Integrated Analysis of Gut Microbiome, Inflammation, and Neuroimaging Features Supports the Role of Microbiome–Gut–Brain Crosstalk in Schizophrenia

Abstract Background and Hypothesis Gut microbiota has been implicated in the pathogenesis of schizophrenia (SZ) and relevant changes in the brain, but the underlying mechanism remains elusive. This study aims to investigate the microbiota–gut–brain crosstalk centered on peripheral inflammation in SZ patients. Study Design We recruited a cohort of 182 SZ patients and 120 healthy controls (HC). Multi-omics data, including fecal 16S rRNA, cytokine data, and neuroimaging data, were collected and synthesized for analysis. Multi-omics correlations and mediation analyses were utilized to determine the associations of gut microbiome with inflammatory cytokines and neuroimaging characteristics. Additionally, machine learning models for effective SZ diagnosis were separately generated based on gut microbial and neuroimaging data. Study Results Gut microbial dysbiosis, characterized by a decrease in butyrate-producing bacteria and an increase in proinflammatory bacteria, has been identified in SZ patients. These key microbial taxa were associated with increased inflammatory cytokines, potentially through mediating lipid metabolic pathways such as steroid biosynthesis and linoleic acid metabolism. Further analysis revealed altered microbial genera to be correlated with disrupted gray matter volume and regional homogeneity in SZ patients. Importantly, certain inflammatory cytokines mediated the relationship between the SZ-enriched genus Succinivibrio and aberrant activity of anterior cingulate cortex and left inferior temporal gyrus in the SZ group. Moreover, the classification model based on gut microbial data showed comparable efficacy to the model based on brain functional signatures in SZ diagnosis. Conclusions This study presents evidence for the dysregulated microbiota–gut–brain axis in SZ and emphasizes the central role of peripheral inflammation.