Four months of intranasal manganese chloride exposure in mice triggered coordinated microbiome disruptions across oral, nasal, lung, and gut compartments while simultaneously altering brain metabolism in the striatum. The study revealed decreased beneficial bacteria like Butyricicoccus and Blautia alongside increases in potentially harmful taxa including Alistipes and Stenotrophomonas. Metabolomic analysis showed perturbations in amino acid and lipid pathways within brain tissue. This research fundamentally reframes our understanding of environmental neurotoxicity by demonstrating that manganese doesn't just affect the brain directly—it orchestrates a complex multi-organ microbial response that may amplify neurological damage. The finding is particularly significant given widespread manganese exposure through occupational settings, contaminated water, and certain dietary supplements. While the gut microbiome's role in neurological health has gained attention, this study breaks new ground by mapping how respiratory and oral microbiomes also contribute to neurotoxic responses. The coordinated nature of these microbial changes suggests therapeutic interventions targeting multiple microbial sites could potentially mitigate manganese-induced neurological damage, though human studies are needed to validate these mouse findings.