Associations between genetic predispositions for specific gut microbiota, serum ferritin, and blood lipids: A Mendelian randomization study

Our study explores the bidirectional causal relationship between gut microbiota and serum ferritin and investigates the mediation of serum ferritin in the causal relationship between specific gut microbiota and circulating lipids. We utilized genome-wide association study databases of 211 gut microbiomes and serum ferritin to explore the bidirectional causal relationship. A 2-step 2-sample Mendelian randomization (MR) analysis was conducted to investigate the mediation of serum ferritin in the causal relationship between specific gut microbiota and circulating lipids. A comprehensive sensitivity analysis was performed to verify the robustness of the results. The 2-sample bidirectional MR analysis identified that Ruminococcaceae UCG010[g] is positively associated with serum ferritin (Beta ± SE: 0.367 ± 0.088, P < .001, PFDR = .049). In the other direction, no gut microbiota was found to be affected by serum ferritin in the reverse direction. Ruminococcaceae UCG010[g] is positively correlated with high-density lipoprotein cholesterol (HDL-C) (Beta ± SE: 0.051 ± 0.014, P < .001) and apolipoprotein A-I (Beta ± SE: 0.051 ± 0.014, P < .001), while negatively correlated with triglyceride (Beta ± SE: -0.057 ± 0.026, P = .026) and apolipoprotein B (Beta ± SE: -0.042 ± 0.021, P = .045). A 2-step MR analysis revealed that serum ferritin was negatively associated with HDL-C levels (Beta ± SE: -0.018 ± 0.007, P = .014), but no significant effects were observed on other circulating lipids (low-density lipoprotein cholesterol, triglyceride, apolipoprotein A-I, and apolipoprotein B). This suggests that serum ferritin may act as a mediating factor that partially counteracts the HDL-C-promoting effect of Ruminococcaceae UCG010[g]. This study revealed a positive causal effect of Ruminococcaceae UCG010[g] on serum ferritin through a 2-sample MR analysis, and this microbial group may have a beneficial impact on the blood lipid profile. Serum ferritin, as a mediator between Ruminococcaceae UCG010[g] and HDL-C, partially disrupts this mechanism. These findings provide novel causal evidence supporting the interactions within the "gut microbiota (serum ferritin) blood lipids" regulatory network.