Cocaine-Enriched Oral Streptococcus parasanguinis Promotes Neuroimmune Dysfunction and Memory Impairment.

Chronic cocaine use is associated with neuroinflammation and cognitive dysfunction, but the underlying mechanisms remain unclear. We previously identified oral enrichment of Streptococcus parasanguinis (SP) and other species in individuals with cocaine use disorder (CUD), and here demonstrate that cocaine selectively enhanced SP growth in vitro . To investigate causality, antibiotic-pretreated wild-type C57BL/6 mice received chronic oral inoculation of SP, S. salivarius , Neisseria flavescens , or vehicle. SP-treated mice exhibited spatial memory impairment, increased brain IL-1β, and non-region-specific microglial activation, without detectable bacterial translocation into the brain. While amyloid-associated signaling changes were observed across all bacterial treatment groups, only SP induced cognitive deficits and neuroinflammation. Untargeted metabolomics identified distinct SP-associated oral-to-brain metabolite signatures, including cysteine S-sulfate (CSS) and altered histamine-associated metabolites. CSS and histamine induced neuroinflammatory and amyloid-associated responses in vitro . Together, these findings identify a cocaine-associated oral pathobiont that promotes neuroinflammation and neurodegeneration, suggesting a novel oral microbiome-brain axis in CUD.