Experimental experience suggests that probiotics and prebiotics (representative microbial agents) play a critical role in defending against respiratory virus infection. We aim to systematically examine these agents' effect on respiratory viral infection. An electronic literature search was conducted from published data with a combination of a microbial agents search component containing synonyms for microbial agents-related terms and a customized search component for respiratory virus infection. Hazard ratio (HR), risk ratio (RR) and standard deviation (SD) were employed as effect estimates. In 45 preclinical studies, the mortality rates decreased in the respiratory viral infection models that included prebiotics or prebiotics as interventions (HR, 0.70; 95% CI 0.56–0.87; p = 0.002). There was a significant decrease in viral load due to improved gut microbiota (SD, -1.22; 95% CI -1.50– -0.94; p < 0.001). Concentrations of IFN-α (SD, 1.05; 95% CI 0.33–1.77; p = 0.004), IFN-γ (SD, 0.83; 95% CI 0.01–1.65; p = 0.05) and IL-12 (SD, 2.42; 95% CI 0.32–4.52; p = 0.02), IL-1β (SD, 0.01; 95% CI -0.37–0.40; p = 0.94) increased, whereas those of TNF-α (SD, -0.58; 95% CI -1.59 to 0.43; p = 0.26) and IL-6 (SD, -0.59; 95% CI -1.24– 0.07; p = 0.08) decreased. Six clinical studies had lower symptom scores (SD, -0.09; 95% CI -0.44–0.26; p = 0.61) and less incidence of infection (RR, 0.80; 95% CI 0.64–1.01; p = 0.06). Our research indicates that probiotics and prebiotics pose a defensive possibility on respiratory viral infection and may encourage the clinical application.

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