Polyphenols-rich Indian barberry berries extract alleviates inorganic arsenic exposure-induced cognitive impairments and associated gut microflora alterations.

Arsenic, a globally prevalent environmental toxin that can lead to neuro-behavioural changes. Oxidative stress and activation of inflammatory cascades are prominent mechanisms underlying these effects. The present study investigated the effects of polyphenol-rich extracts from Berberis aristata (Indian barberry) against inorganic arsenic-induced cognitive impairments in a murine model and presented mechanistic insights into its functional food properties. Response Surface Methodology (RSM)-guided hydro-alcoholic extracts were prepared and chemically characterized for their antioxidant activity, total phenolic contents (TPC) and free radical scavenging activities (RSA). UHPLC and LC-MS-based profiling of polyphenols, anthocyanins, and proanthocyanidins was performed. In-vitro toxicity studies in hepatic and colonic cancer cell lines, followed by in-vivo evaluation of these extracts in inorganic arsenic-exposed mice for spatial navigation tasks and passive avoidance-based learning were performed. Further assessments included neurotransmitter levels, histopathological investigations, qRT-PCR-based gene expression analysis, inflammatory cytokines and oxido-nitrosative stress markers in the brain and gastrointestinal tract, Evan's blue dye-based ileum permeability, and short chain fatty acids (SCFAs) estimation, along with Oxford Nanopore-based 16S rRNA metagenomics in cecal contents and PICRUSt2-based functional prediction of metagenomic data. RSM-optimized methods for polyphenol extraction yielded extracts with high TPC and RSA, with flavanols, phenolic acids, and proanthocyanidins identified as major polyphenols, and no in-vitro toxicity was observed. The extracts significantly prevented arsenic exposure-induced cognitive impairment, altered neurotransmitter turnover, neuroinflammation and gastrointestinal tract inflammation, oxidative stress-induced damage, increased ileum permeability, SCFA alteration, and gut microbial dysbiosis. These findings underscore the therapeutic/preventive potential of this polyphenol-rich extract against environmental toxicant-induced neurotoxicity, potentially involving gut microbiota-associated pathways.