Chad Griesbach

Introduction. Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder characterized by social deficits, repetitive behaviors, and restricted interests. The prevalence of ASD has dramatically increased recently, rising from 4.5 in 10,000 in 1966, to 1 in 68 children aged eight years in 2010⁶. Gastrointestinal comorbidities are common among ASD patients, which has sparked interest in the role of the gut microbiome in ASD⁶. These studies have focused on short chain fatty acids (SCFAs), namely propionic acid, after propionic acid producing bacteria were found in increased levels within stool samples of ASD patients⁴. This research primarily examines the effects of injected propionic acid in rodent models and it has found that propionic acid alters gene expression, causes mitochondrial dysfunction, and glutamate excitotoxicity^1,2,4. As we learn more, the challenge becomes identifying definitively the causative agent(s) of the very complex profile of behaviors and symptoms in ASD. Methods. Propionic acid was administered to rats. Reverse transcription polymerase chain reaction was used to identify and examine gene expression in the hippocampus¹. An acyl-carnitine panel was used to evaluate the function of the fatty-acid oxidation pathway. Glutathione metabolism was measured by taking fasting blood samples and using high-pressure liquid chromatography with electrochemical detection and metabolite quantitation⁴. Rats were treated with PPA and an assay for GABA by ELISA and Glutamate/Glutamine by HPLC were performed². The probiotic Protexin was used and fecal samples were analyzed using ELISA and culture plating³. Behavioral models used ethnovision and video recordings to quantify behavioral patterns in response to stimuli⁵. Results. GFAP and TNF-alpha were significantly increased in expression¹. C16OH, C14, and C4OH were increased above normal. Total GSH and free GSH were reduced, while free GSSG was elevated⁴. Glutamate was elevated, GABA was reduced². Probiotic treated samples showed reduced Glutamate/GABA ratio³. Increased repetitive behavior, decreased social interaction, and increased object fixation found in behavioral model⁵. Conclusion. Studies show that propionic acid is a metabolite of species of the gut microbiota, elevated in ASD patients with GI comorbidities. Propionic acid increases an astrocyte marker and pro-inflammatory marker, and results in mitochondrial dysfunction, which together constitute a reduction in neural plasticity. Further, glutamate toxicity helps explain the repetitive and social behaviors in these patients. Behavioral studies confirm that PPA mimics ASD symptoms in rodent models. The elucidated molecular mechanisms, behavioral studies, and probiotic effects together constitute a strong implication of PPA in the pathogenesis of ASD, and demand further study.

1. Choi J, Lee S, Jin Y, et al. Pathophysiological and neurobehavioral characteristics of a propionic acid-mediated autism-like rat model. PLoS One. 2018;13(2).
2. El-Ansary A, Al-Salem HS, Asma A, Al-Dbass A. Glutamate excitotoxicity induced by orally administered propionic acid, a short chain fatty acid can be ameliorated by bee pollen. Lipids Health Dis. 2017;16(96).
3. El-Ansary A, Bacha AB, Bjørklund G, et al. Probiotic treatment reduces the autistic-like excitation/inhibition imbalance in juvenile hamsters induced by orally administered propionic acid and clindamycin. Metabolic Brain Disease. March 2018:1-10.
4. Frye RE, Melnyk S, MacFabe DF. Unique acyl-carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrum disorder. Transl Psychiatry. 2013;3(1).
5. MacFabe D. Autism: Metabolism, Mitochondria, and the Microbiome. Global Advances in Health and Medicine. 2013;2(6):52-66
6. Mayer, Emeran A, Padua, David, Tillisch, Kirsten. Altered brain-gut axis in autism: comorbidity or causative mechanism? Bioessays 10 Sep. 2014