Etiology of autistic features: the persisting neurotoxic effects of propionic acid

Abstract

BackgroundRecent clinical observations suggest that certain gut and dietary factors may transiently worsen symptoms in autism. Propionic acid (PA) is a short chain fatty acid and an important intermediate of cellular metabolism. Although PA has several beneficial biological effects, its accumulation is neurotoxic.MethodsTwo groups of young Western albino male rats weighing about 45 to 60 grams (approximately 21 days old) were used in the present study. The first group consisted of oral buffered PA-treated rats that were given a neurotoxic dose of 250 mg/kg body weight/day for three days, n = eight; the second group of rats were given only phosphate buffered saline and used as a control. Biochemical parameters representing oxidative stress, energy metabolism, neuroinflammation, neurotransmission, and apoptosis were investigated in brain homogenates of both groups.ResultsBiochemical analyses of brain homogenates from PA-treated rats showed an increase in oxidative stress markers (for example, lipid peroxidation), coupled with a decrease in glutathione (GSH) and glutathione peroxidase (GPX) and catalase activities. Impaired energy metabolism was ascertained through the decrease of lactate dehydrogenase and activation of creatine kinase (CK). Elevated IL-6, TNFα, IFNγ and heat shock protein 70 (HSP70) confirmed the neuroinflammatory effect of PA. Moreover, elevation of caspase3 and DNA fragmentation proved the pro-apoptotic and neurotoxic effect of PA to rat pupsConclusionBy comparing the results obtained with those from animal models of autism or with clinical data on the biochemical profile of autistic patients, this study showed that the neurotoxicity of PA as an environmental factor could play a central role in the etiology of autistic biochemical features.

Elimination of high-refined-sugar diet as treatment strategy for autistic features induced in a rodent model

“…NA has also been shown to limit neuroinflammation in the CNS [14]. This result can also be easily related to the significant elevation of IL-6, TNF α, and IFN γ in the brain homogenates of PPAtreated rats [4]. This could provide support for the contribution of PPA and ampicillin as environmental factors related to altered gutmicrobiota in the pathogenesis of autism.…”

“…The remarkable decrease in 5-HT in the three groups studied can be easily related to the imbalance between inhibitory/excitatory transmission reported in autistic patients and rodent models of autism [4,15]. 5-HT interacts with DA, NE, GABA, and glutamate systems [16,17] and is critical for the maturation of the GABA phenotype in the ventral spinal cord via 5-HT1B receptors [16].…”

“…Overgrowth of this species has also been reported in autistic patients [2].Furthermore, the induction of persistent autistic features in rodent modelswas achieved by MacFabe et al [3] and El-Ansary et al [4] through propionic acid (PPA) exposure. A concomitant increase in the fecal concentrations of PPA in children with autism may indicate the role by which microbial metabolites alter brain function through the gut-brain axis.…”

“…Group I served as the control and received only phosphate buffered saline; Group II was administered with PPA (250 mg/kg body weight/day) for three days [4]; Group III was treated with an oral dose of ampicillin (50 mg/kg for three weeks) with a standard diet; and Group IV was given the same dose of ampicillin with a high-sucrose diet for 10 weeks. The study was approved by the Ethics Committee of King Saud University with approval no.KSU-IRB008E.…”

Envolvimento Da Flora Intestinal Na Modulação De Doenças Psiquiátricas

“…Em particular, um estudo utilizando o modelo de camundongo MIA, demonstrou que o tratamento com a espécie de bactéria probiótica B. fragilis pode reverter as anormalidades comportamentais e fisiológicas relacionadas com o autismo observadas nestes roedores (97). Outra evidência revela que crianças autistas tendem a apresentar elevação da concentração de SCFAs no intestino, especialmente propionato, devido a uma alta atividade de Clostridia e a presença de outras bactérias incomuns ao indivíduo não autista (108). Importante, a administração central de propionato em ratos causa comportamentos característicos de pacientes autistas, como déficits sociais e cognitivos (109).…”