Case–control study links schizophrenia with altered gut microbes and metabolites

People with schizophrenia showed differences in gut microbial composition and untargeted metabolomic features compared with healthy controls in a small case–control study. Researchers collected fecal samples from 30 patients with schizophrenia and 30 healthy controls; qualified 16S rRNA gene sequencing data were obtained from 30 patients and 29 controls. The investigators also performed untargeted metabolomic profiling using ultra-high-performance liquid chromatography–tandem mass spectrometry. Their results support an association between schizophrenia and microbiota–metabolite alterations, but they do not establish whether the differences are caused by schizophrenia, medication or other factors.

The microbial analysis found that participants with schizophrenia had lower microbial richness and diversity than controls, along with marked separation in beta-diversity. The authors used an exploratory random forest model to rank taxa that contributed most strongly to discrimination between the groups. Pseudocitrobacter, Hafnia-Obesumbacterium and Escherichia-Shigella were the leading features in that analysis. The result identifies organisms associated with group membership in this dataset; it does not validate them as diagnostic biomarkers or establish their biological role in schizophrenia.

Several taxa differed in relative abundance between the two groups. Escherichia-Shigella was significantly enriched in the schizophrenia group, with a median relative abundance of 2.377% in group S compared with 0.119% in group H; the false-discovery-rate-adjusted q value was 0.00031 and Cliff’s delta was 0.646. In the opposite direction, Faecalibacterium had a median relative abundance of 2.630% in the patient group and 7.275% in the control group. Agathobacter was also more abundant in controls, with medians of 0.903% in patients and 2.874% in healthy controls. These measurements describe differences in the sampled fecal communities and do not show that the bacteria caused psychiatric symptoms or that they can identify an individual patient reliably.

Untargeted metabolomics also revealed differences between patients and controls, predominantly involving metabolites and pathways associated with amino acid and lipid metabolism. In combination with the microbial findings, the chemical profile was consistent with distinct microbiota–metabolite features in the schizophrenia group. The supplied study abstract does not identify which organisms produced or modified the measured metabolites, nor does it establish the order of events linking schizophrenia, medication, microbial changes and metabolic changes. The two sets of measurements therefore show parallel differences in biological features, rather than a proven causal pathway.

The study’s main constraints are its small sample size, cross-sectional design and antipsychotic exposure. Because the work was cross-sectional, it cannot determine whether the observed microbial and metabolomic differences preceded schizophrenia, developed alongside it or were partly related to treatment. The authors state that medication-related effects could not be separated from disease-specific effects, so the findings should be treated as exploratory observations. They call for confirmation in larger longitudinal cohorts and independent validation datasets. Until such evidence is available, the results indicate that gut microbial composition and untargeted metabolomic profiles differ between this group of patients with schizophrenia and healthy controls, without proving causality, establishing a clinical test or showing that the findings generalize to all people with schizophrenia.

Subject of Research: Gut microbiota and untargeted metabolomic differences in schizophrenia

Article Title: Altered gut microbiota and untargeted metabolomic features in patients with schizophrenia: a case–control study

Article References: Mi, Y., Sun, P., Hao, Q., Yang, Y., Dong, C., Kong, C., Li, L., Zhao, C., & Yin, H. (2026). Altered gut microbiota and untargeted metabolomic features in patients with schizophrenia: a case–control study. Frontiers in Psychiatry, 17, Article 1981601. https://doi.org/10.3389/fpsyt.2026.1981601

Image Credits: AI Generated

DOI: 10.3389/fpsyt.2026.1981601

Keywords: schizophrenia, gut microbiota, untargeted metabolomics, 16S rRNA sequencing, case–control study, amino acid metabolism, lipid metabolism, Escherichia-Shigella, Faecalibacterium, microbiota–metabolite associations, Altered, microbiota