Deoxycholic acid induces NLRP3-associated neuroinflammatory responses and cognitive dysfunction

The microbiota-gut-brain (MGB) axis is a dynamic network connecting gut microorganisms and the brain through various signaling pathways, playing a crucial role in the diagnosis and treatment of complex neurological disorders. Bile acids (BAs), synthesized in the liver and transformed by the gut microbiota, are known to modulate gastric inflammation. However, their potential roles within the MGB axis and their impact on neuroinflammation and neurological disorders have not yet been investigated. Deoxycholic acid (DCA) and cholic acid (CA), which are secondary and primary BAs, respectively, were treated to microglial BV-2 cells to find out alteration in the signaling pathway. DCA and CA were administered to healthy mice to examine their effect on neurological function. Clostridium scindens , which converts CA into DCA in the gut, was administered to mice to investigate the potential contribution of gut microbial conversion of CA to DCA to neurological outcomes. Levels of BA-converting bacteria and enzyme were analyzed in human fecal samples. First, we observed that DCA elicited stronger pro-inflammatory response than CA in BV-2 microglial cells and increased NLRP3-associated inflammasome signaling. These responses were attenuated by pharmacological inhibition of FXR and S1PR2, with reduced MAPK/NF-κB and NLRP3-associated signaling. Then, DCA was orally administered to normal mice, and it was found that increased DCA concentration increased glial activation and activated microglial NLRP3-associated signaling in the brain. In addition, DCA administration induced memory impairment and altered the AKT/ERK/CREB/BDNF signaling pathway. The concentration of DCA in the hippocampus of mice was significantly correlated with the fear memory score and neuroinflammatory markers. Co-administration of CA and C. scindens was associated with alterations in memory-related behavioral outcomes. In human-derived samples, we observed that the levels of BA-converting bacteria, including C. scindens , and related enzymes were increased in the feces of patients with mild cognitive impairment. These results demonstrate that DCA promotes NLRP3-associated neuroinflammatory responses and neuronal dysfunction, potentially involving FXR- and S1PR2-related signaling pathways. These findings suggest that elevated DCA exposure may contribute to gut–brain axis dysfunction and cognitive impairment under experimental conditions.