Abstract
The gut microbial metabolite Trimethylamine N-oxide (TMAO) is increasingly implicated in the functioning and pathology of the central nervous system. Here, we demonstrate that chronic systemic TMAO exposure in mice induces significant cognitive impairment, as shown by significant deficits across multiple metrics in a battery of behavioral tests, including the novel object recognition, Y-maze, and Morris water maze (p < 0.05). This behavioral deficit was associated with severe hippocampal neurodegeneration, including a 20.5% loss of pyramidal neurons in the CA1 subregion, and marked mitochondrial damage. Mechanistically, TMAO-induced neurotoxicity was driven by PANoptosis, a coordinated inflammatory cell death pathway. We observed robust activation of the sensor ZBP1 and downstream executioner proteins, including cleaved Caspase-1/-3/-8, phosphorylated MLKL, and subsequent gasdermin D-mediated membrane pore formation. Crucially, pharmacological co-inhibition of RIPK3 (GSK-872) and caspases (Emricasan) significantly rescued neuronal viability, confirming PANoptosis as the core pathogenic pathway. These findings establish a novel mechanistic link between a gut-derived metabolite and cognitive decline, identifying TMAO possesses neurotoxicity that drives neurodegeneration via PANoptotic cell death. Our work suggests that strategies targeting systemic TMAO levels may hold therapeutic potential for neurodegenerative disorders.