Association of gut microbiota with COVID-19 susceptibility and severity: A two-sample Mendelian randomization study

Evidence supports the observational associations of gut microbiota with the risk of COVID-19; however, it is unclear whether these associations reflect a causal relationship. This study investigated the association of gut microbiota with COVID-19 susceptibility and severity. Data were obtained from a large-scale gut microbiota data set (n = 18 340) and the COVID-19 Host Genetics Initiative (n = 2 942 817). Causal effects were estimated with inverse variance weighted (IVW), MR-Egger, and weighted median, and sensitivity analyses were implemented with Cochran's Q test, MR-Egger intercept test, MR-PRESSO, leave-one-out analysis, and funnel plots. For COVID-19 susceptibility, IVW estimates suggested that Gammaproteobacteria (odds ratio [OR] = 0.94, 95% confidence interval [CI], 0.89-0.99, p = 0.0295] and Streptococcaceae (OR = 0.95, 95% CI, 0.92-1.00, p = 0.0287) had a reduced risk, while Negativicutes (OR = 1.05, 95% CI, 1.01-1.10, p = 0.0302), Selenomonadales (OR = 1.05, 95% CI, 1.01-1.10, p = 0.0302), Bacteroides (OR = 1.06, 95% CI, 1.01-1.12, p = 0.0283), and Bacteroidaceae (OR = 1.06, 95% CI, 1.01-1.12, p = 0.0283) were associated with an increased risk (all p < 0.05, nominally significant). For COVID-19 severity, Subdoligranulum (OR = 0.80, 95% CI, 0.69-0.92, p = 0.0018), Cyanobacteria (OR = 0.85, 95% CI, 0.76-0.96, p = 0.0062), Lactobacillales (OR = 0.87, 95% CI, 0.76-0.98, p = 0.0260), Christensenellaceae (OR = 0.87, 95% CI, 0.77-0.99, p = 0.0384), Tyzzerella3 (OR = 0.89, 95% CI, 0.81-0.97, p = 0.0070), and RuminococcaceaeUCG011 (OR = 0.91, 95% CI, 0.83-0.99, p = 0.0247) exhibited negative correlations, while RikenellaceaeRC9 (OR = 1.09, 95% CI, 1.01-1.17, p = 0.0277), LachnospiraceaeUCG008 (OR = 1.12, 95% CI, 1.00-1.26, p = 0.0432), and MollicutesRF9 (OR = 1.14, 95% CI, 1.01-1.29, p = 0.0354) exhibited positive correlations (all p < 0.05, nominally significant). Sensitivity analyses validated the robustness of the above associations. These findings suggest that gut microbiota might influence the susceptibility and severity of COVID-19 in a causal way, thus providing novel insights into the gut microbiota-mediated development mechanism of COVID-19.