Background and rationale:Compelling support has accumulated for the concept that psychosis develops along a continuum. The model proposes a dimensional continuity between subclinical psychotic experiences in healthy individuals from the general population (also termed schizotypy) and clinically relevant psychosis. Schizotypy can be understood as a developmental mediator between early endophenotypes and later risk for developing overt psychosis. Hippocampal dysregulation might be a key factor for the developmental trajectory of psychotic disorders and is related to poorclinical outcomes. Recent evidence from the emerging field of gut-brain communication further shows that gut microbiota can greatly influence hippocampus function. While preliminary studies indicate alterations in gut microbiota in patients with schizophrenia, it remains completely unknown whether gut microbiota alterations are already evident in people with high level of schizotypy from the general population and whether they are related to hippocampus divergences.
Overall objective: To explore aberrantgut microbiota- hippocampus interactions in non-clinical individuals with high positive schizotypy from the general population.
Specific aimsare to investigate differences in 1) hippocampus function and neurochemistry and 2) gut microbiota composition between people from the general population with low and high positive schizotypy and 3) whether hippocampal measures can predict different microbial profiles.
Methods:1) Hippocampus function and neurochemistry:Hippocampal perfusion and activation at rest and during verbal learning will be measured with arterial spin labeling (ASL) and functional magnetic resonance imaging (fMRI). Hippocampal GABA and glutamate concentrations will be assessed with magnetic resonance spectroscopy (MRS). Imaging analyses will be performed with Statistical Parametric Mapping using two-sample t tests to compare groups (p < 0.05, corrected for family-wise error (FWE) rate). 2) Gut microbiota: state-of the-art Quantitative Microbiome Profiling based on 16S ribosomal RNA sequencing. Alpha-diversity by means of richness and species abundance will be tested using nonparametric Kruskal-Wallis test. Differences in species abundance (beta-diversity) will be calculated using Bray-Curtis distances and group differences will be assessed with permutational analysis of variance. 3) Gut microbiota – hippocampus synergisms: Clusters of enterotypes will be determined based on Dirichlet Multinomial Modeling. ANOVA will be conducted to test whether participants belonging to different enterotypes show differences in hippocampal measures. Furthermore, sparse partial least squares discriminant analysis will be performed to determine if hippocampal measures can predict enterotype membership.
Expected results:Most prominent hippocampus differences between high and low schizotypy will be hypothesized in GABA and glutamate concentrations, with lower GABA and higher glutamate concentrations in people with positive schizotypy. We expect increased abundance of short-chain fatty acid producing bacteria in people with high positive schizotypy compared to those with low schizotypy. Finally, we expect that enterotype can be predicted by hippocampal measures with above-chance accuracy, while GABA and glutamate concentrations will provide the most explanatory power.
Impact for the fieldThis project may deliver novel prognostic and predictive biomarkers for improving psychosis prediction and developing novel interventions targeted toimprove hippocampus functioning and prevent related clinical outcomes in non-clinical and clinical people at increased risk of developing psychosis. |
