Gut Microbiota and Autism: The Role of Propionic Acid in the Pathogenesis of Autism Spectrum Disorders
INTRODUCTION. Autism (ASD) includes a spectrum of developmental disorders characterized by early-onset impairments in social interaction and physical and cognitive behaviors.1 Though global prevalence is reported to be about 1%, the prevalence of ASD in the US has doubled from 2007 to 2012.2 Treatment is difficult, most likely because the pathophysiology underlying ASD is unclear.1, 3 However, due to the high proportion of autistic children suffering from GI comorbidities, alterations in the composition of the gut microbiome may be associated with ASD symptoms.4, 5 Studies have identified unique microbial signatures in the guts of ASD patients, but more research is needed to establish these microbial alterations as causative.6 Some studies suggest that exposure to propionic acid (PPA), a metabolic end-product of enteric bacteria, may be associated with ASD and its related GI symptoms.7 This association could further define the mechanism underlying ASD, as well as support gut-targeted therapy in the treatment of ASD patients. METHODS. In one study, fecal microbial flora was collected from ASD patients with GI symptoms, sibling controls, and non-sibling controls and was analyzed using bacterial tag encoded FLX amplicon pyrosequencing (bTEFAP).8 In another study, social behavior was observed in adult male rats following intracerebroventricular injection of PPA or control compounds. Behavior was analyzed using the EthoVision behavior tracking system and by blind scoring of videotapes of social behaviors.9 In the final study, brain tissue from rats previously infused with PPA was extracted and assessed for neuropathological markers via immunohistochemistry.10 RESULTS. There was a significantly higher diversity of bacteria found in the feces of autistic subjects compared to controls. The increased microflora of autistic children may contain harmful species – particularly, Bacteroidetes, which is known to produce PPA – contributing to the severity of autistic symptoms.8 Rats injected with PPA presented with social behavior impairments, namely signiﬁcantly greater mean distance apart, reduced time spent in close proximity, reduced playful interaction, and altered responses to playful initiations.9 Additionally, immunohistochemical analysis of brain tissue taken from rats treated with PPA revealed reactive astrogliosis, indicating a neuroinﬂammatory response.9, 10 CONCLUSIONS. The microbiome of children with ASD are characterized by increased diversity of enteric bacteria, some of which are known to produce PPA. Studies have found that PPA consistently impaired rat social behavior. Furthermore, these impairments are consistent with symptoms of human ASD and, thus, support the significance of PPA in not only the development of ASD pathophysiology, but in that of therapeutic interventions, as well.
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- Shultz S.R., Macfabe D.F., Ossenkopp K.P., Scratch S., Whelan J., Taylor R., Cain D.P. Intracerebroventricular injection of propionic acid, an enteric bacterial metabolic end-product, impairs social behavior in the rat: implications for an animal model of autism. Neuropharmacology. 2008;54:901–911.
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