Gut microbiota and blood metabolites: unveiling their roles in hippocampal volume changes through Mendelian randomization and mediation analysis.

Changes in hippocampal volume (HV) are linked to various neuropsychiatric disorders. Observational studies suggest associations of gut microbiota (GM) and blood metabolites (BM) with changes in HV; however, their causal relationships remain unclear. We aimed to use Mendelian randomization (MR) to investigate the causal associations of GM and BM with changes in HV and to explore the potential mediating role of BM. Using two-sample MR (TSMR) analysis, we examined 412 GM traits and 1,400 BM traits with a focus on their causal relationships with age-independent/dependent longitudinal changes in HV, primarily using the inverse variance weighted method. Furthermore, we explored the mediating role of BM through a two-step MR design. We identified 44 GM traits and 175 BM traits having nominally significant causal associations with age-independent/dependent longitudinal changes in HV. In addition, the glycine-to-pyridoxal ratio (mediation proportion: 7.38%) and the phosphate-to-citrate ratio (mediation proportion: 12.55%) mediated the effect of the pathway of L-arginine degradation II on the reduction of age-independent longitudinal changes in HV. Our study reveals the causal effects of GM and BM on longitudinal changes in HV and identifies BM traits with mediating roles. These findings offer valuable insights for the prevention and treatment of the related neuropsychiatric disorders.