Gut microbiota-derived 5-HTP penetrates the host blood–brain barrier and ameliorates autism symptoms

Autism spectrum disorder (ASD), a highly prevalent neurodevelopmental condition, is increasingly recognized for its strong association with the intestinal microbiome. However, the development of gut microbiota-targeted therapies has been impeded by a limited understanding of the molecular mechanisms underlying interactions between commensal bacteria and the host nervous system. In this study, shotgun metagenomic sequencing and UPLC–MS/MS targeted metabolic analyses identified altered tryptophan metabolites in the gut microbiota of both human ASD patients and ASD mouse models. Notably, we demonstrate that commensal bacteria-derived 5-hydroxytryptophan (5-HTP), metabolite of tryptophan, ameliorates anxiety, stereotypical and repetitive behaviors, as well as social deficits in these mouse models. Furthermore, 5-HTP is capable of crossing the blood–brain barrier and inhibits the overexpression of receptor tyrosine kinase (RTK) ligands, thereby suppressing the downstream RTK/MAPK/ERK signaling cascade. This inhibition subsequently normalizes the excessive stabilization of dendritic spines in the hippocampus in MeCP2 mouse. Our research demonstrates that gut microbiota producing 5-HTP improves ASD symptoms in various ASD animal models, elucidates the molecular mechanisms between gut microbiota and the onset and treatment of ASD, and provides a promising therapeutic approach for ameliorating ASD through the expression of neuron-regulated small molecules by gut indigenous bacteria.