Targeted Restoration of the Microbial Tryptophan Oxidative Pathway Ameliorates Autism-Like Behavioral and Synaptic Deficits.

Autism Spectrum Disorder (ASD) is associated with gut microbiota dysbiosis, yet the contribution of specific microbial metabolic pathways remains unclear. Reanalysis of a public ASD cohort revealed reduced functional potential in microbial tryptophan oxidative metabolism. We therefore designed targeted microbial tryptophan oxidative pathway (MTOP) interventions comprising Lacticaseibacillus rhamnosus C502, highland barley β-glucan, or their synbiotic combination. These interventions enhanced oxidative tryptophan metabolic output and restored associated indole derivatives in ASD fecal cultures. In a VPA-induced autism-like mouse model, MTOP-targeted interventions alleviated behavioral deficits, normalized social-stimulus-associated CA3 calcium responses, and improved hippocampal synaptic architecture. These effects were accompanied by gut microbiota remodeling, improved intestinal barrier integrity, increased fecal and brain IAA levels, and restoration of ERK-CREB-BDNF-associated signaling. Microbiota depletion abolished the synbiotic-mediated benefits, whereas oral IAA supplementation partially reproduced behavioral, neuronal, and selected synaptic improvements. Neuronal AhR knockdown in the retrosplenial cortex attenuated the synbiotic-mediated rescue, supporting a required role for neuronal AhR. Independent clinical metabolomic analysis supported an association between lower circulating IAA and ASD symptom severity. Collectively, these findings identify impaired MTOP-related metabolism as a gut-brain metabolic vulnerability and support MTOP restoration as a candidate synbiotic strategy for ASD-related conditions characterized by impaired microbial tryptophan oxidative metabolism.