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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 \u03b2\u2010glucan, or their synbiotic combination. These interventions enhanced oxidative tryptophan metabolic output and restored associated indole derivatives in ASD fecal cultures. In a VPA\u2010induced autism\u2010like mouse model, MTOP\u2010targeted interventions alleviated behavioral deficits, normalized social\u2010stimulus\u2010associated 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\u2010CREB\u2010BDNF\u2010associated signaling. Microbiota depletion abolished the synbiotic\u2010mediated benefits, whereas oral IAA supplementation partially reproduced behavioral, neuronal, and selected synaptic improvements. Neuronal AhR knockdown in the retrosplenial cortex attenuated the synbiotic\u2010mediated 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\u2010related metabolism as a gut\u2010brain metabolic vulnerability and support MTOP restoration as a candidate synbiotic strategy for ASD\u2010related conditions characterized by impaired microbial tryptophan oxidative metabolism.<\/jats:p>","DOI":"10.1002\/advs.202522265","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:00:31Z","timestamp":1790532031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeted Restoration of the Microbial Tryptophan Oxidative Pathway Ameliorates Autism\u2010Like Behavioral and Synaptic Deficits"],"prefix":"10.1002","author":[{"given":"Rui","family":"Guo","sequence":"first","affiliation":[{"name":"College of Food Science and Engineering Northwest A&F University Yangling Shaanxi China"},{"name":"Northwest A&F University Shenzhen Research Institute Shenzhen Guangdong 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