Blood metabolites mediate gut microbiota effects on depression: A Mendelian randomization study

Accumulating evidence indicates that gut microbiota (GM) influence depression via gut-brain axis signaling, yet the causal relationships and underlying mechanisms are not fully understood. We conducted bidirectional Mendelian randomization (MR) to assess GM-Depression causal effects, with additional analyses examining blood metabolite mediation. We conducted a two-sample Mendelian randomization (MR) analysis using genetic instruments for gut microbiota (GM) from the FINRISK 2002 cohort ( n = 5959). Depression data were obtained from the FinnGen R11 database ( n = 448,069, European ancestry), along with three additional independent datasets: Pan-UK Biobank ( n = 370,457), Jamapsy_Giannakopoulou ( n = 194,548), and PGC-noUKBB ( n = 688,808). A Mendelian randomization meta-analysis was performed combining these datasets. Mediation analysis was conducted using multivariable MR (MVMR) with blood metabolite data from the Canadian Longitudinal Study on Aging (CLSA, n = 8299). Pathway analysis was performed using MetaboAnalyst 5.0. Our bidirectional MR identified Bifidobacteriaceae as a protective factor against depression (IVW OR = 0.93, 95 % CI: 0.89–0.97, P < 0.001), confirmed by meta-analysis (β = −0.05, P = 0.002). The protection was mediated by metabolites (e.g., glycolithocholate sulfate; OR = 0.80, 95 % CI: 0.71–0.90) enriched in BCAA pathways (FDR = 0.013). Conversely, N egativibacillus sp000435195 showed nominal risk effects in IVW (OR = 1.09, 95 % CI: 1.04–1.15, P < 0.001), though meta-analysis did not support this ( P > 0.05; I 2 = 68.5 %). Its potential risk involved metabolites (e.g., sulfated piperine; OR = 1.27, 95 %CI:1.13–1.42) enriched in glycine/serine/threonine pathways (FDR = 0.002). Reverse MR excluded reverse causation (all P > 0.05). Our findings provide genetic evidence for the causal involvement of specific GM in Depression, mediated by distinct metabolic pathways, suggesting potential microbiota-based interventions for Depression treatment. • Bifidobacteriaceae reduce the risk of depression via branched-chain amino acid (BCAA) metabolism. • Negativibacillus raises depression risk by disrupting glycine, serine, and threonine metabolism. • Mendelian randomization minimizes confounding in microbiota-depression research. • Probiotic-dietary interventions may present a new therapeutic intervention for depression