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Background  Growing evidence has shown that alterations in the gut microbiota composition were associated with a variety of neuropsychiatric conditions. However, whether such associations reflect causality remains unknown. We aimed to reveal the causal relationships among gut microbiota, metabolites, and neuropsychiatric disorders including Alzheimer’s disease (AD), major depressive disorder (MDD), and schizophrenia (SCZ).    Methods  A two-sample bi-directional Mendelian randomization analysis was performed by using genetic variants from genome-wide association studies as instrumental variables for gut microbiota, metabolites, AD, MDD, and SCZ, respectively.    Results  We found suggestive associations of host-genetic-driven increase in  Blautia  (OR, 0.88; 95%CI, 0.79–0.99;  P  = 0.028) and elevated γ-aminobutyric acid (GABA) (0.96; 0.92–1.00;  P  = 0.034), a downstream product of  Blautia -dependent arginine metabolism, with a lower risk of AD. Genetically increased  Enterobacteriaceae family  and  Enterobacteriales order  were potentially associated with a higher risk of SCZ (1.09; 1.00–1.18;  P  = 0.048), while  Gammaproteobacteria class  (0.90; 0.83–0.98;  P  = 0.011) was related to a lower risk for SCZ. Gut production of serotonin was potentially associated with an increased risk of SCZ (1.07; 1.00–1.15;  P  = 0.047). Furthermore, genetically increased  Bacilli class  was related to a higher risk of MDD (1.07; 1.02–1.12;  P  = 0.010). In the other direction, neuropsychiatric disorders altered gut microbiota composition.    Conclusions  These data for the first time provide evidence of potential causal links between gut microbiome and AD, MDD, and SCZ. GABA and serotonin may play an important role in gut microbiota-host crosstalk in AD and SCZ, respectively. Further investigations in understanding the underlying mechanisms of associations between gut microbiota and AD, MDD, and SCZ are required.

Associations between gut microbiota and Alzheimer’s disease, major depressive disorder, and schizophrenia