Characterize Oral-to-Blood Microbial DNA Translocation in Individuals with Cocaine Use Disorder

Background. Cocaine disrupts gut barriers in animal models, potentially enabling microbial translocation and inflammation in the periphery and central nervous system (CNS), but its direct role in inducing inflammation remains controversial. This study aimed to determine if the oral cavity is a source of circulating microbial DNA translocation in individuals with current cocaine use disorder (COC). Results. A cross-sectional case-control study was conducted, comparing COC and demographically matched non-drug controls. Ten COC (via smoking or vaping) and 24 controls provided paired saliva and blood samples. Microbial 16S rRNA V4 region was sequenced in isolated microbial DNA from saliva and plasma. Single-cell RNA sequencing (scRNAseq) was analyzed in human peripheral blood mononuclear cells. Saliva from COC, but not plasma, exhibited reduced alpha diversity and altered beta diversity, characterized by enriched Streptococcus and depleted Fusobacterium, Neisseria, and other taxa relative to controls. Controls exhibited low to undetectable microbial translocation in plasma. By contrast, plasma Streptococcus and several S. species displayed COC-specific oral enrichment and evidence of translocation into the bloodstream. In vitro, cocaine selectively enhanced S. parasanguinis growth, consistent with COC-enriched oral pathobionts and translocation into circulation in vivo. S. parasanguinis, but not cocaine alone, induced IL-1β and TNF-α production in human primary monocytes. scRNAseq further revealed innate immune activation, impaired T cell function, and heightened susceptibility to infection in COC. Conclusions. This is the first study demonstrating that COC via smoking or snorting exhibited oral microbial dysbiosis and selective oral-to-blood microbial translocation in vivo. These findings suggest that compromised oral-to-blood barrier, rather than cocaine itself, promotes immune perturbations in COC.