Propionic Acid and Gut Dysbiosis: Therapeutic Targets for Autism Spectrum Disorder
Introduction. Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex etiology, involving many environmental and genetic risk factors.1 The term “spectrum” describes the wide range of clinical presentations and severity, including deficits in communication and social interaction, restricted interests, and repetitive behaviors.1 Additionally, children with autism frequently experience gastrointestinal (GI) symptoms, such as constipation, abdominal pain, and diarrhea.2,3 Specifically, ASD is associated with “gut dysbiosis,” a disruption in microflora homeostasis in the GI tract.4 Recent research has emphasized the role of the “gut-brain axis” in the pathogenesis of ASD and investigated how microbial metabolites may cause this dysbiosis.4 Studies show that children with ASD exhibit increased Clostridium, Bacteroides, and Desulfovibrio bacterial species, all of which produce propionic acid (PPA) as a metabolite during fermentation.2,5 PPA is a short-chain fatty acid that induces inflammation, oxidative stress, and neurotoxicity when in excess.5,4,6,7 While definitive causal mechanisms of ASD are poorly understood, making it difficult to develop treatments, recent research has investigated whether prebiotics and probiotics address these gut and behavioral symptoms.1,4 Methods. PPA injection was used to create a rodent model for ASD by inducing social deficits and restricted behaviors, which were observed via behavioral testing.5,6 Brain tissue was examined via histological evaluation, immunostaining, and electron microscopy.5,6 Other studies compared PPA-injected rodents given probiotics or placebo and performed biochemical analyses on fecal pellets and brain tissue.7 Lastly, a prospective clinical trial with 30 children assessed symptoms before and after probiotic treatment using the Autism Treatment Evaluation Checklist.3 Results. PPA modified morphology and connectivity in the hippocampus, phenotypes that have been previously observed in individuals with ASD.5,8 Prebiotics and probiotics, which promote microflora homeostasis, decreased PPA-producing bacterial species and reduced levels of the pro-inflammatory cytokine interferon-gamma (IFN-g), which was elevated by PPA.3,4,7 They also counteracted oxidative stress caused by PPA by increasing levels of glutathione, a free radical scavenging enzyme, and by reducing lipid peroxides, a sign of membrane damage due to toxic reactive oxygen species.4,9,7 In addition, probiotics corrected the PPA-induced neural excitation-inhibition imbalance by increasing levels of the inhibitory neurotransmitter GABA and preventing excitotoxicity.6,7 Finally, probiotics decreased the severity of behavioral symptoms in children with ASD by improving sociability and sensory awareness, with most significant improvements in speech and communication.3 Conclusions. Probiotics restored microflora homeostasis, ameliorated PPA-induced damage and gut dysbiosis, and improved the severity of behaviors associated with ASD.3,4,9,7 Although more clinical trials are needed, prebiotics and probiotics show great promise as potential therapeutic interventions for ASD.
- Lord C, Brugha TS, Charman T, et al. Autism spectrum disorder. Nat Rev Dis Primers. 2020;6(1):5. Published 2020 Jan 16. doi:10.1038/s41572-019-0138-4
- Fattorusso A, Di Genova L, Dell’Isola GB, Mencaroni E, Esposito S. Autism Spectrum Disorders and the Gut Microbiota. Nutrients. 2019;11(3):521. Published 2019 Feb 28. doi:10.3390/nu11030521
- Shaaban SY, El Gendy YG, Mehanna NS, et al. The role of probiotics in children with autism spectrum disorder: A prospective, open-label study. Nutr Neurosci. 2018;21(9):676-681. doi:10.1080/1028415X.2017.1347746
- Abuaish S, Al-Otaibi NM, Aabed K, et al. The Efficacy of Fecal Transplantation and Bifidobacterium Supplementation in Ameliorating Propionic Acid-Induced Behavioral and Biochemical Autistic Features in Juvenile Male Rats. J Mol Neurosci. 2022;72(2):372-381. doi:10.1007/s12031-021-01959-8
- Lobzhanidze G, Japaridze N, Lordkipanidze T, Rzayev F, MacFabe D, Zhvania M. Behavioural and brain ultrastructural changes following the systemic administration of propionic acid in adolescent male rats. Further development of a rodent model of autism. Int J Dev Neurosci. 2020;80(2):139-156. doi:10.1002/jdn.10011
- Choi J, Lee S, Won J, et al. Pathophysiological and neurobehavioral characteristics of a propionic acid-mediated autism-like rat model. PLoS One. 2018;13(2):e0192925. Published 2018 Feb 15. doi:10.1371/journal.pone.0192925
- 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. Metab Brain Dis. 2018;33(4):1155-1164. doi:10.1007/s11011-018-0212-8
- Banker SM, Gu X, Schiller D, Foss-Feig JH. Hippocampal contributions to social and cognitive deficits in autism spectrum disorder. Trends Neurosci. 2021;44(10):793-807. doi:10.1016/j.tins.2021.08.005
- Aabed K, Shafi Bhat R, Moubayed N, et al. Ameliorative effect of probiotics (Lactobacillus paracaseii and Protexin®) and prebiotics (propolis and bee pollen) on clindamycin and propionic acid-induced oxidative stress and altered gut microbiota in a rodent model of autism. Cell Mol Biol (Noisy-le-grand). 2019;65(1):1-7. Published 2019 Jan 31.