A Multimodal Observational Case-Control Study Exploring Gut Microbiota–Hippocampus Alterations in Individuals With High Positive Schizotypy From the General Population

Abstract

Background

The hippocampus plays a critical role in psychosis, with reduced volume observed across the psychosis continuum. These structural changes are associated with cognitive deficits, symptom severity, and increased risk of psychosis progression. Elevated hippocampal perfusion and glutamate/GABA (gamma-aminobutyric acid) imbalance further suggest metabolic dysregulation as a key mechanism. Gut microbiota composition can influence hippocampal metabolism, but their interplay remains to be explored.

Methods

In this cross-sectional study, we recruited 142 healthy participants from the general population, yielding 69 individuals with high schizotypy (HS) and 72 individuals with low schizotypy. All underwent clinical and cognitive testing, multimodal neuroimaging, and gut microbiota analysis via 16S ribosomal RNA gene sequencing. Hippocampal subfield volumes (structural magnetic resonance imaging), perfusion (arterial spin labeling) and glutamate/GABA levels (proton magnetic resonance spectroscopy), and microbial taxa (abundance, diversity, enterotypes) were assessed.

Results

Group comparisons of cognition, multimodal neuroimaging, and gut microbiome composition did not reveal significant differences after correction for multiple comparisons. Within the HS group, glutamate (r = 0.38, p = .003) and GABA (r = −0.36, p = .003) ratios were linked to social withdrawal. Across the entire sample, left hippocampal subfield volumes and glutamate/GABA levels differed significantly between predominant gut microbial enterotypes.

Conclusions

Our results suggest a potential relationship between aberrant gut microbial composition and hippocampal alterations in people with positive schizotypy from the general population. Our findings inform future large-scale research that further explores specific mechanisms of gut microbiome-hippocampus interactions in psychosis and the potential of tailored microbial interventions targeting hippocampal-mediated symptoms.