The gut microbiome–amino acid pathway to emotional lability: a multi-step Mendelian randomization study
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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] = 1.570, 95% confidence interval [CI]: 1.090–2.261, P = 0.015), followed by CAG-485 sp002362485 (OR = 1.323, 95% CI: 1.080–1.619, P = 0.006). Each standard deviation (SD) increment in CAG-485 sp002362485 was linked to a 32.3% higher risk of EL. This bacterium was specific to EL and correlated with glycine/serine/threonine metabolites. Reverse MR analyses ruled out reverse causality.
Author summary
Emotional lability—defined as frequent, rapid shifts in mood and emotional state—is a pervasive symptom across many psychiatric disorders, and it is associated with poorer treatment outcomes and higher risks of self-harm. Despite its clinical significance, the biological causes of emotional lability remain largely unknown. Accumulating evidence points to a link between the gut microbiota (the community of microbes living in the human digestive tract) and brain function via the gut-brain axis, but it has remained unclear whether gut microbes directly cause changes in emotional stability, and what biological pathways might mediate such effects.
To answer these questions, we employed a multi-step Mendelian randomization approach. This method uses natural genetic variation as a tool to help distinguish causal relationships from simple correlations, reducing bias from confounding factors. We first tested the causal link between gut microbiota and emotional lability, then identified microbial markers specific to emotional lability by comparing them with other common psychiatric disorders. Finally, we investigated whether blood metabolites act as intermediate messengers that connect gut microbial activity to emotional regulation.
We identified 16 gut bacterial species that causally influence susceptibility to emotional lability, with three showing independent effects: two bacteria increase risk, while one is protective. The strongest risk-associated bacterium, CAG-485 sp002362485, was found to act in part by disrupting amino acid metabolism, particularly pathways involving glycine, serine, and threonine. We also confirmed that the effect flows from gut microbiota to emotional state, rather than emotional changes altering the gut microbiome.
These findings clarify the causal role of gut microbiota in emotional dysregulation and reveal key metabolic pathways that underpin the gut-brain connection. They not only improve our understanding of why emotional lability occurs, but also suggest new potential strategies for intervention, such as targeting gut microbes or related metabolic processes.
