Bisphenol S (BPS), broadly used in consumer products and food packaging, raises mounting toxicological concerns. Puerarin (PUE), a neuroprotective antioxidant from pueraria lobata, is largely uncharacterized for its efficacy in mitigating BPS-triggered neurotoxicity. This study investigates how BPS impairs the intestinal mucosal barrier, induces inflammation and gut dysbiosis to elicit neurotoxicity, and evaluates the protective effects of PUE on these gut-mediated damages. Thirty-six male mice were randomly divided into four groups (control, BPS (50 mg/kg bw), BPS + PUE(150 mg/kg bw). The Open field test and Morris water maze were adopted to evaluate learning, memory and spontaneous behaviors. H&E and PAS staining were performed to assess pathological lesions in colon and hippocampal tissues. 16S rRNA sequencing and gas chromatography were used to profile gut microbiota composition and short-chain fatty acids (SCFAs) levels, respectively. ELISA, RT-qPCR, Western blotting, and immunohistochemistry were further applied to detect the expression levels of associated molecules in intestinal and brain tissues. Behavioral testing revealed that PUE rescued BPS-induced spatial memory deficits, depressive-like behaviors and synaptic damage. PUE also alleviated gut microbial dysbiosis and restored BPS-mediated reduction of SCFAs Moreover, PUE mitigated colitis and preserved colonic mucosal integrity and tight junction proteins (ZO-1, OCLN, MUC2 and CLDN1) disrupted by BPS. BPS exposure suppressed synaptic architecture and inhibited the Brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)/cAMP response element-binding protein (CREB) signaling cascade; these adverse changes were significantly reversed by PUE supplementation. Collectively, these findings highlighted that PUE ameliorates BPS-triggered neurobehavioral dysfunction by remodeling gut microbiota and microbial metabolism via the gut-brain axis, and the BDNF/TrkB/CREB pathway participates in this neuroprotective process.
