Glycodeoxycholic and deoxycholic bile acids impair recognition and spatial memory in adult mice, and reduce central CREB-BDNF signaling and cytokine expression with neuroanatomical specificity.

Emerging evidence suggests that bile acids, traditionally recognized for their role in digestion, also influence brain function and memory. This study examined the effects of two microbiota-derived secondary bile acids, deoxycholic acid (DCA) and glycodeoxycholic acid (GDCA), on memory in mice and the associated molecular mechanisms. Male and female mice received daily oral administration of DCA, GDCA, or vehicle, and spatial working and reference memory (Y-maze) and recognition memory (novel object recognition task) were assessed. After testing, gene expression and signaling activity were measured in the frontal cortex and hippocampus. Administration of GDCA after 10 d disrupted recognition memory, whereas DCA intake for 12 d impaired spatial reference memory. Neither bile acid administered for 5 d affected spatial working memory. GDCA reduced NMDA receptor subunit (GluN1, GluN2A) mRNAs and encoded protein and brain-derived neurotrophic factor (BDNF) mRNA expression and attenuated CREB signaling in the frontal cortex, which is consistent with the observed recognition memory deficit. GDCA did not alter the abundance of transcripts encoding bile acid receptors (FXR or TGR5) or their corresponding protein levels. In contrast, DCA modified the FXR and TGR5 mRNAs and proteins in a region-specific manner and decreased CREB signaling in the hippocampus, likely contributing to spatial memory deficits. In the frontal cortex, DCA increased GluA1 phosphorylation and reduced IL-1β and IL-6 expression, which may have helped preserve recognition memory. Exploratory metagenomic analysis of fecal samples showed no significant microbial differences, though subtle, non-significant functional gene changes suggested early adaptations. These findings reveal that DCA and GDCA exert distinct, receptor- and region-specific effects on cognition, identifying bile acids as modulators of microbiome-gut-brain communication.