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Prenatal valproic acid (VPA) exposure, a known environmental risk factor, induces ASD-like phenotypes in rodents, although the mechanisms linking gut microbiota dysbiosis to neurobehavioral deficits remain unclear. Evidence suggests gut\u2013brain axis dysregulation via altered microbial diversity and reduced short-chain fatty acid (SCFA)-producing taxa contributes to ASD pathogenesis. This study investigated whether prenatal VPA exposure drives ASD-like behaviors through gut dysbiosis and SCFA-producer depletion (e.g., Clostridia, Lachnospiraceae), exploring neuroinflammation and oxidative stress as mechanisms. An ASD rat model was established by maternal VPA injection during specific gestational days. Behavioral tests assessed anxiety, sociability, repetitive behaviors, and cognition. Gut microbiota composition (16S rRNA sequencing), cytokine levels (ELISA), oxidative stress markers (biochemical assays), and microglial activation (Iba1 immunofluorescence) were analyzed. VPA-exposed offspring showed ASD-like behaviors accompanied by neurodevelopmental toxicity, manifesting as social deficits, repetitive grooming, and impaired memory. Concurrently, gut analysis revealed reduced alpha diversity and depleted SCFA-producers (e.g., Clostridia, Lachnospiraceae), alongside increased Bacteroidia and Enterobacteriaceae. Neuroinflammation (elevated IL-1\u03b2, IL-6, TNF-\u03b1, microglial activation) and oxidative stress (reduced GSH, SOD; elevated MDA, NO) were evident. Multivariate analyses linked dysbiosis to behavioral impairments. Prenatal VPA exposure induces gut microbiota dysbiosis, potentially exacerbating neuroinflammation and oxidative stress to drive ASD-like phenotypes. This establishes a mechanistic link between prenatal insults, gut\u2013brain axis disruption, and neurodevelopmental abnormalities, highlighting microbial modulation and SCFA supplementation as potential ASD therapeutics. Furthermore, integrating behavioral, microbial, and molecular analyses advances understanding of gut\u2013brain interactions in ASD and identifies microbiota\u2013metabolite pathways as targets for neurodevelopmental disorders.<\/jats:p>","DOI":"10.3390\/ijms26188931","type":"journal-article","created":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T07:33:02Z","timestamp":1758007982000},"page":"8931","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Altered Gut Microbial Diversity and Depletion of SCFA-Producing Taxa Associated with ASD-like Phenotypes in a Prenatal VPA Rat Model"],"prefix":"10.3390","volume":"26","author":[{"given":"Caixia","family":"Wu","sequence":"first","affiliation":[{"name":"Institute of Biological and Medical Engineering, Guangdong Academy of Sciences, Guangzhou 510316, China"},{"name":"National Engineering Research Center for Healthcare Devices, Institute of Biological and Medical Engineering, Guangdong Academy of Sciences, Guangzhou 510316, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianjie","family":"Li","sequence":"additional","affiliation":[{"name":"National Engineering Research Center for Healthcare Devices, Institute of Biological and Medical Engineering, Guangdong Academy of Sciences, Guangzhou 510316, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Wang","sequence":"additional","affiliation":[{"name":"National Engineering Research Center for Healthcare Devices, Institute of Biological and Medical Engineering, Guangdong Academy of Sciences, Guangzhou 510316, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8585-3472","authenticated-orcid":false,"given":"Zhaoming","family":"Liu","sequence":"additional","affiliation":[{"name":"Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e11103","DOI":"10.7717\/peerj.11103","article-title":"The autistic-like behaviors development during weaning and sexual maturation in VPA-induced autistic-like rats is accompanied by gut microbiota dysbiosis","volume":"9","author":"Kong","year":"2021","journal-title":"PeerJ"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Khodaverdi, M., Rahdar, M., Davoudi, S., Hajisoltani, R., Tavassoli, Z., Ghasemi, Z., Amini, A.E., Hosseinmardi, N., Behzadi, G., and Janahmadi, M. 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