Cadmium-induced gut dysbiosis precedes the onset of hippocampus-dependent learning and memory deficits in mice

Cadmium (Cd) is a heavy metal recognized as a neurotoxicant, but the detailed mechanisms contributing to its neurotoxicity remain to be fully elucidated. The gut-brain axis—a bidirectional communication pathway between the gut microbiome and the central nervous system—has been implicated in various neurological disorders. Since Cd targets the gut microbiome, it is important to investigate whether this axis contributes to Cd-induced neurotoxicity. In this study, adult male mice were exposed to environmentally relevant levels of Cd (3 mg/L) via drinking water for nine weeks. Cognitive function was assessed throughout the exposure period, and fecal samples were collected biweekly to track changes in the gut microbiome. We found that Cd exposure caused gut dysbiosis before the onset of cognitive deficits, with specific bacterial species correlating with impaired cognition. RNA sequencing revealed alterations in the expression of genes involved in cognition and neuroinflammation in the hippocampus. Additionally, Cd exposure reduced the expression of genes related to intestinal barrier integrity, increased levels of inflammatory cytokines, and altered the levels of neuroactive microbial metabolites. These findings suggest a critical role for the gut-brain axis in mediating Cd neurotoxicity and highlight the gut microbiome as a potential target for therapeutic strategies to prevent or mitigate Cd-induced cognitive decline.