Brittany Witt

Introduction. Autism Spectrum Disorder (ASD) includes a broad range of social communication deficits characteristically accompanied by repetitive patterns of behavior, GI disturbances, and self-injury.^1,2 Approximately 1 in 59 children have ASD in the US, making the disorder increasingly significant to understand.³ A new area of study revolves around the gut-brain axis as a potential trigger. High exposure to antibiotics, usually from repeated infections early in life, can create an environment favorable for overgrowth of enteric bacteria such as Clostridia. These bacteria produce Propionic Acid (PPA), a short chain fatty acid that can influence neural and hormonal regulation throughout the body.⁴ These alterations in gut microbiota and subsequent gene expression may provide insight into the understanding, prevention, and treatment of ASD.^1,2  Methods. Rat pheochromocytoma cells (PC12 cells) were transfected with PPA via electroporation, and gene expression was analyzed after 24 hours via Northern and Western blots.⁵ PPA-treated rats were evaluated for behavior, and their brains were histologically analyzed to determine genetic and pathoneurologic alterations.⁶ Rats with pesticide-induced mitochondrial injury were treated with a carnitine derivative, PMX-500FI, and their brains were histologically evaluated for neuroprotective effects.⁷ Children with ASD were treated with oral vancomycin for 14 days, followed by oral or rectal Standardized Human Gut Microbiota and a stomach acid suppressant for 7-8 weeks in a trial of fecal microbial transplant (MTT) as therapy for ASD.⁸  Results. In both pre- and postnatally exposed mouse models, PPA inhibits histone deacetylase, altering expression of genes for catecholamine synthesis and other proposed ASD-associated genes.⁴ PPA-injected PC12 cells display increased expression of Tryptophan 5-hydroxylase 1 and GTP cyclohydrolase 1, two key enzymes in the serotonin synthesis pathway.⁵ PPA was also associated with altered GFAP and depleted OCT4 levels in young rat brains, as well as decreased thickness and number of neural stem cells in the hippocampus.⁶ Carnatinoid PMX-500FI demonstrated neuroprotection by restoring long-term potentiation deficits elicited by the pesticide.⁷ MTT-treated children displayed alleviated behavior and GI symptoms at least 8 weeks longer than children treated with vancomycin alone.⁸  Conclusions. Increased levels of PPA from enteric bacteria can disrupt normal neural development through decreased catecholamine gene expression, reduced neuroplasticity, and mitochondrial dysfunction. These changes may account for many of the behavioral symptoms associated with ASD. Carnatinoid supplementation can provided protection to neurons from mitochondrial insult, and microbial transplantation can ameliorate ASD symptoms by promoting a healthy gut environment and reducing PPA production.

1. Yang Y, Tian J, Yang B. Targeting gut microbiota: A novel and potential therapy for autism. Life Sci. 2017;194(12):111-119. http://www.sciencedirect.com/science/article/pii/S0024320517306653
2. MacFabe DF. Enteric short-chain fatty acids: microbial messengers of metabolism, mitochondria, and mind: implications in autism spectrum disorders. Microbial Etiology in Health and Disease. 2015;26(5):28177. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451098/
3. Centers for Disease Control and Prevention. Autism Spectrum Disorder. https://www.cdc.gov/ncbddd/autism/data.html. Accessed May 10, 2018
4. Foley KA, Ossenkopp KP, Kavallers M, MacFabe DF. Pre- and Neonatal Exposure to Lipopolysaccharide or the Enteric Metabolite, Propionic Acid, Alters Development and Behavior in adolescent Rats in a Sexually Dimorphic Manner. PLoS One. 2014;9(1). http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087072
5. Nankova BB, Agarwal R, MacFave DF, La Gamma EF. Enteric Bacterial Metabolites Propionic and Butyric Acid Modulate Gene Expression, Including CREB-Dependent Catecholaminergic Neurotransmission, in PC12 Cells – Possible Relevance to Autism Spectrum Disorders. PLoS One. 2014;9(8) http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0103740
6. Choi J, Lee S, Won J, Jin Y, Hong Yu, Hur TY, Kim JH, Lee SR, Hong Yo. Pathophysiological and neurobehavioral characteristics of a propionic acid-mediated autism-like rat model. PLoS One. 2018;13(2);https://doi.org/10.1371/journal.pone.0192925
7. Moos WH, Maneta E, Pinkert CA, Irwin MH, Hoffman ME, Faller DV, Steliou K. Epigenetic Treatment of Neuropsychiatric Disorders: Autism and Schizophrenia. Drug Development Research. 2016;77(2);53-72. https://www.ncbi.nlm.nih.gov/pubmed/26899191
8. Yang Y, Tian J, Yang B. Targeting gut microbiota: A novel and potential therapy for autism. Life Sci. 2017;194(12):111-119. http://www.sciencedirect.com/science/article/pii/S0024320517306653