Sara Benitez

Introduction: Autism Spectrum Disorder, a neurobehavioral disorder that involves impairment in social interaction and communication, is more prevalent in boys and occurs in 1 out of every 68 children¹. Due to comorbid GI disturbances commonly reported among these patients and the fact that the intestinal microbiome is established early in life, the idea that the gut-brain-microbiome axis may play a role in the development of this disorder is a potential hypothesis². Moreover, products of the intestinal microbiome have gained increased attention due to their significant role in maintaining intestinal permeability and involvement in both GI and CNS physiology. Short-chain fatty acids (SCFAs) are neuroactive microbial metabolites that can cross the blood-brain barrier and modulate CNS functions, brain development, and behavior³. This study sought to establish the pathologic role of SCFAs and their relationship to autism. Methods: Various mouse models were compared to analyze the findings related to intestinal permeability and SCFA function. Only studies examining intestinal permeability, SCFA effects, and their relationship to autistic behaviors were included.  Results: The maternal immune activation and the germ-free mouse models of autism showed decreased expression of tight junction proteins within the colon and an increase in BBB permeability⁴. The valproic-acid mouse model of ASD showed a significant increase in butyric acid, a SCFA, in the stool samples of mice, which was coupled to an increase in intestinal inflammation, decrease in social behavior scores, and changes in the neurotransmitter serotonin³. In another study, the experimenters added propionic acid (PPA), a SCFA, to a rat pheochromocytoma (PC12) cell system, along with a tyrosine hydroxylase (TH) promoter, and found that PPA induced TH gene transcription, indicating an increase in catecholamine production⁵. A different study also evaluated the effects of pre-and post-natal PPA administration on behavior in male and female adolescent rats. This study found that PPA led to a deficit in pre-pulse inhibition and an augmented startle response, both measures of sensory processing⁶.  Conclusion: The presence of elevated SCFAs in mouse models of autism demonstrated the detrimental effects these intestinal microbiome metabolites have on the development of ASD. SCFAs affected not only intestinal permeability, but also altered neurotransmission and behavior in mouse models. These findings suggest that SCFAs are environmental and epigenetic factors that require further study in order to gain a better understanding of the gut-brain-microbiome- axis and its relationship to the development of autism.

1. Rosenfeld CS. Microbiome disturbances and autism spectrum disorders. Drug Metabolism and Disposition. 2015; 43: 1557-1571.
2. Mangiola F, Ianiro G, Franceschi F, Fagiuoli S, Gasbarrini G, Gasbarrini A. Gut microbiota in autism and mood disorders. World Journal of Gastroenterology. 2016; 22(1): 361-368.
3. de Theije CG, Wopereis H, Ramadan M, van Eijndthoven T, et al. Altered gut microbiota and activity in a murine model of autism spectrum disorders. Brain, behavior, and immunity. 2014; 37, 197-206.
4. Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde, et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell. 2013; 155(7), 1451-1463.
5. Nankova BB, Agarwal R, MacFabe 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).
6. Foley KA, MacFabe DF, Kavaliers M, Ossenkopp KP. Sexually dimorphic effects of prenatal exposure to lipopolysaccharide, and prenatal and postnatal exposure to propionic acid, on acoustic startle response and prepulse inhibition in adolescent rats: relevance to autism spectrum disorders. Behavioural brain research. 2015; 278, 244-256.