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TheEnteric(Gut)MicrobiomeModulatesMitochondrialFunction
Richard E. Frye, M.D., Ph.D.Child and Behavioral Neurologist
Arkansas Children’s HospitalUniversity of Arkansas for Medical Sciences
The Microbiome and the Microchondria
TalkingPoints
Theenteric(gut)microbiomehasanimportantinfluenceinonhealthanddiseasestatesinhumans.
Theentericmicrobiomeinfluencesthehumanhostusingchemicalmediators,someofwhichcandirectlyeffectmitochondrialfunction
Shortchainfattyacidsproducedbygutbacterianotonlymodulatemitochondrialfunctionandcellularregulatorypathways,butcanalsobeusedasmitochondrialfuels.
The Microbiome and the Microchondria
Bacteriauseacomplexcommunicationnetworktothriveinanenvironment
The Microbiome and Neurodevelopmental Disorders
Themicrobiota induceshostimmunetoleranceThe Microbiome and Neurodevelopmental Disorders
SegmentedFilamoentous BacteriaGutassocatied lymphoidtissue
The Microbiome and Neurodevelopmental Disorders
The Microbiome and Neurodevelopmental Disorders
The Microbiome and Neurodevelopmental Disorders
The Microbiome and Neurodevelopmental Disorders
The Microbiome and Neurodevelopmental Disorders
The Microbiome and Neurodevelopmental Disorders
The Microbiome and Neurodevelopmental Disorders
The Microbiome and Neurodevelopmental Disorders
AutismSpectrumDisorder
andthe
Microbiome
The Microbiome and Neurodevelopmental Disorders
PropionicAcid
ModelofAutism:
AnimalModels
The Microbiome and Neurodevelopmental Disorders
The Microbiome and Neurodevelopmental Disorders
The Microbiome and Neurodevelopmental Disorders
The Microbiome and Neurodevelopmental Disorders
CA1 & CA2 CA3/Dentate Hippocampus Total0
10000
20000
30000
40000
50000
60000
70000
*
*Mea
n Ar
ea (µ
m2 )
Saline PPA500
Hippocampus - GFAP
*
Propionate increases GFAP, Marker of Reactive Astrocytes and immunoreactivity in hippocampus
Neuropathology Quantification
The Microbiome and Neurodevelopmental Disorders
CD68markerofMicroglia
Control (PBS) PPA
PPA increases activated microglia (neuroinflammation)
The Microbiome and Neurodevelopmental DisordersInterleukin 6PBS PPA
White Matter
Hippocampus
The Microbiome and Neurodevelopmental Disorders
PBS Vehicle High Dose PPA
PPA causes increase anti Nitro-tyrosine immunoreactivity in hippocampal formation, a measure of oxidative stress
Nitrotyrosine Immunoreactivity, a measure of oxidative stress
Developmental delay in pupsEye Opening
Post-natal day12 13 14 15 16
# ey
es o
pen
0
1
2 2-VEH (38)LPS (42)5-VEH (43)PPA (47)
*
**^^
***
Developmental milestones are delayed in pups prenatally exposed to PPA and LPS (ie. pinna detachment, incisor eruption).(PPA similar to valproic acid- mitochondrial function/gene expression)
** p < .01, *** p < .001: PPA^^ p < .01: LPS
The Microbiome and Neurodevelopmental Disorders
Acoustic startle response: Prenatal PPA and LPS produce hyper-sensitivity to stimulus
SexMale Female
Aver
age
star
tle re
spon
se
0
200
400
600
800
1000 2-VEH LPS 5-VEH PPA
**** **
**
n = 14-15 per group
** p < .01: LPS, PPAMales higher than females,regardless of treatment.
Other anxiety-like behaviour also present in PPA and LPS animals.
The Microbiome and Neurodevelopmental Disorders
The Microbiome and Neurodevelopmental Disorders
PropionicAcid
ModelofAutism:
ParallelsofChildrenwithAutism
• 213ASDpatientsscreenedwithacyl-carnitinebiomarkers
• 74(35%)with>=3fastingacyl-carnitine elevations
• Acyl-carnitine abnormalitieswereconfirmedin48%
• Correctedprevalenceof17%ofASDchildrenscreened.
The Microbiome and Neurodevelopmental Disorders
AutisticChildren Rodents
The Microbiome and Neurodevelopmental Disorders
Rodents ASDChildren
The Microbiome and Neurodevelopmental Disorders
DecreasedComplexIActivity
The Microbiome and Neurodevelopmental Disorders
The Microbiome and Neurodevelopmental Disorders
The Microbiome and Neurodevelopmental Disorders
The Microbiome and Neurodevelopmental Disorders
GI-After=GISymptomsstartedaftertheonsetofAutismsymptomsGI-Before/Same=GISymptomsstartedbeforeoratthesametimeasAutismsymptoms
The Microbiome and Neurodevelopmental Disorders
The Microbiome and Neurodevelopmental Disorders
EarlyImmuneActivation
ModelofAutism:
AnimalModelandProbioticTreatment
The Microbiome and Neurodevelopmental Disorders
The Microbiome and Neurodevelopmental Disorders
The Microbiome and Neurodevelopmental Disorders
The Microbiome and Neurodevelopmental Disorders
The Microbiome and Neurodevelopmental Disorders
The Microbiome and Neurodevelopmental Disorders
The Microbiome and Neurodevelopmental Disorders
The Microbiome and Neurodevelopmental Disorders
The Microbiome and Neurodevelopmental Disorders
The Microbiome and Neurodevelopmental Disorders
MicrobiotaTransferTherapy(MTT)
The Microbiome and Neurodevelopmental Disorders
The Microbiome and Neurodevelopmental Disorders
The Microbiome and Neurodevelopmental Disorders
The Microbiome and Neurodevelopmental Disorders
The Microbiome and Neurodevelopmental Disorders
Questions
