[Abstract] A multimodal observational case-control study exploring gut microbiota – hippocampus alterations in high positive schizotypy individuals from the general population

Background: Hippocampal dysfunction is widely implicated in the pathophysiology of psychosis and is increasingly recognized in individuals with subclinical psychotic traits, such as those exhibiting high positive schizotypy. Across the psychosis continuum, reduced hippocampal volume, regional hyperperfusion, and an imbalance between glutamate and gamma-aminobutyric acid (GABA) have been associated with cognitive impairments and increased risk for progression to clinical disorders. Parallel research highlights the gut microbiota’s influence on brain metabolism and inflammation, particularly through short-chain fatty acid (SCFA) production. Despite growing interest in the gut–brain axis, the role of microbial composition in shaping hippocampal structure and function in healthy individuals with schizotypy has not been sufficiently investigated. Aim: This study aimed to explore whether individuals with high positive schizotypy (HS) from the general population differ from low schizotypy (LS) controls in hippocampal volume, perfusion, and neurotransmitter levels, and whether these neural markers are associated with alterations in gut microbiota composition. Methods: In a cross-sectional, multimodal case-control design, 142 healthy participants were grouped into HS (n = 69) or LS (n = 72) based on the Unusual Experiences subscale of the sO-LIFE questionnaire. All participants underwent comprehensive clinical and cognitive testing, structural magnetic resonance imaging (MRI), arterial spin labeling (ASL) to assess cerebral blood flow in hippocampal regions, and proton magnetic resonance spectroscopy (H-MRS) to quantify hippocampal glutamate and GABA concentrations. Fecal samples were analyzed using 16S rRNA sequencing to assess microbial diversity, taxonomic abundance, and enterotype distribution. Statistical analyses included t-tests, Mann–Whitney U tests, chi-squared tests, and Spearman correlations within groups. Correlation differences between HS and LS were evaluated using Fisher’s r-to-z transformation, with Benjamini–Hochberg correction applied by modality. Results: Compared to LS participants, the HS group exhibited significantly lower performance in selective attention (Cohen’s d = 0.42), processing speed (d = 0.34), and working memory (d = 0.46). Neuroimaging showed trends toward increased volume in the right presubiculum body (d = 0.30) and reduced volume in the left hippocampus–amygdala transitional area (d = 0.32). While no group differences were observed in mean glutamate or GABA concentrations, Glu/GABA (r = 0.38, p = .003) and GABA/NAA (r = –0.36, p = .003) ratios were significantly associated with social withdrawal in HS. Gut microbiota analysis identified lower abundance of SCFA-producing genera, including Gordonibacter (z = –2.23, punc = .006) and Eubacterium D (z = –2.09, punc = .031), in HS. These taxa correlated with both hippocampal markers and schizotypal traits, although results did not withstand multiple comparison correction. Conclusions: This study is the first to combine multimodal neuroimaging and microbiota profiling in a nonclinical schizotypy sample. Results suggest that subtle hippocampal alterations and microbial shifts co-occur in subclinical psychosis. These associations, though preliminary, support the hypothesis that gut–brain interactions may influence early psychosis risk. Longitudinal, mechanistic studies integrating neuroimaging, metagenomics, and metabolomics are needed to clarify causal pathways and assess microbiome-targeted interventions.