Integrative evidence for causal links between gut microbiota and Schizophrenia: A Mendelian randomization and 16S...

Schizophrenia is a severe psychiatric disorder with a complex etiology. Emerging evidence implicates the gut microbiota in its pathogenesis via the microbiota-gut-brain axis, although causal relationships remain unclear.

We used a two-sample Mendelian randomization (MR) approach to investigate potential causal links between gut microbial taxa and schizophrenia. To provide a biological context for these findings, we performed 16S rRNA V3-V4 sequencing of fecal samples from an independent cohort of individuals with schizophrenia (SCZ, n = 21) and matched healthy controls (HC, n = 21).

Forward MR analysis revealed a significant causal association between seven microbial taxa and schizophrenia risk. Notably, a higher genetically predicted abundance of Bifidobacterium was associated with increased schizophrenia risk (OR = 1.47, 95 %CI: 1.05-2.05), with results robust to multivariable adjustment. Reverse MR found no evidence of reverse causation. In the independent cohort, exploratory 16S rRNA analysis of the top 15 most abundant genera revealed nominal differences, including Bifidobacterium, Megamonas, Streptococcus, and Fusicatenibacter, but none remained significant after FDR correction (all Q > 0.05). However, a targeted confirmatory analysis of four MR-identified taxa revealed significant group differences for three taxa (all Q = 0.010), whereas Lachnospiraceae did not.

By integrating MR with 16S rRNA V3-V4 sequencing, this study provides convergent evidence for a potential causal role of specific gut microbial taxa, particularly Bifidobacterium, in contributing to schizophrenia risk. Our findings underscore the context-dependent nature of host-microbiota interactions and support the need for strain-level and functional studies to further elucidate schizophrenia pathogenesis.