The role of gut microbiota in the pathophysiology of schizophrenia

Annotation

Schizophrenia (SZ) is a severe psychiatric disorder affecting 0.32–0.45% of the population (GBD 2019 Mental Disorders Collaborators, 2022). Hallucinations, delusions, disruption of will, and cognitive deficits result from interactions between genetic and environmental factors (Jauhar, Johnstone, & McKenna, 2022). These interactions begin affecting the brain during early development (Riglin et al., 2017; Akkouh et al., 2024), although symptoms typically manifest in adolescence or later. Currently, SZ diagnosis relies solely on cognitive and behavioral symptoms, as objective biomarkers are yet to be identified.

Heterogeneity of Schizophrenia and Research Objectives

SZ is a heterogeneous disorder. Our long-term goal is to identify its subtypes for improved diagnosis and targeted treatment. At the National Institute of Mental Health (NUDZ), we have established one of the world’s largest biobanks of patients in the early stages of psychotic illness through the ESO study. Patients experiencing their first episode of illness (FEP) undergo comprehensive assessments at baseline, after one year, and after three years. These assessments include multimodal MRI, neuroimaging MRI, blood samples, and, in some cases, stool samples. The study aims to analyze extensive clinical and laboratory data to classify patients based on different neurobiological backgrounds using longitudinal data.

Key Findings

This research has led to several groundbreaking discoveries:

Longitudinal MRI analysis of cortical morphometry revealed three patient subgroups:
1. Those exhibiting early cortical atrophy.
2. Those demonstrating cortical volume expansion.
3. Those showing no significant cortical changes.
Gut microbiota analysis identified a correlation between increased levels of the bacterium Collinsella and cortical atrophy in a specific brain region in FEP patients.

These findings highlight the heterogeneity of SZ and suggest distinct cortical pathology patterns in the early stages of the disease. The higher abundance of Collinsella may trigger a degenerative process leading to cortical thinning in vulnerable individuals.

Research Goals and Methodology

Building on previous findings, this project aims to explore unknown pathogenic pathways between gut microbiota—particularly Collinsella—and pathophysiological processes in the brains of SZ patients, leading to cortical morphology changes.

Specific Aims:

Compare the gut microbiota of FEP patients with healthy controls.
Investigate how increased Collinsella in the gut affects the brain at a cellular level through:
- In vivo experiments manipulating Collinsella levels in animal models.
- In vitro experiments assessing gut-induced changes in brain cells, determining whether these are caused by chemical alterations or immune responses.
Identify biological markers reflecting gut-brain axis deviations in SZ by examining antibody levels and protein changes in blood samples. These markers could serve as diagnostic tools for SZ subtyping.

The preliminary data obtained will guide future large-scale validation studies, which can be conducted at NUDZ thanks to the ongoing ESO study.

Collaboration and Translational Research Approach

This project benefits from collaboration with Professor Li Wen, M.D., Ph.D., from Yale University, an expert in microbiota-induced immune processes. Dr. Wen, a leading translational immunologist, has pioneered research on the microbiota’s role in type 1 diabetes (Wen et al., 2008) and leads a top-tier laboratory utilizing microbiota for diagnostic applications in various diseases.

Translational research bridges clinical and basic science, requiring effective communication between disciplines. This can be particularly challenging for early-career scientists. To address this, the project incorporates strategies fostering interaction between basic and clinical research. The leadership team comprises four physician-researchers with extensive interdisciplinary experience. Additionally, regular mini-conferences will be held with five experts and emeritus academics, whose insights are crucial for addressing this complex project.

Training and Career Development

The junior research team includes three doctoral candidates and two postdoctoral researchers, reflecting NUDZ’s commitment to gender equity, as recognized by the European Commission’s "HR Excellence in Research Award." All team members have demonstrated exceptional scientific potential and are promising candidates for advanced research training.

The role of gut microbiota in the pathophysiology of schizophrenia (LUAUS25249)

Basic information