The Effects of Gut Microbiota, Plasma Metabolites, Immune Cells, Blood Cells and Cytokines on Schizophrenia: A Bidirectional Two-Sample Mendelian Randomisation Study

BACKGROUND: The aberrant traits of the gut-metabolite-immune network in schizophrenia imply a crucial interrelationship among them. The exploration of the association between the gut-metabolite-immune network and schizophrenia will create novel opportunities for future studies on the disorder. METHODS: This study utilised the Mendelian randomisation (MR) method to examine the causal relationships among gut microbiota, plasma metabolites, immune cells, blood cells, cytokines and schizophrenia. Additionally, mediation analysis was performed to identify and verify potential mediators involved in the pathway linking gut microbiota to schizophrenia. RESULTS: A total of 62 traits with causal connections to schizophrenia were identified from the gut microbiota, plasma metabolites, immune cells, blood cells and cytokines (11 traits from the gut microbiota [odds ratio (OR) = 0.683-2.104, p = 0.005-0.047], 35 traits from plasma metabolites [OR = 0.596-1.597, p = 0.005-0.049], 14 traits from immune cells [OR = 0.813-1.105, p = 0.005-0.049], 1 trait from blood cells [OR = 1.112, p = 0.038] and 1 trait from cytokines [OR = 0.864, p = 0.041]). Among them, 30 traits were classified as risk factors for schizophrenia. Additionally, we determined nine pathways by which gut microbiota influences schizophrenia (via 7 plasma metabolites and 2 immune cells). Moreover, in our MR analyses, several sensitivity analyses were employed to eliminate heterogeneity and horizontal pleiotropy, ensuring reliable MR results. Meanwhile, the outcomes of various analyses revealed that the gut microbiota most significantly associated with schizophrenia belonged to the Firmicutes phylum. CONCLUSIONS: These discoveries not only deepen our understanding of the pathogenic mechanism of schizophrenia but also offer significant impetus for the development of future diagnostic studies and therapeutic strategies.