Metabolic network analysis of pre-ASD newborns and 5-year-old children with autism spectrum disorder
Communications Biology volume 7, Article number: 536 (2024 ) Cite this article
Classical metabolomic and new metabolic network methods were used to study the developmental features of autism spectrum disorder (ASD) in newborns (n = 205) and 5-year-old children (n = 53). Eighty percent of the metabolic impact in ASD was caused by 14 shared biochemical pathways that led to decreased anti-inflammatory and antioxidant defenses, and to increased physiologic stress molecules like lactate, glycerol, cholesterol, and ceramides. CIRCOS plots and a new metabolic network parameter, \(\dot{{{\boldsymbol{V}}}}\!\) net, revealed differences in both the kind and degree of network connectivity. Of 50 biochemical pathways and 450 polar and lipid metabolites examined, the developmental regulation of the purine network was most changed. Purine network hub analysis revealed a 17-fold reversal in typically developing children. This purine network reversal did not occur in ASD. These results revealed previously unknown metabolic phenotypes, identified new developmental states of the metabolic correlation network, and underscored the role of mitochondrial functional changes, purine metabolism, and purinergic signaling in autism spectrum disorder.
Autism spectrum disorder (ASD) now affects 1 in 36 children born in the United States1. Despite clinical heterogeneity, all children with ASD share the three core features of difficulty with language, social communication, and restricted or repetitive behaviors or interests. With current therapy, only about 20% of children diagnosed with ASD in childhood gain independence as adults2. Advanced methods in biochemical genetics and metabolomics over the past 65 years have shown that many metabolic changes can be found in children and adults with ASD, but the specific differences change by age, sex, and severity of symptoms3,4,5,6,7,8,9. The developmental nature of metabolic changes in ASD has been attributed in part to a delayed maturational program10,11,12, which in turn, is coupled to corresponding developmental changes in brain structure and function, immunity, the microbiome, and the autonomic nervous system4,13,14,15. A root regulator of these multisystem changes in ASD has not yet been discovered.
