Causal links among gut microbiota, immune-inflammatory and compensatory immune-regulatory systems, and schizophrenia

Schizophrenia (SCZ) has been increasingly linked to disruptions in gut microbiota (GM) and immune system dysregulation, including the immune-inflammatory response system (IRS) and compensatory immune-regulatory system (CIRS). To investigate their causal roles and potential confounding effects, we applied genetically informed Mendelian randomization (MR) using genome-wide association study (GWAS) data from a large SCZ meta-analysis (52,017 cases and 75,889 controls), 72 GM genera, and 22 traits of IRS, CIRS, and immune cell indices of European ancestry cohorts. We followed the STROBE-MR guidelines for the MR approach. We found complex causality involving both protective and risk effects. Our analysis revealed protective causal effects of GM genera Barnesiella, Desulfovibrio, Gordonibacter, and Romboutsia (OR = 0.85-0.93, p = 0.005-0.00018), and a risk effect from Clostridium innocuum (OR = 1.09, p = 0.007). Notably, Barnesiella and Gordonibacter represent novel findings. Among immune traits, tumor necrosis factor receptor 1 (sTNF-R1) showed a protective effect (OR = 0.83, p = 0.047), whereas regulatory T cell (Treg) counts increased the risk of SCZ (OR = 1.05, p = 0.006). Multivariate MR confirmed the independent effects of Desulfovibrio, Gordonibacter, and sTNF-R1 after adjusting for other traits. The identified bacterial genera and immune measures exhibit biological relevance to the pathogenesis of SCZ. These findings suggest that specific GM and immune traits contribute independently to SCZ pathogenesis. Particularly, cumulating evidence supporting Tregs as a therapeutic target for psychosis underscores the significance of our results. Further research on their function is needed to validate the causal role of the identified gut microbes and immune mechanisms in SCZ.