Butyrate preserves entorhinal-hippocampal spatial coding and blood brain barrier integrity in mice with depleted gut microbiome

ABSTRACT Given the widespread and increasing consumption of oral antibiotics globally, understanding their impact on cognition through the gut-brain axis is crucial. We investigated whether broad-spectrum antibiotics disrupt spatial cognition by altering behavior, neural dynamics, brain metabolism, and blood- brain barrier integrity. Here we show that male mice receiving antibiotic-treated water display significant impairments in spatial memory tasks and abnormal encoding of space by entorhinal grid cells and hippocampal place cells. These cognitive deficits are accompanied by altered brain metabolism and blood-brain barrier permeability in the hippocampal formation. Remarkably, supplementation with butyrate, a key microbiome-derived metabolite, preserves spatial cognition, neural dynamics, and blood-brain barrier function despite antibiotic treatment. These findings reveal that gut microbiome depletion disrupts the hippocampal-entorhinal network underlying spatial cognition, while suggesting butyrate supplementation as a potential therapeutic approach to mitigate antibiotic-induced cognitive impairments.