The Role of Microbiota Metabolites Propionic Acid, p‐Cresol, and 4‐Ethylphenyl Sulfate in Autism Susceptibility: A Systematic Review

The etiopathogenesis of Autism Spectrum Disorder (ASD) encompasses complex interactions between genetic and environmental risk factors. The high prevalence of gastrointestinal disorders in autistic individuals has propelled a growing interest in the possible involvement of gut dysbiosis in ASD pathogenesis. Thousands of different bacterial strains are found in the human gut, which produce numerous metabolites that can enter the bloodstream and often pass the blood-brain barrier, potentially influencing neurodevelopment and brain function. This systematic review aims to provide a comprehensive outlook on the role of three metabolic compounds derived from gut bacteria, propionic acid (PPA), p-cresol, and 4-ethylphenyl sulfate (4-EPS), in modulating neuronal function and conferring susceptibility to ASD. To achieve this, we screened 411 records collected through a systematic search of current scientific literature in PubMed, Web of Science, and Scopus, ultimately reviewing a total of 90 records, which included data from ASD human cohorts as well as animal and cellular models of autism. Human studies provided compelling evidence of altered metabolic profiles in ASD individuals, especially for PPA and p-cresol, but also to a smaller extent, for 4-EPS. Furthermore, data obtained from the exposure of experimental models to each one of these three metabolic compounds identified several behavioral anomalies induced in treated animals and highlighted common neurobiological mechanisms. Overall, current literature supports the contribution of gut metabolites to ASD susceptibility and/or a significant modulatory role on the clinical expression of ASD, strongly encouraging further research in the field in order to improve autism diagnostics and management.