Potential role of fermentative microbial metabolites butyrate and propionate as targets in gut microbiome-based therapeutics for subtypes of autism spectrum disorder

Vincent Provasek

Introduction Autism spectrum disorder (ASD) is a serious neurodevelopmental disorder affecting millions in the US. Recent data have noted a steady increase in the prevalence of ASD, with up to 1-2.5% of US children and adolescents being affected1-3. While the exact etiology of ASD remains unclear, ASD is understood to be highly heterogenous in terms of clinical manifestation, and the product of complex and multifactorial gene-environment interactions4,5. Increasing evidence has revealed marked differences in the gut microbiome (GMB) of ASD patients that are also found in some animal models of the disease. The GMB of ASD individuals is typically less diverse with a decreased Bacteroidetes:Firmicutes ratio5,6. At least one potential mechanism by which such changes in microbial composition may influence the pathology of ASD is through the relative production of two short chain fatty acid metabolites, propionate and butyrate. Methods The effects of butyrate and propionate on mitochondrial function were evaluated using lymphoblastoid cell lines obtained from control and two groups of ASD patients (those with atypical and typical mitochondrial function). Seahorse assays for ATP-linked respiration, Proton-Leak Respiration, and Maximum Respiratory Capacity of mitochondria were evaluated with and without the addition of Reactive Oxygen Species (ROS) following incubation with butyrate or propionate. The ability of butyrate to rescue behavioral deficits and alter gene transcription within brain tissue of BTBR mouse models of ASD was also investigated. Results Propionate initially had a beneficial effect on mitochondria with ASD mitochondria demonstrating the greatest enhancement. ROS addition, however, negated this benefit with ASD mitochondria showing the greatest detriment7. Conversely, butyrate exposure attenuated respiratory parameters in control mitochondria, but had the opposite effect in the atypical ASD mitochondria. Interestingly, ROS addition modulated this effect by increasing respiratory parameters for all groups8. In the animal model of ASD, butyrate was shown to attenuate certain social deficits, and induce opposite effects on inhibitory and excitatory neurotransmitter gene expression within the prefrontal cortex9.  Conclusion At least one possible mechanism underlying the effect of the GMB on ASD could lie with the balance of butyrate and propionate producing fermentative bacteria. The balance of these metabolites may affect the neural development and/or function of ASD patients by modulating mitochondrial function and neuronal gene expression. Moreover, butyrate may prove therapeutically useful by increasing social behaviors through modulation of the excitatory/inhibitory balance in the prefrontal cortex of ASD subjects9.


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