Attenuation of inorganic arsenic exposure-induced cognitive impairments by polyphenols-rich fraction of wild Rubus ellipticus berries via reshaping gut microbiota and reduction of oxidative stress-lead neuro-intestinal inflammation

Abstract

The neurotoxic effects of inorganic arsenic exposure and consequential neurobehavioral outcomes involve activation of inflammatory cascades and reactive oxygen species (ROS)-mediated neuronal damage. Functional foods with characterized bioactive(s) are gaining attention in environmental contaminants-exposure induced pathologies. Here, we investigated the use of an ultrasonication-assisted extraction (UAE) and response surface methodology (RSM)-optimized process for polyphenols-rich extract from a Himalayan berry, Rubus ellipticus, against inorganic arsenic [iAs(III)]-induced cognitive impairments in mice. Total phenolic content (TPC), in-vitro antioxidant activity and cytotoxicities, along with UHPLC and LC-MS based polyphenolic profiles were determined. iAs(III)-exposure-induced spatial navigation tasks and passive avoidance-based learning performances were assessed. Neurochemical estimations, oxido-nitrosative stress markers, histological analysis and qRT-PCR-based gene expression in brain, ileum and, colon, pro-inflammatory cytokines and LPS levels, gut permeability, short chain fatty acids (SCFAs) levels, along with nanopore-based 16s rRNA metagenomics were performed. RSM-optimized UAE methods showed high TPC and antioxidant activities in polyphenol-rich (flavanols, phenolic acids and, proanthocyanidins) extract from R. ellipticus. The extract showed no potential cytotoxicity and significantly prevented iAs(III)-exposure-induced cognitive impairment, especially long-term spatial learning and memory. It also prevented altered neurotransmitter turnover, neuro-/ ileal/ colonic inflammation, and ROS-induced damages, increased ileum permeability, reduced SCFA level, and gut perturbations caused by iAs(III)-exposure. These findings suggest that the polyphenol-rich extract from Rubus ellipticus may offer protection against environmental toxicant [iAs(III)]-induced neurotoxicity and behavioral effects, potentially through combined modulation of oxidative stress, neuroinflammation, and gut-related pathways.