocarcinomaincidence;totaltumorincidence;bothdosesstainingof-cateninandcellcellGanodermaAqueous8-weekmice(14/0.2-0.4%ofdiet(youngfungi);0.33or0.66%ofdiet(mature5weeksInjectedIPOVAdays7,14,21;aerosolizedOVAtwiceduringweek4Insplenocytes,bothdosesofbothextractsIL-2andIL-2/IL-4ratios,0.2%youngextractand0.66%matureIL-4;inMø,0.66%matureextract,bothdosesofbothextractsextractsGrifolafrondosaDfractionMice:1)ICR,2)C3H/HeN,3)1.5mgeveryotherday,day213daysImplantedSC:1)Sarcoma-180,2)MM-46carcinoma,or3)IMCcarcinomacellstumorweight&tumorgrowthrate:1)58%,2)64%,and3)75%,respectivelyrespectively5-weekBALB/cmice2mg,days15-3045daysInjectedinthebackwith3-MCA,day1(62.5%)#ofanimalswithproductionbyplasmaMø;cytotoxicTcellactivityactivityHordeumvulgareb-1,3;1,4orAthymicnu/nu40or400IGfor4weeks31weeksMicewithhumanxenografts(SKMel28melanoma,A431epidermoidcarcinoma,BT474breastcarcinoma,Daudilymphoma,orLAN-1neuroblastoma)±mAb(R24,528,Herceptin,Rituximab,or3F8,respectively)therapytwiceweeklyg+mAbgrowth&survival;highertumorgrowthrateforbothdosesdosesb-1,3;1,4-D-glucansAthymicBALB/cmice4,40,or400gfor3-4weeks1monthMicewithneuroblastoma(NMB7,LAN-1,orSK-N-ER)xenografts,±3F8mAbtherapytwiceweekly40and400gdoses+mABtumorgrowth;400survival.SerumNKcellsrequiredforeffectsontumorsizesizeC57BL/6WTandCR3-deficientmice0.4mgfor3weeks100daysInjectedSCRMA-S-MUC1lymphomacellsday1±IV14.G2aoranti-MUC1mAbevery3rddaytumordiameter;diameter;RambergetalNutritionJournalhttp://www.nutritionj.com/content/9/1/54Page4of22 Table1ImmunomodulatoryGlucanExtracts:OralAnimalStudiesFoxChaseICRimmune-deficient(SCID)mice(9/group)days1-2950daysMicewithhuman(Daudi,EBV-BLCL,Hs445,orRPMI6666)lymphomaxenografts,±RituximabmAbtherapytwiceweeklytumorgrowthandandLaminariadigitataLaminarinICR/HSDmice(3/group)1mg1dayHealthyanimalsMøexpressionofDectin-1inGALTcells;expressioninPeyerspatchdendriticcellscellsWistarrats5%ofdietdays1-4,10%ofdietdays5-2526daysInjectedIPE.coliLPSday25liverALT,AST,andLDHenzymelevels;cells,.peroxidase-positivecellsinliver;monocytes,TNF-,PGE2,PGE2,LentinulaedodesSME6-weeknude0.1mlwaterSME/10gbodyweightdays1-19,50daysInjectedSCprostatecancer(PC-3)cellsday1tumorsize[80]3-and8-weekBALB/cmice(15/50,100or1-2weeksHealthyanimals250gdosespleencellIL-2secretionsecretion3-and8-weekBALB/cmice(15/50,100or1-2weeksInjectedmurinemammarycarcinoma(Ptas64)cellsintomammaryfatpads2weeksbeforetreatmenttumorweightLentinan6-weekpathogenfreerats(10/group)1mgtwiceHealthyanimalsTcell#s,helper-cell#s&helper/suppressorratio,suppressorcelllevelat4,butnot8weeksweeks5-6-weekpre-leukemicAKRmice(10/3mg,days3weeksInjectedSCK36murinelymphomacellsday7tumorweight;inhibitionrate(94%)(94%)5-6-weekathymicmice5weeksInjectedSCcoloncancer(LoVoandSW48,SW480andSW620,orSW403andSW1116)cellsday7tumorweight,inhibitionrate�(90%)AKRmice3mg1dayPre-leukemicmiceserumIFN-andTNF-peakat4handthenbacktonormalat24h;IL-2andIL-,peakat2handbacktonormalat24h;CD3+T,CD4+T,CD8+T,BlymphocytesesPhellinuslinteusprecipitatedC57BL/6mice200mg/kgindrinking1monthHealthyanimalsproductionandsecretionofIFN-byconAstimulatedTcellscellsSaccharomycesScleroglucanmice(3/group)1mgonedaybefore(day1)6daysIVStaphylococcusaureusCandidaalbicansday2long-termsurvival[29](particulate)3and8-weekBALB/cmice50,100or1-2weeksInjectedmurinemammarycarcinoma(Ptas64)cellsintomammaryfatpads2weeksbeforetreatmenttumorweight[27]etalNutritionJournalhttp://www.nutritionj.com/content/9/1/54Page5of22 albicansinjectionsfedS.cerevisiaeglucans(scleroglu-can)[29];andanimalswithfecalsolutioninjectionsfedanaqueousextractofA.subrufescensA.blazeiMurrill)l)Additionalcontrolledhumanandanimalstudieshaveshownanti-inflammatoryandanti-allergyeffectsofsomepolysaccharideproducts.InanRCTofadultswithseasonalallergicrhinitis,S.cerevisiae-1,3;1-6glucansdecreasedIL-4,IL-5andpercenteosinophils,andincreasedIL-12innasalfluid[47],whileaplacebo-con-trolledstudyofpatientswithrecurrentaphthousstoma-titis(cankersores)consuming-1,3;1-6glucansfoundincreasedlymphocyteproliferationanddecreasedUlcerSeverityScores[48].Animalmodelsofinflammatoryboweldiseasehaveshownanti-inflammatoryeffectsofCladosiphonokamuranusTokidafucoidans[49],Cyamopsistetragono-galactomannans[50],spp.pectins[51],andmixedpolysaccharidesupplements[52].Animalschal-lengedwithovalbuminhavedemonstratedanti-inflamma-tory/allergyeffectsofA.subrufescensaqueousextracts[22],anaqueousextractofGanodermatsugae[53],andPyruspyrifoliapectins[54].Anti-inflammatoryeffectshavealsobeenseeninanimalswithcottonpelletimplan-tationsfedaPholiotanamekoheteroglycan(PNPS-1)[55].Trametesversicolorglucanshavedemonstratedanti-cancereffectsinhumans.IntwoRCTsandfivecon-trolledtrials,PSKfromT.versicolormyceliaincreasedsurvivalofadvancedstagegastric,colonandcolorectalcancerpatients[56-62]withonestudyshowingincreasedimmuneparameters(includingbloodNKcellactivity,leukocytecytotoxicity,proportionofhelpercells Table1ImmunomodulatoryGlucanExtracts:OralAnimalStudies-1,3-glucanHealthyanimalsAll3dosesphagocyticactivityofbloodmonocytes&neutrophils&spleencellIL-2secretionWTorC57BL/6mice0.4mgfor3100daysInjectedSCRMA-S-MUC1lymphomacells±14.G2aoranti-MUC1mAbIVinjectionevery3tumordiameterwhenincludedwithmAb;survivalwithandwithoutwithoutC57BL/6mice(4/group)25mg1weekHealthyanimals#intestinalIELs;#TCR+,TCR+,CD8+,CD4+,+,CD8+TcellsinexpressioninIELsandspleenspleenSclerotiniasclerotiorumSSG6-8-weekpathogen-free40or80mg/kgdays2weeksHealthyanimals10mgdosephosphataseactivityofperitonealMø(day14)14)40,80or160mg/kgdays35daysImplantedSCMethaAfibrosarcomacellsday180mgdosetumorweightpathogen-free40,80or160mg/kgdaysInjectedIDIMCcarcinomacellsday1pathogenfreemiceofBDF1andC57BL/6mice0.5,1,2,or4mgdays1-2-3weeksInjectedIVLewislungcarcinoma(3LL)cells2mg#of3LLsurfacelungnodulesat2weeksweeksSclerotiumrofsiiphosphatemice(3/group)1mg1dayHealthyanimalssystemicIL-6;expressionofDectin-1inGALTcells;TLR2expressionindendriticcellsfromPeyerPeyerTrametes(Coriolus)versicolorPSP6-8-weekBALB/cmicegdays5-29in29daysImplantedSCSarcoma-180cellsday1tumorgrowth&vascularvascularRambergetalNutritionJournalhttp://www.nutritionj.com/content/9/1/54Page6of22 Table2ImmunomodulatoryNon-GlucanExtracts:OralAnimalStudiesExtractSourceAnimalOraldose/dayDurationTreatmentSignificanteffectsReferencemice,10/group0.05%w/wof56daysDSS-inducedUCdiseaseactivityindexandmyeloperoxidaseactivity;#ofB220-positivecolonicBcolonicMLNIFN-andIL-6andIL-10andcolonicIgG;colonicepithelialcellIL-6,,andTLR4mRNAmRNAUndariapinnatifida5-weekBALB/cmice(10-12/group)5mg,days1-14or7-142weeksInjectedHSVintocorneaday7facialherpeticlesions;survival,particularlyinpre-treatedanimalsanimals10mg1weekAdministered5-fluorouracilplasmaNKcellactivityInjectedSCHSVcytotoxicsplenicTlymphocyteactivity0.1or0.5mg3weeksInjectedIPHSVBothdosesneutralizingAbtiters,weeks2and3ddYmice50,100,200400500mg/kgdays1-283weeksInjectedwithEhrlichcarcinomainbackday14200-500mg/kgmg/kg6-weekBALB/cmice(8/group)40mg/kgalternatingdays19daysInjectedIPMethAfibrosarcomaday1tumorgrowthSDrats450or900mg/kgin1weekHealthyanimalsBothdosesspleenIl-2andIFN-followingConAorLPSproportionoftotalMLNandPeyerpatchCD3+cells&activatedTcells;highdosespleencellIL-1productionfollowing48hConAstimulation.ion.Galacto-mannan(partiallyhydrolyzedguargum)5%ofdiet3weeksDSS-inducedUCatbeginningofweek3diseaseactivityindexcolonicmucosalmyeloperoxidaseactivity&lipidperoxidation;proteinlevels&mRNAexpressionupregulatedbyDSSexposureexposureGalacto-mannans(guargum)8-month-SDrats,5%ofdiet3weeksOlderanimalsserumIgG;lymphocyteIgA,IgMandIgGproductionproductionGlucomannan(KS-2)LentinulaedodesDD1mice(10-20/140mg/kgdays50daysInjectedIPEhrlichascitestumorcellsday1survival[84]0.1,1,10,or100mg/kgdosedays100daysInjectedSarcoma-180tumorcellsday11,10,and100mg/kgHeteroglycanMice(10/group):1)NIH;6week-mice;3)8-weekBALB/cnude;4)5-weekC3H/HcN100or300mg/kgdays2-118weeksImplantedSC1)Sarcoma-180,2)Shionogicarcinoma42,3)MethAfibrosarcoma,or4)EhrlichascitescarcinomacellsBothdosesSarcoma-180tumorsizeat4weeks&survival;300mg/kgperitonealmacrophageandC3-positivecells;300mg/ShionogiandMethAtumorsizesat4weeks.BothdosessurvivalofEhrlichascitesmicemiceRambergetalNutritionJournalhttp://www.nutritionj.com/content/9/1/54Page7of22 Table2ImmunomodulatoryNon-GlucanExtracts:OralAnimalStudiesHeteroglycanKunmingmice5,10or20mg/kg10daysInjectedSCSarcoma-180cells5&10mg/kgindex;alldoseslipidperoxidationinserum,liverandspleen&lymphocyteproliferation,cytotoxicTcellactivity,IL-2IL-2HeteroglycanSDrats(5/group)100,200or400mg/kgdays1-88daysImplantedSCcottonpelletsinscapularday1granulomagrowthpositivelycorrelatedwithdose:11%,18%and44%,respectivelyyHeteroglycancmice(3/group)10mg24days6Gygammacolonyformingcells,granulocyteCFUs/Mø,erythroidburst-formingunits,andmyeloidprogenitorcellsinbonemarrow;inducedproliferationofgranulocyteprogenitorcellsinboneserumlevelsofGM-CSF,IL-6,IL-1IL-1Mixedpoly-(Ambrotose®orAdvancedspp,andotherplantSDrats(10/37.7or377mg/kgAmbrotose®powderor57.4or574mg/kg2weeks5%DSSindrinkingwaterbeginningday574mg/kgAdvancedAmbrotosepowderscores;377mg/kgAmbrotosecomplex&bothdosesAdvancedAmbrotosepowderlengthandmonocytecountcountPectinPyruspyrifoliamice(11/group)days1-722daysInjectedIPOVAday7,provokedwithOVAaerosolday21bronchialfluid:IL-5;spleniccells:IL-5;normalizedpulmonaryhistopathologicalchanges;serumIgEIgEPectins(bupleurum2IIc)Bupleurumfalcatum6-8-weekspecific-pathogen-freeC3H/HeJmice250mg/kg1weekHealthyanimalsspleencellproliferation[35]Pectins(highlymethoxylated)spp.8-month-SDrats5%ofdietvs.cellulosecontrol3weeksOlderanimalsMLNlymphocyteIgA&&PectinsCitrusspp.5-weekF344rats15%ofdiet34weeksInjectedSCAOMonceaweek,weekscolontumorincidence[86]spp.5-weekmice(6/group)5%ofdiet2weeksHealthyanimalsfecalIgAandMLNCD4+/CD8+Tlymphocyteratio&IL-2&IFN-secretionbyConA-stimulatedMLNlymphocyteses5-weekBALB/cmice(6/group)5%ofdietdays5-19vs.cellulose19daysDSS-inducedUCdaysSignificantlyincreasedMLNlymphocytesIgA,andsignificantlydecreasedIgE;significantlydecreasedConA-stimulatedIL-4andrats(20-21/group)20%ofdiet32weeksInjectedSCAOMonceaweek,weeks2-12colontumorincidence[85]rats(19-20/group)10or20%of32weeksInjectedSCAOMonceaweek,weeks2-12Bothdosescolontumorincidence;20%occupiedarea&bloodanddistalcoloncolonRambergetalNutritionJournalhttp://www.nutritionj.com/content/9/1/54Page8of22 Table2ImmunomodulatoryNon-GlucanExtracts:OralAnimalStudiesCitrusspp.2-4-monthBALB/cmice(9-10/group)0.8or1.6mg/mldrinkingwater,days8-2020daysInjectedSCwith2×2mmsectionofhumancolon-25tumoronday1Bothdosestumorsize[87]NCRnu/numice1%(w/v)drinkingwater16weeksOrthotopicallyinjectedhumanbreastcarcinomacells(MDA-MB-435)intomammaryfatpadonday7tumorgrowthrate&volumeat7weeks,lungmetastasesat15weeks,#ofbloodvessels/tumorat33dayspost-injectionpost-injectionNCRnu/numice1%(w/v)drinkingwater7weeksInjectedhumancoloncarcinomacells(LSLiL6)intocecumonday7tumorweightsandmetastasestothelymphnodesandliverSDrats(7-8/group)0.01%,0.1%or1.0%wt/volofdrinkingwater,days4-301monthInjectedSCMAT-LyLuratprostatecancer0.1%and1.0%metastases;1.0%nodediseaseincidence Table3ImmunomodulatoryPolysaccharide-RichPlantPowders:OralAnimalStudiesSourceAnimalOraldose/DurationTreatmentSignificanteffectsReferencesubrufescens(fruitbodies)C57BL/6,C3H/HeJandBALB/cmice(3/group)16,32or642weeksHealthyanimals32and64mglivermononuclearcellcytotoxicityityGrifolafrondosa6-weekICRmice(10-15/5%ofdiet36weeksOralN-butyl-Nbutanolnitrosaminedailyforfirst8#sofanimalswithbladdertumors;tumorweight;peritonealMøchemotacticactivity,spleniclymphocyteblastogenicresponse&cytotoxicactivityactivityLaminariaangustataWeanlingSDrats(58/group)5%ofdiet26weeksIGDMBA,beginningofweek5timetotumordevelopmentandofadenocarcinomasinadenocarcinoma-bearinganimalsanimalsLentinula(Lentinus)edodes6-weekICRmice(10-17/5%ofdiet36weeksOralBBNdailyforfirst8weeks#ofanimalswithbladdertumors;tumorweight;Møchemotacticactivity,spleniclymphocyteblastogenicresponse,cytotoxicactivityactivity7-8-weekSwissmice(10/1%,5%or10%ofdietof4differentlineagesdays16daysInjectedIPN-ethyl-N-nitrosoureaday15All3dosesofonelineageandthe5%doseoftwootherlineages#sofmicronucleatedbonemarrowpolychromaticerythrocyteserythrocytesLentinulaedodes(fruitbodies)5-weekICRmice(14/group×2)10%,20%or30%ofdiet25daysInjectedIPSarcoma-180ascitesAll3dosesSarcoma-180tumortumorMice:1)CDF;2)C3H;3)BALB/c;4,5)C57BL/6N(9/group×3)20%ofdiet25daysInjectedSC1)IMCcarcinoma,2)MM-46carcinoma,3)Meth-Afibrosarcoma,4)B-16melanoma,or5)LewislungcarcinomacellsgrowthofMM-46,B-16,Lewislung,andIMCtumors;lifespaninLewislungandMM-46animalsICRmice(14/group×2)20%ofdietdays1-7,days7-31ordays31daysInjectedIPSarcoma-180ascitestumorweight&growthwhenfeddays7-31or14-31Mice:1)CDF;2)C3H(5/group×4)20%ofdiet7-12InjectedSC:1)IMCcarcinomaor2)MM-46carcinomacellsspreadingrateofactivatedMøphagocyticactivitymice(10/group)2mg1monthHealthyanimalsserum&splenocyteIgEproduction;proportionofsplenicCD4Tcells&splenocyteIFN-IFN-Pleurotusostreatus6-weekICRmice(10-20/group)5%ofdiet36weeksOralBBNdailyforfirst8weeks#sofanimalswithbladdertumors;tumorweight;plasmaMøchemotacticactivity,spleniclymphocyteblastogenicresponse,cytotoxicactivityactivityRambergetalNutritionJournalhttp://www.nutritionj.com/content/9/1/54Page9of22 Table4ImmunomodulatoryPolysaccharideProducts:OralHumanStudiesExtractSourceStudyPopulationN(experimental/Dose/dayDura-SignificanteffectsReferenceoccidentalisHealthyadults8/154g6%CD8+lymphocytes&bloodlymphocyteproliferationonArabino-galactans(ResistAid)Healthyadultspneumococcalvaccinationsday3021/244.5g72plasmaIgGsubtypes[19]pinnatifidasporophyllsHealthyadults25(75%fucoidan,63g1275%fucoidan:#sbloodleukocytes,lymphocytesplasmastromalderivedfactor-1,IFN-,CD34+cells;CXCR4-expressingCD34+cellscellsFuranoseextract(Cold-FX®)Panaxquinque-foliumRandomized,double-blind,placebo-controlledHealthyolderadultsgivenimmunizationattheendofweek422/21400mg4Duringweeks9-16,ofacuterespiratoryillness,symptomdurationdurationGlucansAgaricusCervical,ovarianorendometrialcancerpatientsreceiving3chemotherapy39/615.4g(estimated)NKcellactivity,chemotherapysideeffectseffectsGlucans(b-1,3;1,6)NotidentifiedPlacebo-controlledRecurrentaphthousstomatitispatients31/4220mg20PBLlymphocyteUlcerSeveritySeverityGlucans(b-1,3;1-6)S.cerevisiaeAdultswithseasonalallergic12/1220mg1230minutesafternasalallergenprovocationtest,nasallavageIL-4,IL-5,%eosinophils,eosinophils,Glucans(PSK)TrametesversicolorRandomized,controlledPatientswithcolorectalcancerchemotherapy221/227200mg3-5disease-freesurvivalandoverallsurvivalsurvivalControlledPost-surgicalcoloncancerpatientsreceivingchemotherapy123/1213gfor4alternatingwith104-weekcoursesofchemo-7yearssurvivalfromcancerdeaths;nodifferenceindisease-freeoroverallsurvivalsurvivalPost-surgicalcolorectalcancerpatientsreceivingchemotherapy137/683gdaily2yearssurvivalinstageIIIpatients;recurrenceinstageII&IIIIIIPost-surgicalgastriccancerpatientsreceivingchemotherapy124/1293gfor4alternatingwith104-weekcoursesofchemo-5-yeardisease-freesurvivalrate,overall5-yearsurvivalsurvivalRambergetalNutritionJournalhttp://www.nutritionj.com/content/9/1/54Page10of22 andlymphocytesuppressorcells)[62].AnRCTofadvancedstagelungcancerpatientsconsumingPSPT.versicolorfruitbodiesfoundincreasedIgGandIgMantibodiesandtotalleukocyteandneutrophilcounts,alongwithadecreaseinthenumberofpatientswithdrawingfromthestudyduetodiseaseprogression[63].AnRCTofovarianorendometrialcancerpatientsconsumingA.subrufescensglucansshowedincreasedNKcellactivityandfewerchemotherapysideeffectssInnumerousanimalmodelsofcancer,awiderangeofpolysaccharideshaveshownanti-tumorogeniceffects.GlucanproductssourcedfromA.subrufescensstratinganti-canceractivitiesinanimalmodelsincludeanaqueousextract[65],anaqueous,acid-treatedextract[66],andanaqueousextractwithstandardizedlevelsof-glucans[23].Anti-cancereffectshavebeenreportedfollowingintakeofaqueousextractsofG.lucidum[67-69];thepowderandDfractionofG.frondosa[70-72];Hordeumvulgare-glucans[73-76];Laminariaangustatapowder[77];Lentinulaedodesproducts(pow-ders[70,78,79],SME[80],-glucans[27],andlentinan[81,82]);Pleurotusostreatuspowder[70],Saccharomycescerevisiaeparticulate-1,3;1,6and-1,3glucans[27,73];andaglucanfromSclerotiniasclerotiorum[30,83].AglucomannanfromL.edodes(KS-2)improvedsurvivalofanimalswithcancercellinjections[84];appleandcitruspectinshaveexertedanti-cancereffects,includingdecreasedtumorincidence[85-90].Finally,heteroglycansfromLyciumbarbarum(LBPLentinus(PG101)andA.subrufescens(ATOM)demon-stratedanumberofimmunestimulatingeffectsinanimalcancermodels[91-93].Interestingly,onlyoneanimalstudyhasbeenperformedusingglucansfrom(PSP):animalswithcancercellimplantationsshoweddecreasedtumorgrowthandvasculardensityyMostpolysaccharideproductsappeartobesafe,basedonNOAEL,acuteand/orchronictoxicitytestinginrodents(Table6).Aswouldbeexpected,powders,extractsandproductsthathavenotbeenfullycharacter-izedposethemostconcerns.Otherthanforaloeveragel,whichwasshowninasmallhumantrialtoincreasetheplasmabioavailabilityofvitaminsCandE[95],theimpactofpolysaccharideintakeontheabsorptionofnutrientsandmedicationsisnotknown.Whileonerattoxicitystudyraisedconcernswhenguargumcom-prised15%ofthedailydiet[96],theproductwassafeinhumansstudieswhen18-39.6g/daywasconsumedforuptoayear(Table4).Productcontaminationmayexplainthreecasereportsofhepatotoxicityand/ordeathfollowingintakeofanA.subrufescensaqueousextract[97].Sevenanimalstudiesreportingpositiveimmunolo-giceffectsofA.subrufescensextractsinhealthyanimalsoranimalswithcancersfoundnoevidenceoftoxicity(Tables1and2).Inhumans,sixweeksofA.subrufes-glucansintakewassafeforcancerpatients,andfourmonthsof3g/dayintakeby24healthyadultsand24adultswithliverdiseasereportednoevidenceoftoxicity(Table4).AnothercasereportassociatedlivertoxicitywithG.lucidumintake,buttheelderlysubjectalsotookanunidentifiedproductamonthprevioustoheradmissionfortesting[98].Threeanimalstudiesreportedimmunologicbenefitsandnoadverseeffects Table4ImmunomodulatoryPolysaccharideProducts:OralHumanStudiesgastricorcolorectalcancer16daily;17everyother3gdailyoronalternatedaysbeforesurgerydaysor14daytreatment:peripheralbloodNKcellactivity,PBLcytotoxicity,proportionofPBLhelpercells;proportionofPBLinducercells;daytreatment:responsetoPSKandConA,proportionofregionalnodelymphocytesuppressorcellscellsRandomized,double-blind,placebo-controlledPost-surgicalstageIII-IVcolorectalcancer56/553gfor2months,2gfor22months,1gthereafterremission&survivalrates[61]ControlledPost-surgicalstageIIIgastriccancerpatientschemotherapy32/213g1yearsurvivaltime[60]Conventionally-treatedstageIII-IVnon-smallcelllungcancer34/343.06g1bloodIgG&IgM,totalleukocyteandneutrophilcounts,%bodyfat;withdrawalduetodiseasediseaseRambergetalNutritionJournalhttp://www.nutritionj.com/content/9/1/54Page11of22 Table5ImmunomodulatoryPolysaccharideProducts:CompositionandStructureSourceCategoryFeaturesMWMonosaccharidecompositionAgaricussubrufescensA.blazei)Extract-1,6-D-glucan10,000NA[66]Agaricussubrufescens(fruitbody)Extract-1,6-and-1,4glucanswith-1,6-glucopyranosylbackbone(629.2mcg/mgpolysaccharides,43.5mcg/mgprotein)170,000glucose[24]-1,4glucans&-1,6glucans-1,3sidebranches;glucans;-1,6;1-3glucans,glucans;-1,3glucans;1,3glucans;riboglucans,galactoglucomannans,1,3glucomannansNAglucose,mannose,galactose,[25,117,118]Agaricussubrufescens(mycelia)Extract-1,6-D-glucan,proteincomplex,5%protein100,000-1,000,000glucose,mannose,galactose,galactose,Aloebarbadensis(leafgel)WholetissueDryweight:10%polysaccharides;acemannan,aloemannan,aloeride,pecticacid,galactans,arabinans,glucomannans2,000,000mannose,glucose,galactose,arabinose,xylose,rhamnoserhamnoseExtract(aloemannan)neutralpartiallyacetylatedglucomannan,mainlymannans�200,000mannose,glucose[121]NA4,000,000-7,000,00037%glucose,23.9%galactose,19.5%mannose,10.3%arabinosearabinoseExtract(acemannan)b-1,4acetylatedmannan80,000mannose[123]Aloebarbadensis,(leafgel),sp.(bark),AnogeissuslatifoliaAstragalusgummiferOryzasativa-1,4acetylatedmannan,arabinogalactans,polysaccharidegums,ricestarch,5.4%protein26.4%950,000mannose,galactose,arabinose,glucose,galacturonicacid,rhamnose,xylose,fructose,fucose,glucosamine,galacturonicAloebarbadensis(leafgel),sp.(bark),UndariapinnatifidaAnogeissuslatifoliaAstragalusgummiferOryzasativaglucosamine-1,4acetylatedmannan,arabinogalactans,polysaccharidegums,fucoidans,ricestarch,6%protein,1%fatty13%=1,686,667;46%=960,00030%spp.(seedendosperm)Extract-1,3;1,4particulate(1-31,100,000glucose[43]spp.(seed)Extract-1,4,1,3particulateglucans(linearchainsofglycopyranosylunits;70%2,000,000NA[41,124]Buplerumfalcatum(root)Extract6linkedgalactosylchainswithterminalglucuronicacidsubstitutedto-galactosylNAgalactose,glucuronicacid,acid,Citrusspp.(fruit)Extract-1,4-linkedpartiallyesterifiedD-anhydrogalacturonicacidunitsinterruptedperiodicallywith1,2-rhamnose70,000-100,000galactose,galacturonicacid,arabinose,glucose,xylose,xylose,Cladosiphonokamuranus(frond)Extract-1,3-fucopyranosesulfate56,000fucose:glucuronicacidacidCordycepssinensis(mycelia)Extract-1,3-D-glucanwith1,6-branchedchainsNANA[127]Cyamopsistetragonolobus(seed)Extract(guarMainchainofmannopyranosylunitswith-galactopyranosylunits220,000mannose,galactose[36,128]etalNutritionJournalhttp://www.nutritionj.com/content/9/1/54Page12of22 Table5ImmunomodulatoryPolysaccharideProducts:CompositionandStructureguargum)NA20,000mannose,galactose[50]FlammulinavelutipesExtractNANAglucose,mannose,galactose[117]Flammulinavelutipes(fruitbody)Extract-1,3glucanNAglucose[129]GanodermalucidumWholetissueLinear-1,3-glucanswithvaryingdegreesofD-glucopyranosylbranching,-glucan/proteincomplexes,heteropolysaccharides400,000-1,000,000glucose,galactose,mannose,xylose,uronicacidacidExtractNA7,000-9,000NA[67]Ganodermalucidum(fruitbody)ExtractNA7,000-9,000NA-linkedheteroglycanpeptide513,000fructose,galactose,glucose,rhamnose,xylose(3.167:0.556:6.89:0.549:3.61)549:3.61)GanodermatsugaeExtract55.6%carbohydrates(12.5%polysaccharides);12%triterpenes,1.7%sodium,0.28%protein,0%lipidNANA[53]Ginkgobiloba(seed)Extract89.7%polysaccharidesNAglucose,fructose,galactose,se,GrifolafrondosaWholetissue-1,3;1,6-glucans,mannoxyloglucans,xyloglucans,mannogalactofucansNAglucose,fucose,xylose,mannose,galactosegalactoseGrifolafrondosa(fruitbody)Extract(Dfraction)-1,6-glucanwithbranches,30%proteinNAglucose[132](Xfraction)-1,6-D-glucanwithbranches,35%protein550,000-558,000glucosespp.(seed)Extract-1,3;1,4-and-1,3;1,6-D-glucans45,000-404,000glucose[75]PrimarilylinearNAglucose[124]-1,3;1-6glucan7,700glucose[29]-1,3glucanwithsomebranchesandasmallamountofprotein4,500-5,500glucose[44]ExtractFucoidanNANA[133]Larixoccidentalis(bark)Extract-1,3;1,6-D-galactanswitharabinofuranosylandarabinopyranosylsidechains19,000-40,000galactose:arabinose(6:1),uronicacidacidLentinulaedodesExtract(SME)-1,3-glucans(4-5%),glucan(8-10%),proteinNAglucose[80]-glucan1,000glucose[27]WholetissueLinear-1,3-glucans,glucans,heterogalactanNAglucose,galactose,mannose,fucose,xylosexyloseExtract(lentinan)b-1,3-glucanwith2glucopyranosidebranchingsforevery5-1,3-glucopyranosidelinearlinkages500,000glucose[136]Lentinulaedodes(fruitbody)Lentinulaedodes-1,3-Dglucanwithtwo-1,6glucosidebranchesforeveryfive-1,3units400,000-800,000glucose[137]Peptideunitsandmannanconnectedby-glycosidic60,000-90,000mannose,glucoseetalNutritionJournalhttp://www.nutritionj.com/content/9/1/54Page13of22 Table5ImmunomodulatoryPolysaccharideProducts:CompositionandStructureLentinulaedodes(myceliaorfruitExtractTriplehelical-1,3-Dglucan-1,6glucosidebranches1,000,000glucose[3]Lentinulaedodes(mycelia)Extract44%sugars,24.6%protein~1,000,000xylose,arabinose,glucose,galactose,mannose,fructosefructoseExtract(PG101)72.4%polysaccharides,26.2%protein,1.4%hexosamineNA55.6%glucose,25.9%galactose,18.5%mannosemannoseLyciumbarbarumWholetissue-1,4;1,6-D-glucans,lentinan,-1,3;1,6heteroglucans,heterogalactans,heteromannans,xyloglucansNAglucose,galactose,mannose,mannose,Lyciumbarbarum(fruitbody)Extract88.36%sugars,7.63%protein157,000galactose,glucose,rhamnose,arabinose,mannose,xylose(molarratioof1:2.12:1.25:1.10:1.95:1.76))Panaxquinquefolium(root)ExtractPoly-furanosyl-pyranosylsaccharidesNAarabinose,galactose,rhamnose,galacturonicacid,glucuronicacidacidNANAglucose,mannose,xylose[140]90%poly-furanosyl-pyranosyl-saccharidesNAfuranose[20]Phellinuslinteus(fruitbody)Extract-and-linked1,3acidicproteoglycanwith1,6branches150,000glucose,mannose,arabinose,e,Phellinuslinteus(mycelia)Extract83.2%polysaccharide(4.4%-glucan),6.4%protein,0.1%fatNAglucose[142]Pholiotanameko(fruitbody)Extract(PNPS-NA114,000mannose,glucose,galactose,arabinose,xylose(molarratioof1:8.4:13.6:29.6:6.2).6:6.2)Pleurotusostreatus(mycelia)Extract-1,3;1,6-D-glucans316,260glucose[143]SaccharomycescerevisiaeExtract(WGP)Particulate-1,3;1,6-D-glucanNAglucose[144]-glucanswith-1,6brancheswitha-1,3regionsNAglucose[124]-1,3-D-glucanwith-1,3sidechainsattachedwith-1,6linkages20,000glucose[145]Sclerotiniasclerotiorum(mycelia)Extract-1,3-D-glucan,protein%-3;2.8;é¦ã¤(98%polysaccharide)NAglucose[83]Sclerotiumrofsii-1,3;1,6glucan1,000,000glucose[29]Trametesversicolor(fruitbody)Extract-1,3glucans,10%100,000glucose,arabinose,mannose,mannose,Trametesversicolor(mycelia)Extract-1,4;1,3;1,6-D-glucans,protein94,000glucose(74.6%),mannose(15.5%),xylose(4.8%),galactose(2.7%),fucosefucoseUndariapinnatifida(sporophyll)ExtractGalactofucansulfate9,000fucose:galactose1.0:1.1[148]Galactofucansulfate63,000fucose:galactose:gluc-uronicacid(1.0:1.0:0.04)(1.0:1.0:0.04)b-1,3-galactofucansulphate38,000fucose,galactose[150]UnidentifiedsourceExtractcitruspectin)NA10,000galactose,rhamnose,uronicuronicExtract(highlymethoxylatedNA200,000NA[36]etalNutritionJournalhttp://www.nutritionj.com/content/9/1/54Page14of22 Table6SafetyofImmunomodulatoryPolysaccharideProductsFollowingOralIntakeCategorySourceTestgroupTestDesignResultsEquivalentReference(arabinogalactanPregnantratsDevelop-250,500,or1,00mg/kg,gestationaldays5-19Nodevelopmentaltoxicity:NOAEL=1g/kg68g[151]ratsFertility250,500,or1,00mg/kg,1monthNoeffectsonreproduction:NOAEL=1g/kgRatsSubchronic1.35g/kg,1Noevidenceoftoxicity91.8g[152]Adolescentandandchronic8%ofdiet,6-67Noevidenceoftoxicity8%ofdiet[153]RatsAcuteOne7.06g/kgdose:observed2=7.06g/kg480g[96]andchronic1,2,4,7.5or15%ofdiet,3monthsAlldosesBW;7.5-15%BW;15%bonemarrowkidneyandliver1-15%of19adultswithhypercholesterol-18g/day,1yearShort-termgastricbloating/loosestools,in8subjects,resolvedin7-10days;2withdrewbecauseofdiarrhea.Notoxicityfor13subjectscompletingstudy18g[154]16TypeII26.4-39.6g/day,6Noeffectsonhematologic,hepatic,orrenalfunction39.9g[155]18TypeII30g/day,430ghydrolyzedguarMice&ratsAcuteOne6g/kgdose;2weeks�6g/kg�408g[156]RatsSubchronic0.2,1.0or5%ofdiet,13weeksNoevidenceoftoxicity5%ofdiet0.5or2.5g/kg,1NOAEL�2.5g/kg�170g[157]S.typhimuriumMutagenicityAmestestNotmutagenicNA(aqueousextract)RatsSubchronic0.63,1.25,2.5or5%ofdiet,3NOAEL=5%ofdiet5%ofdiet[158]3womenwithCasereportsSpecificidentityofproducts,doses,anddurationsofintakeunknownSeverehepatotoxicity;twopatientsdiedNA[97](freezedried24normaladultsand24adultswithliver3g,4monthsNoevidenceoftoxicity3g[159]ElderlywomanCasereport1yearG.lucidum(andanotherunidentifiedproduct,initiatedonemonthElevatedliverenzymesandlivertissuedamageNA[98]GrifolafrondosaRatsAcuteOne2g/kgdoseNoevidenceoftoxicity136g[160]etalNutritionJournalhttp://www.nutritionj.com/content/9/1/54Page15of22 followingintakeofG.lucidumaqueousextracts;inonestudyintakewas5%ofthedietfor5months(Table1).Whileadverseeffectswerealsoreportedinastudyinwhich10adultsconsumed4g/dayL.edodespowderfor10weeks[99],immunologicanimalstudiesreportednoilleffectsofeitherL.edodespowder(5studies,upto5%ofthedietuptoninemonths)orextract(7studies,upto40daysintake)(Tables1and3).Finally,whileintakeof319mg/kgofanaqueousextractofP.ostreatusmicefor1monthcausedhemorrhagesinmultipletis-sues[100],therewasnoreportedtoxicitywhenmiceconsumedthemushroompowderas5%oftheirdietforninemonths(Table3).While1gram/dayofversicolorglucanproductsweresafelyconsumedbycan-cerpatientsforupto10years,thelong-termeffectsofingestionoftheotherpolysaccharideproductsdiscussedinthisreviewisalsonotknown.DiscussionThemajorityofstudiesthatqualifiedforinclusioninthisreviewemployedmodelsinvestigatingimmunesti-mulation;fewerexploredanti-inflammatoryeffects.Ani-malstudiesreportedimmunesystemeffectsinthegut,spleen,bonemarrow,liver,blood,thymus,lungs,andsaliva;controlledhumanstudiesreportedevidenceofimmunestimulationintheblood,anti-inflammatory Table6SafetyofImmunomodulatoryPolysaccharideProductsFollowingOralIntakeLentinulaedodes10adultsSafety4g/dayfor10weeks;repeated3-6monthslater50%ofsubjectsexperiencedbloodeosinophilia,eosinophilgranuleproteinsinserumandGIsymptoms4g[99]LentinulaedodesNudemiceSafety10%ofdietdays1-18,33-50Noadverseevents10%ofdiet[80]61menwithprostatecancer0.1g/kg,6monthsNoadverseevents6.8gLentinuslepideusFemalemiceSubchronic0.5g/kg,24daysNoevidenceoftoxicity34g[92]Phellinuslinteus(crudeextract)RatsAcuteOne5g/kgdose;2weeks�5g/kg349g[161](aqueousextract)MiceAcuteOne3g/kgdose;1day�3g/kg�204.g[100]319mg/kg,1monthHemorrhagesinintestine,liver,lung,kidney;inflammationandmicroabscessesinliver21.7gglucan[WGP])RatsAcuteOne2g/kg,observed2weeks�2g/kg�136g[144]2,33.3or100mg/kg,3monthsNOAEL=100mg/kg6.80gHeteroglycansRatsSubchronic1.5,3.0or6.0mg/kg,2monthsNoevidenceoftoxicity408mg[162]Rats&monkeysSubchronicandchronicequivalenthumandose,6monthsNoevidenceoftoxicityNAHumanswithcoloncancerSafety3g/day,upto7yearsNosignificantadverseevents3g[57]Humanswithcolorectalcancer3g/day,2years3g[58]AloeveragelDogsAcuteFedone32g/kg;observed2weeksLD50�32g/kg�2,176gBillPine,RatsOne21.5g/kg;observed2weeksLD50�10g/kg�680g*150lbadultetalNutritionJournalhttp://www.nutritionj.com/content/9/1/54Page16of22 effectsinnasallavagefluidandimprovedsurvivalincancerpatients.Theliteratureishighlyheterogenousandisnotsufficienttosupportbroadstructure/functiongeneralizations.Forthelimitednumberofstudiesthatinvestigatedwell-characterized,isolatedproducts(pri-marilyglucanproducts),effectscanbeunequivocallyattributedtopolysaccharides.Suchassociationsarecer-tainlymoretenuouswhenconsideringproductpowdersorproductsobtainedbyextractionmethodsdesignedtoisolatepolysaccharides,butwithoutcompletecomposi-tionalanalyses.Dietarypolysaccharidesareknowntoimpactgutmicrobialecology[101,102],andadvancesinmicrobialecology,immunologyandmetabolomicsindicatethatgutmicrobiotacanimpacthostnutrition,immunemodula-tion,resistancetopathogens,intestinalepithelialdevel-opmentandactivity,andenergymetabolism[103-107].Otherthanfucoidans,thepolysaccharidesdiscussedinthisreviewappeartobeatleastpartiallydegradedbybacterialenzymesinthehumandigestivetract(Table7).Arabinogalactans,galactomannans,aglucan(laminarin),glucomannans,andmixedpolysaccharideproducts(Ambrotose®products)havebeenshowntobemetabo-lizedbyhumancolonicbacteria.Orallyingestedfucoi-dans,glucansandmannans(ortheirfragments)havebeendetectedinnumeroustissuesandorgansthrough-outthebody[73,108,109],(CarringtonLaboratories,per-sonalcommunication).Weknowofnostudythathasdeterminedthespecificidentityoforally-ingestedpoly-saccharideendproductsinanimalorhumantissues.Onecanonlyspeculateuponthemechanismsbywhichthepolysaccharidesdiscussedinthisreviewinflu-enceimmunologicfunction,particularlywhenonecon-siderstheexceedinglycomplexenvironmentoftheGItract.Itispossiblethatfragmentsofpolysaccharidespartiallyhydrolyzedbygutbacteriamayeitherbindtogutepitheliaandexertlocalizedand/orsystemicimmunesystemeffects,orbeabsorbedintotheblood-stream,withthepotentialtoexertsystemiceffects.Cur-rentstudiesinvestigatingthelinkbetweenthebioconversionofdietarypolysaccharides,theirbioavail-abilityandtheirdownstreameffectsonthehost Table7FateofImmunomodulatoryPolysaccharideProductsFollowingOralIntakeCategoryProductMetabol-izedbyhumangut(method:tissuesdetected)Arabinogalactansspp.yesinvitroNA[163-169]UndariapinnatifidainvitroAb:humanplasma[108,170]GalactomannansCyamopsistetragonolobus(partiallyhydrolyzedguargum)invivoNA[171]CyamopsistetragonolobusinvitroNA[167]HordeumvulgareinvivoFluorescein-labeled:mouseMøinthespleen,bonemarrow,lymphnodesnodesLaminariadigitata(laminarin)yesinvitroNA[29,170,172]Sclerotiumrofsiiglucanphosphate,spp.(laminarin)invivoAlexaFluor488-labeled:mouseintestinalepithelialcells,plasma,GALTGALTSaccharomycescervisiae(particulate)invivoFluorescein-labeled:mousemacrophageinthespleen,bonemarrow,lymphnodesnodesTrametesversicolorinvivoC-labeled:ratandrabbitserum;mouseGItract,bonemarrow,salivaryglands,liver,brain,spleen,pancreaspancreasMannansAloebarbadensis(aloemannan)yesinvitroFITC-labeled:mouse,GItract[121,174]Aloebarbadensis(gelpowder)invitroNA[163]Aloebarbadensis(acemannan)NAinvivoC-labeled:dogsystemic,particularlyliver,bonemarrow,gut,kidney,thymus,spleencommunication)Ambrotosecomplex®,AdvancedAmbrotose®powderinvitroNA[163,175]PectinsNAyesinvitroNA[165-167,176]BuplerumfalcatuminvivoAbbound:mousePeyerspatch,liver[109]etalNutritionJournalhttp://www.nutritionj.com/content/9/1/54Page17of22 metabolismandphysiologyareutilizingmetabolomicandmetagenomicapproachesthatcandetectandtrackdiversemicrobialmetabolitesfromimmunomodulatorypolysaccharides[103].Theseandotherinnovativeapproachesinthefieldofcolonicfermentationarepro-vidingnovelinsightsintogutmicrobial-humanmutual-ism[110,111],itsimpactonregulatinghumanhealthanddisease,andtheimportanceofdietarymodulationodulationAdditionalRCTsofwell-characterizedproductsareneededtomorecompletelyunderstandtheimmunomo-dulatoryeffectsandspecificapplicationsoforalpolysac-charides.Suchstudieswillneedtobetterinvestigatetheoptimaltiminganddurationforpolysaccharideinges-tion.Thatis,shouldtheybeconsumedcontinuously,before,atthetimeof,orafterexposuretoapathogenorenvironmentalinsult?Onlyafewstudieshaveactu-allyinvestigatedtheimpactoftimingofpolysaccharideintaketoachieveoptimalbenefits.Dailyfeedingwithsomepolysaccharidesappearstoresultintolerance(anddiminishedbenefits);thishasbeendemonstratedforsomemushroom-glucans[3,26].Forthosepolysac-charideswhoseimmunologiceffectsaredependentontheirprebioticactivities,regularfeedingwouldbepre-sumednecessary.ConclusionsThedietarypolysaccharidesincludedinthisreviewhavebeenshowntoelicitdiverseimmunomodulatoryeffectsinanimaltissues,includingtheblood,GItract,andspleen.Incontrolledhumantrials,polysaccharideintakestimulatedtheimmunesysteminthebloodofhealthyadults,dampenedtheallergicresponsetoarespiratoryinflammatoryagent,andimprovedsurvivalincancerpatients.AdditionalRCTsofwell-characterizedproductsareneededtomorecompletelyunderstandtheimmuno-modulatoryeffectsandspecificapplicationsoforalListofabbreviations:female;:male;Ab:antibody;AIDS:autoimmunedeficiencysyndrome;AOM:azoxymethane;BBN:N-butyl-N-butanolnitrosamine;BLCL:BurkittsLym-phomaCellLine;BW:bodyweight;CBC:completebloodcount;CD:clusterofdifferentiation;CFU:col-onyformingunit;ConA:concanavalinA;CXCR:CXCchemokinereceptor;DMBA:7,12-dimethylbenzanthracene;DMH:N-N-dimethylhydrazine;DMN:dimethylhydrazine;DSS:dextransulfatesodium;EBV:Epstein-Barrvirus;GALT:gut-associatedlymphoidtis-sue;GI:gastrointestinal;Hhydrogenperoxide;HSV:herpessimplexvirus;ICR:imprintingcontrolregion;ID:intradermal;IEL:intraepitheliallympho-cytes;IFN-:interferongamma;IG:intragastric;IgA:immunoglobulinA;IgE:immunoglobulinE;IgG:immunoglobulinG;IgM:immunoglobulinM;IL:inter-leukin;IMC:invasivemicropapillarycarcinoma;IN:intranasally;IP:intraperitoneal;IV:intravenous;LPS:lipopolysaccharide;Mø:macrophage;mAb:monoclonalantibody;3-MCA:methylcholanthrene;MLN:mesen-tericlymphnodes;MM-46carcinoma:mousemam-marycarcinoma;MW:molecularweight;NK:naturalkiller;NOAEL:noobservableadverseeffectlevel;OVA:ovalbumin;PBL:peripheralbloodleukocytes;PBMC:peripheralbloodmononuclearcells;PHA:phy-tohaemagglutinin;PMA:phorbol12-myristate13-acet-ate;PML:polymorphonuclearlymphocyte;RCT:randomized,controlledtrial;RNA:ribonucleicacid;SC:subcutaneous;SDrats:SpragueDawley;TCR:Tcellreceptor;TLR:tolllikereceptor;TNF-:tumornecrosisfactoralpha;UC:ulcerativecolitis;WT:wildAcknowledgementsTheauthorswouldliketothankBarbaraK.Kinsey,WardMooreandMrs.JenniferApontefortheirassistancewiththepreparationofthismanuscript,andDr.AzitaAlaviandMrs.ChristyDuncanfortheireditorialassistance.JERandEDNconductedliteraturesearchesandwrotethemanuscript.RASprovidedtechnicalguidance.AllauthorsreadandapprovedthefinalCompetinginterestsTheauthorsareemployeesoftheResearch&DevelopmentDepartmentatMannatech,Incorporated,whichsellstwoofthepolysaccharideproducts(Ambrotose®powderandAdvancedAmbrotose®powder)discussedinthisReceived:6May2010Accepted:18November2010Published:18November20101.PaulsenBS:Plantpolysaccharideswithimmunostimulatoryactivities.OrgChem2.YamadaH,KiyoharaH:Complement-activatingpolysaccharidesfrommedicinalherbs.ImmunomodulatoryAgentsfromPlants.Editedby:WagnerHBasel.Switzerland:BirkhauserVerlag;1999:.3.HobbsC:MedicinalMushrooms:AnExplorationofTradition,HealingandSummertown,Tenn:BotanicaPress;2003.4.KusaykinM,BakuninaI,SovaV,ErmakovaS,KuznetsovaT,BesednovaN,etalStructure,biologicalactivity,andenzymatictransformationoffucoidansfromthebrownseaweeds.BiotechnolJAloes.ThegenusaloeBocaRaton,Fla.:CRCPress;2003.6.AndersonJW,SmithBM,GustafsonNJ:Healthbenefitsandpracticalaspectsofhigh-fiberdiets.AmJClinNutr7.WeickertMO,PfeifferAF:Metaboliceffectsofdietaryfiberconsumptionandpreventionofdiabetes.JNutr8.EstruchR,Martinez-GonzalezMA,CorellaD,Basora-GallisaJ,Ruiz-GutierrezV,CovasMI,etalEffectsofdietaryfibreintakeonriskfactorsforcardiovasculardiseaseinsubjectsathighrisk.JEpidemiolCommunity9.PelleyRP,StricklandFM:Plants,polysaccharides,andthetreatmentandpreventionofneoplasia.CritRevOncog10.LullC,WichersHJ,SavelkoulHF:Antiinflammatoryandimmunomodulatingpropertiesoffungalmetabolites.MediatorsInflammetalNutritionJournalhttp://www.nutritionj.com/content/9/1/54Page18of22 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