Emerging evidence has linked the gut microbiome changes to
schizophrenia. However, there has been limited research into the functional pathways by which the gut microbiota contributes to the phenotype of persons with chronic
schizophrenia. We characterized the composition and functional potential of the gut microbiota in 48 individuals with chronic
schizophrenia and 48 matched (sequencing plate, age, sex, BMI, and
antibiotic use) non-psychiatric comparison subjects (NCs) using
16S rRNA sequencing. Patients with
schizophrenia demonstrated significant beta-diversity differences in microbial composition and predicted genetic functional potential compared to NCs. Alpha-diversity of taxa and functional pathways were not different between groups. Random forests analyses revealed that the microbiome predicts differentiation of patients with
schizophrenia from NCs using taxa (75% accuracy) and functional profiles (67% accuracy for KEGG orthologs, 70% for MetaCyc pathways). We utilized a new compositionally-aware method incorporating reference frames to identify differentially abundant microbes and pathways, which revealed that Lachnospiraceae is associated with
schizophrenia. Functional pathways related to
trimethylamine-N-oxide reductase and
Kdo2-lipid A biosynthesis were altered in
schizophrenia. These metabolic pathways were associated with inflammatory
cytokines and risk for
coronary heart disease in
schizophrenia. Findings suggest potential mechanisms by which the microbiota may impact the pathophysiology of the disease through modulation of functional pathways related to immune signaling/response and
lipid and
glucose regulation to be further investigated in future studies.