ObjectiveTo explore the association of intestinal flora with frailty based on two-sample Mendelian randomization (MR) analysis.MethodsGenome-wide association study (GWAS) data of intestinal flora samples and frailty samples were obtained from the databases of MiBioGen and IEU OpenGWAS Project, respectively. Intestinal flora was used as exposure factor, frailty as outcome, and single nucleotide polymorphism (SNP) associated with various intestinal floras was used as instrumental variable. After screening qualified instrumental variable, inverse variance weighting (IVW) method, weighted median (WM) method, and MR-Egger test were used for two-sample MR analysis, respectively. The Cochran′s Q test, MR-Egger intercept test and leave-one-out analysis were used for sensitivity analysis. ResultsBacteroides (IVW method: OR<0, P<0.05) and Bacteroidales (IVW method: OR<0, P<0.05) were the protective factors for the occurrence of frailty, Betaproteobacteria (IVW and WM methods: OR>0, P<0.05), Burkholderiales (WM method: OR>0, P<0.05), Eubacterium (Coprostanoligenes group) (IVW and WM methods: OR>0, P<0.05) and Clostridium (Innocuum group) (IVW method: OR>0, P<0.05) were the risk factors for the occurrence of frailty. No heterogeneity effect was found by the Cochran′s Q test (P>0.05), no horizontal pleiotropy was found by the MR-Egger intercept test (P>0.05), and the results of leave-one-out analysis indicated that the causal effects of the six identified intestinal floras on frailty were not driven by any single SNP.ConclusionThere are causal effects between some intestinal floras and frailty, but the specific mechanisms still need to be further studied.