A bidirectional two-sample Mendelian randomization using the gut microbiota to reveal potential therapeutic targets for primary sclerosing cholangitis

Previous studies indicate that gut microbiota correlates to primary sclerosing cholangitis (PSC), but the causation is still unclear. We sought to reveal the causal relationship between gut microbiota and PSC with a bidirectional two-sample Mendelian randomization (MR) analysis.The large-scale genome-wide association study (GWAS) summary statistics and a bidirectional two-sample MR study were used to assess the causality between gut microbiota and PSC. Multiple sensitivity analyses were used to identify the robustness of our results.Three microbial taxa causally correlated to PSC. Genus Ruminococcaceae UCG002 (OR: 1.855, 95% CI: 1.068-3.220, P = 0.028) increased the risk of PSC. Class Betaproteobacteria (OR: 0.360, 95% CI: 0.171-0.758, P = 0.007), and genus Ruminiclostridium6 (OR: 0.474, 95% CI: 0.219-0.820, P = 0.011) had protective effects on PSC. In addition, we found the causal relationship of PSC with higher abundance of genus Dialister (beta: 0.059, 95% CI: 0.017-0.102, P = 0.006), genus Veillonella (beta: 0.065, 95% CI: 0.016-0.113, P = 0.009), class Melainabacteria (beta: 0.073, 95% CI: 0.012-0.133, P = 0.019), and order Gastranaerophilales (beta: 0.072, 95% CI: 0.011-0.113, P = 0.133).Our study reveals the causality between gut microbiota and PSC, providing new insights into the pathological mechanisms of PSC and facilitating the development of novel biomarkers and disease-modifying therapeutics for PSC from the perspective of gut microbiota.