Distinct Gut Microbial Signatures and Diminished Anti-Inflammatory Effect of Short-Chain Fatty Acids in Schizophrenia With Immune Activation

Background and Hypothesis A subset of patients with schizophrenia (SCZ) exhibit subclinical immune activation. However, the gut microbial features of this subgroup and their interplay with the immune function remain poorly understood. This study aimed to identify the gut microbiome signature of immune-activated SCZ and elucidate the role of short-chain fatty acids (SCFAs) in the gut-immune crosstalk. Study Design In this study, 297 patients with SCZ and 301 healthy controls (HCs) were assessed for 4 serum immune mediators. Immune-activated subgroups were classified based on these biomarkers. Fecal metagenomic sequencing, SCFA metabolomics, and in vitro peripheral blood mononuclear cells (PBMCs) stimulation experiments were performed to analyze the microbial composition, SCFA levels, and immune responses. Study Results We found that 46.5% of the patients with SCZ exhibited elevated immune activation biomarker levels, which displayed unique bacterial signatures. Microbiome-based machine learning classifiers demonstrated robustness in SCZ and immune activation classification. Notably, microbial species abundance, functional metagenomics, and SCFA levels have confirmed an elevated capacity for SCFA production in patients with immune activation. Furthermore, in vitro PBMC stimulation experiments revealed a diminished anti-inflammatory effect of SCFAs in immune-activated patients when exposed to lipopolysaccharide-induced inflammation. Conclusions This study delineates the gut microbiome and SCFA metabolic profiles of immune-activated SCZ patients, revealing an association between gut microbiota dysbiosis, enhanced SCFA production capacity, and diminished anti-inflammatory effect of SCFA. These findings provide new insights into the underlying mechanisms and potential targeted treatments for SCZ patients with immune activation.