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

Area of Science:

• Microbiology
• Neuroscience
• Oral Microbiome Research

Background:

• Chronic cocaine use is linked to neuroinflammation and cognitive deficits.
• The specific mechanisms driving these neurological changes remain largely unknown.
• An oral enrichment of *Streptococcus parasanguinis* (SP) was previously observed in individuals with cocaine use disorder (CUD).

Purpose of the Study:

• To investigate the causal role of *Streptococcus parasanguinis* (SP) in cocaine-induced neuroinflammation and cognitive dysfunction.
• To explore the oral microbiome-brain axis in the context of cocaine use disorder (CUD).

Main Methods:

• Wild-type mice were orally inoculated with SP, *S. salivarius*, *N. flavescens*, or vehicle after antibiotic pretreatment.
• Cognitive function (spatial memory) and neuroinflammation markers (IL-1β, microglial activation) were assessed in mice.
• Untargeted metabolomics was employed to identify oral-to-brain metabolite signatures associated with SP.

Main Results:

• SP-treated mice showed impaired spatial memory, increased brain IL-1β, and microglial activation.
• No bacterial translocation into the brain was detected.
• Distinct SP-associated metabolites, including cysteine S-sulfate (CSS) and altered histamine metabolites, were identified.
• CSS and histamine induced neuroinflammatory and amyloid-associated responses *in vitro*.

Conclusions:

• *Streptococcus parasanguinis* acts as a cocaine-associated oral pathobiont.
• SP promotes neuroinflammation and cognitive deficits, potentially via specific metabolites like CSS and histamine.
• These findings suggest a novel oral microbiome-brain axis contributing to neurodegeneration in cocaine use disorder (CUD).