The Gut Microbiome-Amino Acid Pathway to Emotional Lability: A Multi-Step Mendelian Randomization Study

Emotional lability (EL) is a prevalent cross-diagnostic symptom with unclear etiology. Given the potential role of the gut-brain axis in linking gut microbiota to EL, we adopted a multi-step Mendelian randomization (MR) framework to investigate the causal effects of gut microbiota on EL and the mediating role of blood metabolites. Bidirectional two-sample MR was first implemented to determine the causal relationship and direction between gut microbiota and EL, followed by multivariable MR (MVMR) to assess the direct contributions of individual microbial taxa. We then applied a multistep MR approach to identify gut microbiota specifically associated with EL-related psychopathology. Finally, the mediation effects of blood metabolites were quantified via the coefficient of variation method, and pathway analysis was conducted to verify the biological plausibility of the enriched metabolic pathways. Bidirectional MR detected 16 gut microbiota species associated with EL risk. MVMR identified three causally associated bacteria: RUG013 sp001486445 exerted the strongest positive effect (odds ratio [OR] = 1.500, 95\% confidence interval [CI]: 1.029-2.187, P = 0.034), followed by CAG-485 sp002362485 (OR = 1.398, 95\% CI: 1.118-1.749, P = 0.003). Each standard deviation (SD) increment in CAG-485 sp002362485 was linked to a 39.8\% higher risk of EL. This bacterium was specific to EL and correlated with glycine/serine/threonine metabolites. Reverse MR analyses ruled out reverse causality .