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PennCHOP

MICROBIOME PROGRAM

Theroleofdiets:Standardizationand
characterization
GaryD.Wu,M.D.
FerdinandG.Weisbrod ProfessorofMedicine
DivisionofGastroenterology
PerelmanSchoolofMedicine
UniversityofPennsylvania

Challenges in characterizing the effects


of diet on the human gut microbiome

The utility of animal models in


studying the interaction between diet
and the gut microbiome

Humans are poorly adherent to


standardized dietary regimes

Tight control of defined diets over long


periods of time

Current tools to characterize dietary


composition and intake are imperfect

Multiple biological replicates feasible

The reciprocal nature of dietary composition


to maintain isocaloric consumption make it
difficult to determine the factor responsible
for an observed outcome
Diet can have profound impacts on host
biology independent of the gut microbiota
Both intensive controlled feeding
experiments and large outpatient cohort
studies are expensive and challenging to
complete

Germ-free animals can be used to examine


the effect of diet independent of the gut
microbiome
Defined microbial consortia or complete
human gut microbiota studies can be
performed in gnotobiotic animals
Cause-and-effect relationships involving diet
and the gut microbiota can be determined

Agenda
Functional impact diet on the murine gut microbiota and its
metabolome

Diet and defined bacterial consortia in gnotobiotic mice

Diet and humanized microbiota animal models

The impact of the gut microbiota on the mammalian host


metabolome
Predictability and translatability of preclinical studies to humans

Diet,theGutMicrobiome,anditsMetabolome

Holmesetal.CellMet.2012;16:559

EffectofDietonComposition oftheGut
Microbiota anditsImpactonDisease

Devkota etal.Nature 2012;487:104

SartorRB.Nat.Rev.Gastro.andHep.2012

EffectofDietonMetaboliteProductionbythe
GutMicrobiota anditsImpactonDisease

Wangetal.Nature.2011;472:5763

Inflammatory Bowel Disease (IBD) Afflicts Approximately


1.5 Million People in the U.S. Alone

IncidenceofIBDIncreasingWorldwide
CD

NA&
Europe
(70s80s)

UC

Asia
(2000s)

Molodecky MA. Gastroenterology 2012;142:46-54


Loftus EV. Gastroenterology 2004;126:1504

DefinedFormulaDietsandtheTreatment
ofCrohns Disease
ResponsetoDietaryTherapy
Elemental

Nonelemental

Giaffer,1990
Kobayashi,1998
Mansfield,1995
Middleton,1995
Park,1991
Raouf,1991
Rigaud,1991
Royall,1994
Verma,2000
Sakurai,2002

100
80
60
40
20
0

Adapted from Zachos M. Cochrane Review 2009

TheRelationshipBetweenDiet,theGutMicrobiota,andIBD

Albenberg etal.CurrentOpinionGastro.2012

DefinedformuladietsforthetreatmentofCrohns diseasearethemost
effectivewhenconsumedcompletelyinplaceofanormaldiet(Exclusive
EnteralNutritionEEN).
DoesEENprovidesomethinggoodforpatientswithIBDthatisnotabundantin
theregulardiet?
DoestheconsumptionofEENexcludesomethingthatisbadforpatientswithIBD
intheregulardiet?

Something Bad in the Diet and the


Gut Microbiome?

Agenda
Functional impact diet on the murine gut microbiota and its
metabolome

Diet and defined bacterial consortia in gnotobiotic mice

Diet and humanized microbiota animal models

The impact of the gut microbiota on the mammalian host


metabolome
Predictability and translatability of preclinical studies to humans

Fecal microbiomes and metatranscriptomes of monozygotic twin pairs after consumption of a


fermented milk product (FMP) vs. gnotobiotic mice harboring a 15-species model human gut
microbiota after gavage with all five FMP strains.
No significant changes in humans and only minimal changes in microbiota configuration were
noted in mice.
The human fecal metatranscriptome exhibited significant changes that mirrored changes in
gnotobiotic mice, including those related to plant polysaccharide metabolism.

Agenda
Functional impact diet on the murine gut microbiota and its
metabolome

Diet and defined bacterial consortia in gnotobiotic mice

Diet and humanized microbiota animal models

The impact of the gut microbiota on the mammalian host


metabolome
Predictability and translatability of preclinical studies to humans

Agenda
Functional impact diet on the murine gut microbiota and its
metabolome

Diet and defined bacterial consortia in gnotobiotic mice

Diet and humanized microbiota animal models

The impact of the gut microbiota on the mammalian host


metabolome
Predictability and translatability of preclinical studies to humans

HostGutMicrobiota CoMetabolisminRodentModelSystems

Agenda
Functional impact diet on the murine gut microbiota and its
metabolome

Diet and defined bacterial consortia in gnotobiotic mice

Diet and humanized microbiota animal models

The impact of the gut microbiota on the mammalian host


metabolome
Predictability and translatability of preclinical studies to humans

Extreme and Consistent Effect of the Diet on the


Murine Gut Microbiota

Hidebrandt MA et al. Gastroenterology 2009

PlasmaMetabolomics andtheGut
Microbiota inVegansandOmnivores
Crosssectionalstudy
15vegansand16omnivores
Three24hourdietaryrecallspriortosample
collection
Fastingplasma,urine,andstoolfor
metabolomics
Stoolforassessmentofmicrobiota composition

DietaryComposition
BetweenOmnivores
vs.Vegans

Wuetal.Gut2014

ThePlasmaandUrinary
Metabolome of
Omnivoresvs.Vegans

RandomForrest

UrinaryMetabolome
Bothdietandthe
plasma/urinarymetabolome
aredramaticallydifferent
betweenomnivoresandvegan.

Wuetal.Gut2014

ComparingtheCompositionoftheGutMicrobiota in
Vegansvs.Omnivores
ControlledFeedingExperiment:CAF
Wuetal.Science 2011;334:1058

Wuetal.Gut2014

10Healthyvolunteers
Randomizedtohighfibervs.lowfiberdiet
10dayinpatientstaywithsamemealseachday
Caloricintakeadjustedtomaintaincurrentweight
Dailystoolsamplecollection

TheBidirectionality ofGutMicrobiome Investigation

Definedenvironmentalconditions
Definedgenetics
Monotonousdiet

Highsignaltonoiseratio

Freelivinginahighlyvariable
environment
Geneticdiversity
Variablediet
Lowsignaltonoiseratio
BUT

Proofofconceptcauseandeffect
relationshipsinamodestsizedcohort

Smalleffectsizesoverlarge
populationscanbehighlyimpactful
Examples(FDAdrugdevelopment
paradigmandfoodadditives)

DietaryChallengesinMurine GutMicrobiome Research


Coprophagia inrodentmodels
Responseoftheendogenousmurine gutmicrobiota todietdiffersin
magnitudeandconsistencyrelativetohumans
Mousechowdietinstudiesismonotonousrelativethethevariabilityof
thehumandiet
Murine digestivephysiologyanditsresponsetodietisdifferentfrom
human(i.e.bileacids,importanceoffermentation,etc.)
ImpactofbacterialDNAinmousechowonsequencingresults(e.g.
Lactococcus spp.)
Lackofmousechowstandardizationinstudiesasapossiblecauseof
variance:
Composition:Closedformulavs.opensourcediet,batchtobatchvariation
indiet,phytoestrogen (alfalfa)
Formulation:Sterilizedvs.nonsterilizeddiet
Feedingbehavior:Adlibvs.fasting

AnimalWelfare
Limitedabilitytoexcludethetransferofmicrobiota via
coprophagia betweencohousedmice:
Environmentalstresswiththeusewirebottomcages
Socialisolationofindividuallyhousedmice
Impactoflongtermdietaryinterventionsinvolvingextreme
dietarymodificationsincompositionand/orcaloricintake
ImpactonhostphysiologywiththeintroductionofGRASfood
additivesintochowathighconcentrations

PennIntestinalMicrobiome ProjectGroup
Patient/subjectrecruitmentand
phenotyping,dietaryassessment,
samplecollectionandprocessing
RobertBaldassano,MD(CHOP)
*JamesD.Lewis,MD(Penn)

DNAsequencing,dataanalysis,and
mathematicalmodeling
*FredericD.Bushman,PhD(Penn)
Hongzhe Li,PhD(Penn)
KyleBittinger,PhD(CHOP)
Yun Li(Penn)

*GaryD.Wu,MD(Penn)

Microbiology
MarkGoulian,PhD(Penn)

GaryL.Lichtenstein,MD(Penn)
CharleneCompher,PhD,RD(Penn)

BiologicalOxymetry
SergeiVinogradov,PhD(Penn)

Metabolomics
MichaelBennett,PhD(CHOP)
MarcYudkoff,MD(CHOP)

*CoPrincipalInvestigators

JunChen,SamMinot,SerenaDollive,EricChen,ChristianHoffmann,YingYuChen,KyleBittinger,Jennifer
Hwang,ErinGilroy,Kernika Gupta,LisaNessel,LindseyAlbenberg,JudithKelsen,ColleenJudge,Christel
Chehoud,DavidShen,Rohini Sinha,DavidMetz,TatianaEsipova,SusanParrott,ElliotFriedman,JosieNi,
SarahSmith,LillianChau,EricaPanfen,AndrewLin,SarahSmith,JackJiang

PennCHOP

MICROBIOME PROGRAM

TheJointPennCHOPCenterfor
Digestive,Liver,andPancreaticMedicine

CenterforMolecularStudiesin
DigestiveandLiverDiseases
(P30DK050306)

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