www.milkscienceconference.comVALENCIA
24 · 25 OCTUBRE 2019
Prof. Dr.
Dominique A. VuittonBourgogne Franche-Comté University, France
Profesora Emérita de Inmunología Clínica en la Universidad Bourgogne Franche-Comté, Francia.
Raw milk, allergies, asthma and respiratory infections: main results of the «PASTURE » international project.
Leche cruda, alergias, asma e infecciones respiratorias: principales resultados del proyecto internacional «PASTURE».
with the support of / con el apoyo de:
Rawmilk,allergies,asthmaandrespiratoryinfections:mainresultsofthe«PASTURE»internationalproject
DominiqueAngèleVUITTONProfessoremeritusofClinicalImmunology
UniversityBourgogneFranche-Comté,FranceCorrespondingmemberoftheFrenchNationalAcademyofMedicine,
Inmemoryto
Jean-CharlesDalphin,Onbehalfof
Marie-LaureDalphin,AmandineDivaret-Chauveau,SophieNicklaus,ErikavonMutius
Urbanization&
Development
Increasedstandardofliving
significantlyassociatedwith
DecreasedfamilysizeDecreasednumberofinfectionsinearlylife:
bacteriaandviruses:vaccination,antibiotics,parasites:slaughteringandmeatcontrol…
Increasedhygiene(‘hygiene’hypothesis)Majorchangesinfeedinghabits
From1960to2000:unprecedentedincreaseinallergic/atopicdiseases
• Beingbornandlivingonafarm:majorcircumstancesofprotectionagainstallergy– Timespentwithanimals,inthestable,inthebarn
– Drinkingrawmilk(cf.Braun-FahrländerandvonMutius,2011;vonMutius,2012)
• forthepregnantwomanandherchildinearlylife• Associationfoundincross-sectionalstudiesinmanydifferent
countries
• Alsofoundinurbanchildrendrinkingrawmilk
Rawmilkandallergy:anon-expectedprotectiveassociation…
Observationsincross-sectionalstudies
11.8
1.4
14.8
2.8
16
3.2
19.8
5.1
32.9
12.4
0
5
10
15
20
25
30
35
Asthmadiagnosis
Asthmasymptoms
Hay feverdiagnosis
Hay feversymptoms
Atopy
No exposureMilk onlyStable onlyStable and milk
The‘Alex’study[Riedleretal,TheLancet,2001]
1,000sofquestionnairesonenvironment,diet,behaviour,occupation,health…Blood,milk,andenvironmentalsamplesMedicalvisitsat1,3,4.5,6,10.5,17yearsMicrobiological,immunological,andgenomicstudies
The‘PASTUREcohort’LongitudinalstudyofruralEuropeanchildren(from2002)ü 500bornandlivingonafarmü 500notbornandlivingona
farmFollow-upfrompregnancyto17yrs-old
Rawmilk,rawmilk-products,…rawmilk-cheeses
ThePASTUREstudydidnotspecificallyaddresstheissueofrawmilk-cheeses!Why??
ü Studiesbasedoncorrelationsbetweenü environmentalandbiologicaldata(labmeasurements),ü medicaldata(questionnairesandmedicalvisits),andü datacollectedbytheparents(yearlyquestionnaires,‘first-yeardiary’)
ü ExceptforFrance,differentiationbetweentheoriginofthemilktopreparecheeseswasjudgednon-reliable
ü Thequestionon‘farm-madecheese’didnotcoverallrawmilk-cheeses(mostarepreparedoutsidethefarm)
17yearslater,themessagesofPASTURE
ResultsofthePASTUREcohortconfirm:– Contactwithanimals– Stableandbarnenvironment– Drinkingrawmilk
actuallyandindependentlyprotectagainstoccurrenceofallergicdiseaseslaterinlife– Atopicdermatitis– Asthma– Allergicrhinitis– Allergicsensitization
Inaddition,drinkingrawmilkprotectsagainstacuteinfectionsofthe1styearoflife
17yearslater,themessagesofPASTURE
Correlationsbetweentypeofmilkandoccurrenceofinfectionsinthe1styearoflife[Lossetal,JACI,2014]
1.Diversitymatters!Inthefarmenvironment:– Diversityofexposure• stable,barn,house• Microbes+pollen(hay),plantparticles(straw)
– Diversityofanimals• Farmanimals++,dogsandcats
– Diversityofmicro-organisms• Grampositiveetnegativebacteria,actinomycetes,• Fungi:Absidiaspp.,Eurotiumspp.,Cladosporiumspp.,Penicilliumspp.,• Highdiversityintraditionalfarms
• Earlyfooddiversificationinthe1styearoflife1.Diversitymatters!
Predictiveeffectofafooddiversityscore
onasthma onfoodallergy[Roduitetal,JACI,2014]
1.Bothdiversityandquantitymatter…forcheeses
[Nicklausetal,Allergy,2018]
ü Childrenwhoneverorrarelyatecheesehadhigherriskoffoodallergyandallergicrhinitis
ü Finnishchildrenhadthehighestfrequencyofcheeseconsumption
ü Frenchchildrenhadthemostdiverseconsumptionofcheeses
ü Farmers’andnon-farmers’childrenhadsimilarcheeseconsumption
ü Cheeseconsumptiondiversitywascorrelatedwiththemother’slevelofeducation
2.Rawmilk:THEprotectivefactor
• Mostconstantlyfoundinanalyses• Independentofother‘farm-associated’factors
• Additionaleffectof‘farmmilk-’butter,yoghurt,andcheese
• Mother’sconsumptionisalsoprotectiveforherchild
• Consumptioninearlylife(<6years)ismostimportant
Roleofthemilkmicroflora?Thefirsthypothesis:bacterialendotoxins
2.Rawmilk:THEprotectivefactor
Unboiled raw milk
UHT milk
Pasteurized milk
Boiled raw milk
[Lossetal-GABRIELA.JACI,2011]
ü Nomoreendotoxinsintherawmilkofthestudiedfarmsthanin‘shopmilk’keptbyfamilies
ü Highernumberanddiversityof
micro-organismsinrawmilkü Noassociationbetween
numbersoforganisms(orsinglespecies)andclinicalparameters(allergy,infectionetc.)
ü Associationwithdiversity
(organismssimilartothosefoundinthefarmenvironment)
Roleofnon-microbialcomponents?ü Wheyproteins:changesinα-lactalbumin,etβ-lactoglobulinü Immunitycomponents:lactoferrin,IgA,TGF-βü Lipids:ConjugatedLinoleicAcids(CLA),Ω-3FattyAcids,ShortChainFattyAcids
2.Rawmilk:THEprotectivefactorCo
nten
tinom
éga-3Fa
ttyac
ids
[Bricketal,JACI,2016]
Non-asthmatics Asthmatics
Percen
tage
ofc
hildrenwith
allergen
icsen
sitiz
ation
[Roduitetal,Allergy,2018]
3.Earlyexposureisassociatedwithimmunologicalchanges
• Influenceofmother’sexposuretoprotectivefactorsduringpregnancyonimmuneresponse:trueforrawmilkandrawmilkproducts
Nbofanimalspecies
Unskimmedrawmilk
Farmbutter
FarmYoghurt
Nbofanimalspecies
Nbofhoursinthebarn
Interféron-γ
TNF-αFarmbutter
FarmYoghurt
Productionofcytokinesbytheimmunecellsofthecordblood,accordingtomaternalexposureduringpregnancy
[Pfefferleetal.JACI,2010]
Influenceofearlyrawmilkconsumptionbythechildrenonthedevelopmentof‘innate’and‘adaptive’immunity
3.Earlyexposureisassociatedwithimmunologicalchanges
No raw milk
Unboiled raw milk
Boiled raw milk
StimulusMarkerFarmersvsnon-farmersStayinthestablesRawmilkconsumption
[Lluisetal.JACI,2014]
TLR4TLR5TLR6
[Lossetal.JACI,2012]InfluenceontheexpressionoftheToll-likereceptors
Nb
InfluenceonthedevelopmentofT-regulatorlymphocytes
The‘bigpicture’
Possiblemechanismsoftheeffectsoftraditionalcheesesonhealth?
Gutmicroflora(‘microbiota’):atthecentreoftheimmunesystemregulationaswellasavarietyofmetabolismsIntestinalmicrobiota:- differentinchildrenlivingin‘developed’vs‘traditional’environment- differentinchildrenwithandwithoutallergy;- morediversein‘protectedruralchildren’Confirmationfromcohortstudies[Azad,ClinExpAllergy.2015]
ThePasturestudyü Confirmedtheprotectiveeffectofrawmilk
consumedbythemotherduringpregnancyandbythechildreninthefirst6yearsofageü Againstallergicdisordersü Againstacuteinfectionsofthefirstyearof
ageü Showedthatthiseffectwasincreasedbythe
child’sconsumptionoffarmdairyproductsforthefirstyearoflifeandbythechild’sconsumptionofavarietyofcheeses(includingrawmilk-cheeses+++)forthefirst18months
ü Demonstratedanassociationwithimmunologicalparameters
ü Suggestedinterferencewithgeneticfactorsandintestinalandrespiratorymicrobiota
Thankstothe«PASTURE»team!Prof.Jean-CharlesDalphin
– DrMarie-LaureDalphin– DrVincentKaulek– DrJean-JacquesLaplante– DrAmandineDivaret-Chauveau– DrGabrielReboux– DrBertrandSudre– DrSandrineRoussel– DrSophieNicklaus– CécileTravers– NadiaGuillou– clinicalresearchtechniciansandengineers– Prof.ErikavonMutiusandthecountrycoordinators
Andall‘PASTURE’familiesonboard!
ScientificreferencesofthePASTUREstudy
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2. TaftD,HoS,TancrediD,StephensenC,HindeK,vonMutiusE,KirjavainenP,DalphinJC,LauenerR,RiedlerJ,MorrowA,LewisZ,MillsD.PopulationdurationofbreastfeedingandprevalenceofBifidobacteriumlongumsubspeciesinfantis.CurrDevNutr2019;3:pii:nzz040.OR01-01-19.
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5. RoduitC,FreiR,FerstlR,LoeligerS,WestermannP,RhynerC,SchiaviE,BarcikW,Rodriguez-PerezN,WawrzyniakM,ChassardC,LacroixC,Schmausser-HechfellnerE,DepnerM,vonMutiusE,Braun-FahrländerC,KarvonenA,KirjavainenP,PekkanenJ,DalphinJC,RiedlerJ,AkdisC,LauenerR,O'MahonyL;PASTURE/EFRAIMstudygroup.Highlevelsofbutyrateandpropionateinearlylifeareassociatedwithprotectionagainstatopy.Allergy.2018Nov3.doi:10.1111/all.13660.[Epubaheadofprint]
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7. KarvonenAM*,TischerC*,KirjavainenPV,RoponenM,HyvärinenA,IlliS,MustonenK,PfefferlePI,RenzH,RemesS,SchaubB,vonMutius,E,PekkanenJ.Earlyageexposuretomoisturedamageandsystemicinflammationattheageof6years.IndoorAir.2018May;28(3):450-458.
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15. SchröderPC,CasacaVI,IlliS,SchieckM,MichelS,BöckA,RoduitC,FreiR,LluisA,GenuneitJ,PfefferleP,RoponenM,WeberJ,Braun-FahrländerC,RiedlerJ,LauenerR,VuittonDA,DalphinJC,PekkanenJ,vonMutiusE,KabeschM,SchaubB;PASTUREStudygroup.IL-33polymorphismsareassociatedwithincreasedriskofhayfeverandreducedregulatoryTcellsinabirthcohort.PediatrAllergyImmunol.2016Nov;27(7):687-695.
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