Miscompartmentalization of microbiota-derived TMAO is a reversible driver in autism spectrum disorder

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder. Unlike genetics and gut dysbiosis, ASD appears to be homogeneous when considering tryptophan metabolism. Following these findings, we found that ASD was associated with the miscompartmentalization of the chemical chaperone trimethylamine N-oxide (TMAO). Intracellular TMAO was markedly reduced in ASD, possibly due to altered fluid/electrolyte homeostasis, which appeared to be responsible for most anomalies of tryptophan metabolism described in ASD. Administration of urea in a rat model of ASD that recapitulates the biochemical and behavioral phenotypes observed in humans not only restored biochemical parameters but also broadly improved behaviors. Our results suggest a major role of TMAO miscompartmentalization in the pathophysiology of ASD, although it is not causal for ASD. We anticipate that urea, which is already clinically approved, offers a new therapeutic opportunity for ASD, although careful testing is required to ensure safety and acceptability in this context.