Effect of the gut microbiota–blood metabolite axis on anti-influenza IgG levels after vaccination: A Mendelian randomization study

While antibody responses to influenza viruses have been extensively studied, the immunogenicity of influenza vaccines remains highly variable among individuals. Growing evidence suggests that the gut microbiota (GM) and associated metabolites play a critical yet understudied role in shaping host immunity, including responses to vaccines. However, the mechanistic pathways linking microbial communities, blood metabolites, and influenza vaccine-induced antibody production remain poorly understood. This study investigates the GM-blood metabolite-antibody level axis to identify potential modulators of vaccine immunogenicity. In this study, 2-sample Mendelian randomization (MR) were conducted to identify causality. We performed 2-sample MR using genome-wide association study data from MiBioGen (GM, N = 14,306), Avon Longitudinal Study of Parents and Children (anti-influenza immunoglobulin G (IgG), N = 4735), and metabolite genome-wide association study (N = 7824). Instrumental variables (P < 5 × 10-⁵, r² < 0.01, F > 10) were analyzed via inverse-variance-weighted (IVW) regression with sensitivity analyses (MR-Egger, weighted median). Two-step MR assessed metabolite mediation effects. Our analysis revealed positive correlations between influenza virus subtype influenza A H1N1 virus IgG levels and the Escherichia Shigella genus, Ruminococcaceae UCG002, and Ruminococcaceae UCG003 genera. Conversely, negative correlations were observed with the Erysipelotrichaceae family, Rhodospirillaceae family, Barnesiella genus, and Eubacterium fissicatena group. For influenza virus subtype influenza A H3N2 virus IgG antibodies, positive associations were identified with the Bacteroidales S24-7*group, Defluviitaleaceae family, Adlercreutzia, Desulfovibrio, Eubacterium eligens group, Eubacterium rectale group, and Ruminococcaceae UCG014 genus, while negative associations were noted for the Negativicutes class and Selenomonadales order. Two-step MR analysis suggested mediation effects: the association between the Erysipelotrichaceae family and influenza A H1N1 virus IgG levels was partially mediated by bradykinin, des-Arg(9) (proportion mediated: 27.16%, P = .006). The link between Ruminococcaceae UCG014 and influenza A H3N2 virus IgG levels was partially mediated by alanine (proportion mediated: 26.86%, P = .002). This study demonstrates the potential role of blood metabolites as mediators in modulating the impact of the GM on immunity to influenza.