Evaluation of the brain microbiome and proteome as well as the role of fecal microbiota transplantation (FMT) in schizophrenia - studies in a methylazoxymethanol acetate (MAM-E17) rat model
Project manager: dr Dominika Salamon
Imprementation period: 2022 – 2025
Project type: Sonata 17
The project is carried out in consortium with the Institute of Pharmacology of the Polish Academy of Sciences
RESEARCH PROJECT OBJECTIVES
Schizophrenia (SCZ) is a neurodevelopmental disorder characterized by a complex clinical picture, who can be distinguished between positive symptoms, negative symptoms and cognitive symptoms. Inflammatory factors seem to play a role in its formation, but also the gut-brain axis and factors influencing its functioning. Information on the relationship between the composition of the intestinal microbiome (especially the deficiency of probiotic bacteria) and the development of inflammatory processes that influence the development of SCZ appears in the literature more and more often. Moreover, the gut microbiota can influence the synthesis or metabolism of neurotransmitters or produce them by themselves. These observations led to the assumption that perhaps the gut microbiome contributes to the development of SCZ, the etiology of which has not yet been elucidated and seems to be multivariate and reflects an interaction between genetic vulnerability and environmental contributors
The objective of the project will be a comprehensive evaluation (qualitative and quantitative, using the next-generation sequencing [NGS] method) of the composition of the microbiota of large intestine in SCZ rat model and control group of rats before the introduction of fecal microbiota transplantation (FMT- from control group to SCZ group and from SCZ group to control group), following FMT and additionally a comprehensive evaluation of the composition of the microbiota of blood and brain tissue when experiment will be finished. Simultaneously, an analysis of the correlation of data obtained from NGS sequencing with the results of behavioral tests and data from proteome profiling of selected regions of the brain will be carried out.
RESEARCH METHODOLOGY
The research material will be samples from 120 rats (60 males and 60 females) with SCZ symptoms (rats receiving MAM- methylazoxymethanol acetate) and 120 rats (60 males and 60 females) as control group. Each group is divided into 2 subgroups (FMT receiving group – 60 rats and placebo receiving group – 60 rats). The following samples will be taken: feces from SCZ and control group before FMT, 1 month after FMT and 2 months after FMT, blood and brain tissue at the end of the experiment.
Comprehensive quantitative and qualitative analysis of the microbiota composition (both fungal and bacterial) of the large intestine, and blood and brain tissue in SCZ animal compared to control group will be possible through the use of next-generation sequencing (NSG). Animal tests measuring schizophrenia-relevant behavioral phenotypes (social behavior, ultrasonic vocalization measurement novel object recognition test (NORT), pre-pulse inhibition and locomotor activity) will be used 1 month and 2 months after FMT, at postnatal day (PND) 73 and PND 103 respectively. The obtained homogenates of brain tissue will be used to isolate proteins and proteomics analysis will be carry out. Then, the obtained results will be compared and correlated with NGS data and behavioral test results.
SIGNIFICANCE OF THE PROJECT
The obtained results during the implementation of this project may shed light on the causes and pathomechanism of schizophrenia. They can also contribute to the development of a new model of schizophrenia therapy, based on the modification of the gut microbiota composition with FMT, as well as the development of new drugs, individually designed for each patient and acting systemic in operation (new generation probiotics, antibiotics). It is possible that, on the basis of the data obtained in the course of this project, it will be feasible to determine the gut and blood microbiota profiles predisposing to the development of schizophrenia, or to faster remission and maintaining it longer.