Experimental modeling of autism spectrum disorders using propionic acid

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized, along with impaired social communication, stereotypic or repetitive behavior and varying degrees of mental retardation, as well as excessive glial proliferation, neuroinflammation, neural network disruption, gastrointestinal symptoms, etc. It is considered that ASD is the result of the interaction of genetic predisposition, adverse environmental influences and disorders of the maternal immune system in early pregnancy. Intestinal dysbiosis also plays a certain role in the development of ASD. Patients with ASD exhibit a shift in the microbiome compared to neurotypical peers, which is accompanied by increased levels of intestinal microorganisms Clostridia spp., Bacteriodetes and Desulfovibrio spp., which are active fermenters of dietary carbohydrates and fiber, and leads to the formation of energy metabolic by-products such as acetate, butyrate and, to a greater extent, propionic acid (PPA). PPA is also widely used as a preservative in foods. PPA readily crosses the BBB, normally modulating numerous cellular signaling processes, including energy metabolism, neurotransmitter synthesis and release, and lipid metabolism. Excessive levels of PPA are toxic. PPA causes systematic mitochondrial dysfunction, as evidenced by increased levels of free acyl-carnitine and impaired fatty acid metabolism in experimental rats and in more than 30% of patients with ASD. It has been shown that changes in the microbiome in the maternal intestine during pregnancy (increased consumption of processed foods rich in PPA, combined with pre-existing dysbiosis) can lead to the accumulation of PPA in the gastrointestinal tract, which can pass through the placental barrier and enhance the proliferation and survival of glial progenitor cells and inflammatory profile, causing disruption of the formation of neural structures in the early stages of fetal development and affecting the adult body.

This review provides an analysis of the mechanisms of the effect of PPA on the nervous system and the connection with the occurrence of ASD, and also presents the results of preclinical studies confirming this connection and methods for modeling ASD.