Omnipresent Bisphenol-A (BPA) exposure is linked to neurobehavioral deficits and gut dysbiosis. However, studies assessed its impact on cognitive performance at environmentally unrealistic doses. Nevertheless, the exact mechanism underlying the neurobehavioral phenotype, linking the role of gut microbiota is poorly understood. Here, we evaluated the effects of environmentally plausible dose of BPA-exposure on cognitive task performances with the functional analysis of gut metagenome to elucidate the role of microflora-gut-brain axis in behavioural regulation. Swiss albino mice were exposed to BPA for 5 weeks assessed for working and spatial navigation task performances. qRT-PCR based gene expression, histological investigation, gut permeability, molecular and biochemical markers of neuro-inflammation, leaky gut, oxido-nitrosative stress and 16 s rRNA gene based metagenomics with functional analysis were performed. BPA exposure altered the cognitive task performances (mean difference for transfer latency in elevated plus maze 20.84 ± 5.64 sec in and -13.12 ± 3.53 in Morris' water maze), changed serotonin levels (-70.95 ± 21.43) and acetylcholinesterase activity (0.0032 ± 0.0008), enhanced ileal permeability (12.36 ± 3.56) and systemic and tissue level inflammation (increased brain LPS, TNF-a, IL-1b, IL-6 and circulating TNF-a and IL-1b), coupled with reduced SCFAs levels (acetate; 32.48 ± 8.48, and butyrate; 28.16 ± 9.86). Faecal microbial transplant cohort replicated similar behavioural, biochemical and molecular patterns, suggesting the role of gut-microbiota in the phenotype determination. Functional pathways prediction suggested altered serotonin, dopamine, SCFAs metabolism and LPS biosynthesis. BPA at a much lower but environmentally relevant dose altered the cognitive performances, which has potential linkage to gut-microbiota mediated pathways.
