BACKGROUND: The precise mechanisms of respiratory infection caused by oral anaerobic bacteria remain elusive. Unexpectedly, bacterial microbiota analysis with 16S rRNA revealed "hidden" mixed infections of anaerobic bacteria and commensal oral Streptococcus species in patients with community-acquired pneumonia. The study aimed to elucidate the mechanisms by which Prevotella intermedia exacerbates oral streptococcal pneumonia. METHODS: Oral streptococci were oropharyngeally administered with the culture supernatants of P intermedia (PiSup) in mice to assess survival, microbial burden, inflammatory responses, and host response via unbiased bulk RNA sequencing. Additionally, genetically engineered strains of P intermedia were used to identify pathogenic factors. RESULTS: Seven-week-old female C57BL/6J mice treated with the combination of Streptococcus spp and PiSup exhibited significantly worse survival and increased microbial burden in the lungs and spleen when compared with Streptococcus spp and control medium. RNA sequencing of whole lung revealed disruption of neutrophilic bactericidal activity due to NADPH downregulation, accompanied by reduced myeloperoxidase production in mixed infections, leading to dysfunctional neutrophil accumulation in the lungs. Notably, PiSup from strains bearing mutations in the type IX secretion pathway (ΔporT or ΔporK) failed to worsen the mixed infection. CONCLUSIONS: P intermedia exacerbates pneumonia caused by commensal oral streptococci by inducing neutrophilic dysfunction in mixed infection. Products of the type IX secretion system should be investigated as novel targets independent of reported virulence factors.