Abstract: Objective To explore in depth the causal associations between gut flora, derived metabolites and frailty using Mendelian randomization studies. Methods Inverse variance weighted (IVW) and four MR methods based on different assumptions were used to assess the causal relationship between 207 gut flora and 126 derived metabolites and frailty using pooled data from the Gene-Wide Association Study (GWAS). Cochran's Q test, MR-Egger regression, MR-PRESSO, MR-Steiger and leave-one-out sensitivity analyses were used to verify the reliability of the results. Results IVW results of gut flora showed potential causal associations between 11 species of gut flora, including Verrucomicrobia (OR=0.980), Burkholderiales (OR=0.970), Akkermansia (OR=0.980), Akkermansia muciniphila(OR=0.979), Lactobacillus delbrueckii (OR=0.988), Eubacterium ventriosum (OR=0.978), Eubacterium biforme (OR=0.980), Flavonifractor (OR=1.022), Sutterella (OR=1.044), Sutterella wadsworthensis (OR=1.044), Bacteroides massiliensis (OR=1.031) with frailty. And MR results of gut flora-derived metabolites showed potential causal associations between six gut flora-derived metabolites, including valine (OR=2.042), kynurenine (OR=1.149), stearoylcarnitine (OR=1.194), oleoylcarnitine (OR=1.161), theobromine (OR=0.892), threonate (OR=0.922) with frailty. Conclusions A potential causal association between gut microbes and their derived metabolites and risk of frailty suggests a role in the pathogenesis of frailty.

Key words: Gut microbiota, Gut microbiota-derived metabolites, Frailty, Mendelian randomization, Potential causal relationship