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

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

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

  6. The Microbiome and Neurodevelopmental Disorders

  7. The Microbiome and Neurodevelopmental Disorders

  8. The Microbiome and Neurodevelopmental Disorders

  9. The Microbiome and Neurodevelopmental Disorders

  10. The Microbiome and Neurodevelopmental Disorders

  11. The Microbiome and Neurodevelopmental Disorders

  12. The Microbiome and Neurodevelopmental Disorders

  13. The Microbiome and Neurodevelopmental Disorders

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

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

  16. The Microbiome and Neurodevelopmental Disorders

  17. The Microbiome and Neurodevelopmental Disorders

  18. The Microbiome and Neurodevelopmental Disorders Neuropathology Quantification Hippocampus - GFAP 70000 * 60000 Saline PPA500 50000 2 ) * Mean Area ( µ m 40000 30000 * 20000 10000 0 CA1 & CA2 CA3/Dentate Hippocampus Total Propionate increases GFAP, Marker of Reactive Astrocytes and immunoreactivity in hippocampus

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

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

  21. The Microbiome and Neurodevelopmental Disorders Nitrotyrosine Immunoreactivity, a measure of oxidative stress PBS Vehicle High Dose PPA PPA causes increase anti Nitro-tyrosine immunoreactivity in hippocampal formation, a measure of oxidative stress

  22. The Microbiome and Neurodevelopmental Disorders Developmental delay in pups Eye Opening *** ^^ 2 2-VEH (38) ** LPS (42) 5-VEH (43) PPA (47) # eyes open 1 * ** p < .01, *** p < .001: PPA ^^ p < .01: LPS 0 12 13 14 15 16 Post-natal day 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)

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

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

  25. The Microbiome and Neurodevelopmental Disorders 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. •

  26. The Microbiome and Neurodevelopmental Disorders Autistic Children Rodents

  27. The Microbiome and Neurodevelopmental Disorders Rodents ASD Children

  28. The Microbiome and Neurodevelopmental Disorders Decreased Complex I Activity

  29. The Microbiome and Neurodevelopmental Disorders

  30. The Microbiome and Neurodevelopmental Disorders

  31. The Microbiome and Neurodevelopmental Disorders

  32. The Microbiome and Neurodevelopmental Disorders 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

  33. The Microbiome and Neurodevelopmental Disorders Early Immune Activation Model of Autism: Animal Model and Probiotic Treatment

  34. The Microbiome and Neurodevelopmental Disorders

  35. The Microbiome and Neurodevelopmental Disorders

  36. The Microbiome and Neurodevelopmental Disorders

  37. The Microbiome and Neurodevelopmental Disorders

  38. The Microbiome and Neurodevelopmental Disorders

  39. The Microbiome and Neurodevelopmental Disorders

  40. The Microbiome and Neurodevelopmental Disorders

  41. The Microbiome and Neurodevelopmental Disorders

  42. The Microbiome and Neurodevelopmental Disorders

  43. The Microbiome and Neurodevelopmental Disorders

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

  45. The Microbiome and Neurodevelopmental Disorders

  46. The Microbiome and Neurodevelopmental Disorders

  47. The Microbiome and Neurodevelopmental Disorders

  48. The Microbiome and Neurodevelopmental Disorders

  49. Questions

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