Richard Frye, MD, PhD, FAAP, FAAN, CPI, will discuss: *The enteric (gut) microbiome has an important influence on health and disease states in humans. * The enteric microbiome influences the human host using chemical mediators, some of which can directly affect mitochondrial function * Short chain fatty acids produced by gut bacteria not only modulate mitochondrial function and cellular regulatory pathways, but can also be used as mitochondrial fuels.

1. The Enteric (Gut) Microbiome Modulates
Mitochondrial Function
Richard E. Frye, M.D., Ph.D.
Child and Behavioral Neurologist
Arkansas Children’s Hospital
University of Arkansas for Medical Sciences

2. The Microbiome and the Microchondria
Talking Points
The enteric (gut) microbiome has an important influence in
on health and disease states in humans.
The enteric microbiome influences the human host using
chemical mediators, some of which can directly effect
mitochondrial function
Short chain fatty acids produced by gut bacteria not only
modulate mitochondrial function and cellular regulatory
pathways, but can also be used as mitochondrial fuels.

3. The Microbiome and the Microchondria

4. Bacteria use a complex communication network to
thrive in an environment
The Microbiome and Neurodevelopmental Disorders

5. The microbiota induces host immune tolerance
The Microbiome and Neurodevelopmental Disorders
Segmented Filamoentous Bacteria
Gut assocatied lymphoid tissue

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14. Autism Spectrum Disorder
and the
Microbiome
The Microbiome and Neurodevelopmental Disorders

15. Propionic Acid
Model of Autism:
Animal Models
The Microbiome and Neurodevelopmental Disorders

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CA1 & CA2 CA3/Dentate Hippocampus Total
0
10000
20000
30000
40000
50000
60000
70000
*
*
MeanArea(µm
2
)
Saline
PPA500
Hippocampus - GFAP
*
Propionate increases GFAP, Marker of Reactive Astrocytes and
immunoreactivity in hippocampus
Neuropathology Quantification

19. The Microbiome and Neurodevelopmental Disorders
CD68 marker of Microglia
Control (PBS) PPA
PPA increases activated microglia (neuroinflammation)

20. The Microbiome and Neurodevelopmental Disorders
Interleukin 6PBS PPA
White Matter
Hippocampus

21. 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

22. Developmental delay in pups
Eye Opening
Post-natal day
12 13 14 15 16
#eyesopen
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

23. Acoustic startle response: Prenatal PPA and LPS
produce hyper-sensitivity to stimulus
Sex
Male Female
Averagestartleresponse
0
200
400
600
800
1000 2-VEH
LPS
5-VEH
PPA
**
** **
**
n = 14-15
per group
** p < .01: LPS, PPA
Males higher than females,
regardless of treatment.
Other anxiety-like behaviour also present in PPA and LPS animals.
The Microbiome and Neurodevelopmental Disorders

24. The Microbiome and Neurodevelopmental Disorders
Propionic Acid
Model of Autism:
Parallels of Children with Autism

25. • 213 ASD patients screened with acyl-carnitine biomarkers
• 74 (35%) with >=3 fasting acyl-carnitine elevations
• Acyl-carnitine abnormalities were confirmed in 48%
• Corrected prevalence of 17% of ASD children screened.
The Microbiome and Neurodevelopmental Disorders

26. Autistic Children Rodents
The Microbiome and Neurodevelopmental Disorders

27. Rodents ASD Children
The Microbiome and Neurodevelopmental Disorders

28. Decreased
Complex I
Activity
The Microbiome and Neurodevelopmental Disorders

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32. GI-After = GI Symptoms started after the onset of Autism symptoms
GI-Before/Same = GI Symptoms started before or at the same time as Autism symptoms
The Microbiome and Neurodevelopmental Disorders

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Early Immune Activation
Model of Autism:
Animal Model and Probiotic Treatment

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44. Microbiota Transfer Therapy (MTT)
The Microbiome and Neurodevelopmental Disorders

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49. Questions