Akkermansia muciniphila prevents cadmium-induced cognitive impairment through gut microbiome mediated mechanisms

Akkermansia muciniphila has emerged as a promising next-generation probiotic with beneficial effects on learning and memory, but whether and how it can protect against environmental toxicant-induced cognitive impairment remains unknown. Cadmium (Cd) is a widespread environmental neurotoxicant that disrupts the gut-brain axis and impairs hippocampus-dependent learning and memory, yet effective preventive interventions are lacking. In this study, we discovered that oral supplementation with human fecal microbiome-derived A. muciniphila prevented Cd-induced cognitive impairment in mice throughout 9 weeks of oral Cd exposure at a human body burden-relevant concentration. Notably, brain Cd concentrations were not affected by A. muciniphila supplementation, indicating that cognitive protection was mediated through gut-brain signaling rather than affecting metal accumulation in the brain. Multi-omics characterization identified coordinated gut-brain pathways underlying this protective effect. A. muciniphila preserved Cd-suppressed Lactobacillus taxa (L. crispatus, L. intestinalis, L. taiwanensis), which positively correlated with cognitive performance, and restored intestinal tight-junction integrity across multiple intestinal sections, particularly the ileum. A. muciniphila also normalized Cd-induced cytokine dysregulation in the serum. In addition, colonic branched-chain fatty acids (BCFAs) emerged as candidate gut-brain mediators, with 2-methylpentanoic acid showing a robust negative correlation with cognitive performance. These A. muciniphila-mediated changes across gut microbiome, intestinal barrier, systemic cytokines, and microbial metabolites coincided with reversal of Cd-induced hippocampal transcriptional alterations regulating synaptic and vascular signaling. Together, this study identified A. muciniphila as a preventive microbiome-based strategy against environmental Cd neurotoxicity in mice, demonstrated that the gut microbial homeostasis can confer cognitive resilience independently of brain toxicant burden, and revealed distinct BCFAs as potential gut-brain mediators of heavy-metal-induced cognitive decline.