Causal effects of gut microbiota on schizophrenia: deciphering profiles mediated by cerebrospinal fluid metabolites in the gut-brain axis

Schizophrenia is a severe mental disorder, with growing studies indicating that the “gutbrain axis” may play a vital role in its pathophysiology. This study applied the bidirectional two-sample Mendelian randomisation (MR) analysis to systematically assess the causal relationships among gut microbiota, cerebrospinal fluid (CSF) metabolites, and schizophrenia. Instrumental variables were selected from publicly available genome-wide association study datasets. Inverse-variance weighted method was employed as the primary statistical approach, complemented by sensitivity analyses, reverse MR and Steiger’s directional test. Multivariable MR and MR Bayesian model averaging analyses were performed to further evaluate causality, and prioritize key taxa. Finally, blood metabolite datasets and enrichment analyses were used for validation and functional interpretation. After Bonferroni correction, 20 taxa exhibited borderline risk associations, while 8 taxa emerged as suggestive protective factors. Additionally, 11 CSF metabolites demonstrated weak positive associations with schizophrenia. No potential pleiotropy, heterogeneity, or reverse causality was detected. Mediation analysis identified 23 “gut microbiota-CSF metabolites-schizophrenia” pathways. Klebsiella A emerged as the principal taxon. Blood metabolites replication yielded no positive results. Enrichment analysis revealed significant enrichment in the biosynthesis pathways of phenylalanine, tyrosine, and tryptophan. These findings support causal links between specific gut microbiota, CSF metabolites, and schizophrenia, highlighting potential mechanisms within the gut-brain axis.