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.
DCA and GDCA impact memory in mice through specific molecular pathways, highlighting their potential role in microbiome-gut-brain communication.
Where it sits
this study against the rest of the cyclic glycine-proline (cgp) corpusSummary and findings
This study investigated the effects of deoxycholic acid (DCA) and glycodeoxycholic acid (GDCA) on memory in adult mice. Mice received daily oral doses of DCA, GDCA, or vehicle, and memory was assessed using Y-maze and novel object recognition tasks. GDCA impaired recognition memory after 10 days, while DCA impaired spatial reference memory after 12 days.
Abstract
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.
Background
Bile acids are traditionally known for their role in digestion, but recent evidence suggests they may also affect brain function and memory. This study explores the potential cognitive effects of two microbiota-derived secondary bile acids, deoxycholic acid (DCA) and glycodeoxycholic acid (GDCA), in mice. Understanding these effects is important for elucidating the role of bile acids in microbiome-gut-brain communication.
Methods
The study used a mouse model with both male and female subjects receiving daily oral doses of DCA, GDCA, or a vehicle. Memory was assessed using the Y-maze for spatial working and reference memory and the novel object recognition task for recognition memory. Gene expression and signaling activity were measured in the frontal cortex and hippocampus after the behavioral tests.
Results
GDCA administration for 10 days disrupted recognition memory, while DCA intake for 12 days impaired spatial reference memory. GDCA reduced mRNA expression of NMDA receptor subunits and BDNF in the frontal cortex, affecting CREB signaling. DCA altered FXR and TGR5 mRNAs and proteins in a region-specific manner and decreased CREB signaling in the hippocampus, contributing to spatial memory deficits.
Interpretation
The study suggests that DCA and GDCA have distinct effects on cognition, potentially through receptor- and region-specific mechanisms. While statistically significant, the clinical relevance of these findings in humans remains uncertain due to the animal model. The lack of significant microbial changes implies that the observed cognitive effects are not mediated by major shifts in gut microbiota.
Key findings
- GDCA impaired recognition memory after 10 days.
- DCA impaired spatial reference memory after 12 days.
- GDCA reduced NMDA receptor subunit mRNAs and BDNF mRNA in the frontal cortex.
- DCA decreased CREB signaling in the hippocampus.
- No significant microbial differences were observed in fecal samples.
Limitations
- animal model, not human
- short follow-up period
- no long-term effects reported
- limited to specific bile acids