The impact of microbiome dysbiosis on manganese-induced neurotoxicity: Brain metabolomics and multi-organ 16S rRNA profiling in mice

Manganese (Mn) is an essential metal but becomes neurotoxic upon excessive exposure. Although emerging evidence links Mn toxicity to gut microbiome alterations, little is known about how Mn affects microbial communities across multiple mucosal sites or how these changes relate to brain metabolism. This study aimed to investigate the impact of long-term Mn exposure on microbiota across the oral, nasal, lung, and gut compartments and its association with striatal metabolic alterations. The mice were intranasally exposed to MnCl 2 for four months. Microbiota composition was profiled by 16S rRNA sequencing, and striatal metabolites were assessed by untargeted LC-MS metabolomics. Correlation analyses were performed to identify multisite metabolite–microbiota interaction networks. Chronic Mn exposure impaired locomotor function and elevated serum Mn levels. Mn induced significant dysbiosis across all examined sites, characterized by reduced beneficial taxa (e.g., Butyricicoccus , Blautia ) and increased conditionally pathogenic taxa (e.g., Alistipes , Stenotrophomonas , Xanthomonadaceae ). Some taxa responded across multiple sites but exhibited compartment-specific patterns. Striatal metabolomics revealed perturbations in amino acid and lipid metabolism. Cross-site correlation analyses identified a coordinated metabolite-microbiota network, with gut taxa showing the strongest associations, while oral, lung, and nasal taxa also contributed to the systemic metabolic variability. These findings demonstrate that chronic Mn exposure disrupts microbial homeostasis across multiple compartments and alters key brain metabolic pathways. Overall, this study provides an integrative framework highlighting a multi-organ microbial axis potentially associated with Mn neurotoxicity. • Chronic Mn exposure disrupts microbiota across organs, reducing beneficial bacteria and enriching pathogens. • Mn exposure alters brain metabolism and correlates with multi-site microbiota, especially gut microbes. • Mn-induced neurotoxicity links to microbiota dysbiosis, metal imbalance, and brain metabolic abnormalities.