Gut-Brain Axis in Neurodegeneration (NCT05934188)

Overview

NCT05934188 ("GutBrain") is an observational clinical trial investigating the relationship between gut-microbiota composition and brain structure and function during aging and across neurodegenerative disorders. The study is conducted by [IRCCS San Camillo](https://www.ircsscamillaitalia.org/) in Venice, Italy, and represents one of the most comprehensive multi-disease investigations of the [gut-brain axis](/mechanisms/gut-brain-axis-neurodegeneration) in neurodegeneration to date[@clinicaltrialsgov].

Trial Details

| Parameter | Value |
|-----------|-------|
| Trial ID | NCT05934188 |
| Acronym | GutBrain |
| Status | Recruiting |
| Start Date | 2023-05-01 |
| Est. Completion | 2027-04-30 |
| Sponsor | IRCCS San Camillo, Venezia, Italy |
| PI | Nicola Filippini |
| Collaborators | IRCCS Centro San Giovanni di Dio Fatebenefratelli; Università Ca' Foscari Venezia |
| Study Type | Observational |

Scientific Rationale

Neurodegenerative diseases represent a major health concern due to their growing societal implications and economic costs. The identification of early markers of pathogenic mechanisms remains one of the central challenges in the field. The [gut-brain axis](/mechanisms/gut-brain-axis) has emerged as a primary target because of its transversal role across the neurodegenerative spectrum and its effects on cognition[@clinicaltrialsgov].

The gut-brain axis encompasses multiple signaling pathways between the gastrointestinal tract and the central nervous system, including:

Overview

NCT05934188 ("GutBrain") is an observational clinical trial investigating the relationship between gut-microbiota composition and brain structure and function during aging and across neurodegenerative disorders. The study is conducted by [IRCCS San Camillo](https://www.ircsscamillaitalia.org/) in Venice, Italy, and represents one of the most comprehensive multi-disease investigations of the [gut-brain axis](/mechanisms/gut-brain-axis-neurodegeneration) in neurodegeneration to date[@clinicaltrialsgov].

Trial Details

| Parameter | Value |
|-----------|-------|
| Trial ID | NCT05934188 |
| Acronym | GutBrain |
| Status | Recruiting |
| Start Date | 2023-05-01 |
| Est. Completion | 2027-04-30 |
| Sponsor | IRCCS San Camillo, Venezia, Italy |
| PI | Nicola Filippini |
| Collaborators | IRCCS Centro San Giovanni di Dio Fatebenefratelli; Università Ca' Foscari Venezia |
| Study Type | Observational |

Scientific Rationale

Neurodegenerative diseases represent a major health concern due to their growing societal implications and economic costs. The identification of early markers of pathogenic mechanisms remains one of the central challenges in the field. The [gut-brain axis](/mechanisms/gut-brain-axis) has emerged as a primary target because of its transversal role across the neurodegenerative spectrum and its effects on cognition[@clinicaltrialsgov].

The gut-brain axis encompasses multiple signaling pathways between the gastrointestinal tract and the central nervous system, including:

• Neural pathways: The [vagus nerve](/mechanisms/vagus-nerve-gut-brain) provides direct bidirectional communication between the gut enteric nervous system and the brain
• Hormonal pathways: Gut-derived hormones including GLP-1, PYY, and ghrelin cross the blood-brain barrier and influence neuronal function
• Immunological pathways: Gut-associated lymphoid tissue (GALT) communicates with brain microglia via circulating cytokines
• Metabolic pathways: Microbial metabolites including short-chain fatty acids (SCFAs) influence neuroinflammation and neuronal function

Study Design

Multi-Disease Cohort

This observational study recruits participants across four distinct groups:

This design enables direct comparison of gut microbiome-brain relationships across disease states and healthy aging, providing critical insights into disease-specific versus aging-related alterations.

Clinical Assessments

The trial employs a comprehensive multi-modal assessment battery:

| Assessment | Purpose |
|-----------|---------|
| Magnetic Resonance Imaging | Brain structure and functional connectivity |
| Neuropsychological protocol | Cognitive performance across domains |
| Eating habits questionnaire | Dietary intake patterns |
| Microbiome analyses | Gut bacterial composition |
| Inflammatory markers | Systemic inflammation profiling |
| AD biomarkers | Cerebrospinal fluid and blood AD markers |

Inclusion Criteria

Healthy Subjects

• Age: 20-50 years (young cohort) OR 60-90 years (older cohort)
• Cognitive status: MMSE ≥ 26 (cognitively healthy)
• Neurological: No significant neurological disorders

Prodromal AD Patients

• Subjective cognitive complaint (corroborated by informant)
• Episodic memory deficit on neuropsychological testing
• Clinical Dementia Rating = 0.5
• MMSE ≥ 23
• Independent in activities of daily living

Parkinson's Disease Patients

• Recent PD diagnosis
• Mild-moderate UPDRS score
• MMSE ≥ 26
• Stable dopaminergic therapy for ≥6 months (if on treatment)

Multiple Sclerosis Patients

• Recent relapsing-remitting MS diagnosis
• EDSS score ≤ 4.0
• MMSE ≥ 26
• Stable disease-modifying therapy for ≥6 months (if on treatment)

Exclusion Criteria

• MRI contraindications (metal implants, claustrophobia, pacemakers)
• Severe comorbidities
• Antibiotic treatment within past 3 months

Key Objectives

The primary objectives of this study include:

Expected Outcomes

This trial is expected to provide:

• Microbiome biomarkers for early neurodegeneration detection
• Cross-disease comparisons revealing shared versus disease-specific gut-brain axis alterations
• Baseline data for future interventional trials targeting the gut microbiome
• Neuroimaging correlates linking microbial composition to brain structure

Relevance to NeuroWiki

This trial directly relates to several key [NeuroWiki](/) mechanism pages:

• [Gut-Brain Axis in Neurodegeneration](/mechanisms/gut-brain-axis-neurodegeneration) — primary mechanism page
• [Gut-Brain Axis](/mechanisms/gut-brain-axis) — general mechanisms
• [Microbiome-Parkinson's Disease](/mechanisms/gut-brain-axis-parkinsons-pathogenesis) — PD-specific mechanisms
• [Gut-Brain Axis in AD](/mechanisms/gut-brain-axis-ad) — AD-specific mechanisms

Current Status

As of March 2026, the trial is actively recruiting. The study represents a significant investment by the Italian Ministry of Health (Grant RF-2021-12372224) in understanding the gut-brain axis in neurodegeneration.

Detailed Methodology

Microbiome Analysis Pipeline

The study employs state-of-the-art microbiome analysis techniques:

Neuroimaging Protocol

The MRI component includes:

• Structural MRI: T1-weighted MPRAGE sequence for volumetric analysis (1mm isotropic resolution)
• Diffusion Tensor Imaging (DTI): 30 directions, b=1000 s/mm² for white matter integrity assessment
• Resting-state fMRI: 5 minutes of eyes-closed resting state for functional connectivity analysis
• Quantitative R2 Mapping: Iron deposition assessment in subcortical structures

Statistical Analysis Plan

The primary analysis will employ mixed-effects models to examine:

• Group differences in microbiome diversity indices (Shannon, Simpson, Cha1)
• Correlations between microbial taxa and brain imaging metrics
• Longitudinal changes from baseline to follow-up

Interim Findings and Scientific Context

Gut-Brain Axis in Neurodegeneration: Current Understanding

The gut-brain axis has emerged as a critical pathway in neurodegenerative disease pathogenesis. Key mechanisms include:

1. Microbial Metabolite Signaling
Short-chain fatty acids (SCFAs) including acetate, propionate, and butyrate produced by gut bacteria crosses the blood-brain barrier and modulate microglial activation, neuroinflammation, and synaptic plasticity. Reduced SCFA-producing bacteria have been documented in both [Alzheimer's disease](/diseases/alzheimers-disease) and [Parkinson's disease](/diseases/parkinsons-disease) patients.

2. Vagus Nerve Communication
The [vagus nerve](/mechanisms/vagus-nerve-gut-brain) provides a direct anatomical pathway for gut-derived signals to reach the brainstem and forebrain regions. Alpha-synuclein pathology has been shown to propagate from the gut to the brain via vagal pathways in preclinical models.

3. Systemic Inflammation
Lipopolysaccharide (LPS) and other bacterial products can cross a "leaky gut" and trigger peripheral immune activation. Circulating cytokines then act on brain endothelial cells and perivascular macrophages to induce neuroinflammation.

4. Endocrine Pathways
Gut hormones including GLP-1, PYY, and ghrelin have direct effects on neuronal survival, neurogenesis, and cognitive function. These peptides represent therapeutic targets for neurodegenerative disease.

Disease-Specific Signatures

Alzheimer's Disease

• Decreased microbial diversity
• Reduced Firmicutes/Bacteroidetes ratio
• Lower abundance of anti-inflammatory bacteria (e.g., Faecalibacterium prausnitzii)
• Increased pro-inflammatory taxa (e.g., Escherichia/Shigella)

Parkinson's Disease

• Reduced Prevotella abundance
• Increased Enterobacteriaceae
• Altered SCFA production
• Correlation with motor symptom severity

Multiple Sclerosis

• Reduced microbial diversity
• Decreased Akkermansia muciniphila
• Altered bile acid metabolism

Multi-Disease Comparison: Study Design Rationale

Rationale for Including Multiple Diseases

The simultaneous study of AD, PD, and MS enables:

Cross-Disease Mechanistic Insights

The comparative design allows investigation of:

| Mechanism | AD | PD | MS | Shared? |
|-----------|----|----|----|---------|
| Reduced SCFA producers | +++ | ++ | ++ | Yes |
| Increased intestinal permeability | ++ | +++ | ++ | Yes |
| Altered bile acid metabolism | ++ | ++ | +++ | Partial |
| Vagal dysfunction | + | +++ | + | PD-specific |

Expected Scientific Contributions

Biomarker Discovery

This trial is positioned to identify:

Mechanistic Insights

The comprehensive multi-modal assessments will provide insights into:

Clinical Translation

Expected translational outcomes:

Participant Journey and Study Procedures

Visit Structure

| Visit | Timepoint | Assessments |
|-------|-----------|-------------|
| V1 | Baseline | All assessments |
| V2 | 6 months | MRI, cognitive, microbiome |
| V3 | 12 months | MRI, cognitive, microbiome |
| V4 | 24 months | All assessments |

Sample Handling

• Stool: Collected in OMNIGENE-GUT kit, stored at -80°C within 2 hours
• Blood: Fasting blood draw for plasma, serum, and CBC; processed within 30 minutes
• CSF (subset): Lumbar puncture for AD biomarker assessment
• MRI: Standardized 3T protocol across all sites

Ethical Considerations

Privacy Protection

The study implements:

• De-identified sample coding
• Separate storage of personal identifiers
• Secure database access with audit logging
• GDPR compliance for European sites

Risk Mitigation

For observational procedures:

• MRI: Screening for contraindications, monitoring for claustrophobia
• Lumbar puncture: Standardized technique, informed consent for CSF collection
• Blood draw: Trained phlebotomists, immediate pressure application

Research Team Expertise

Lead Investigators

Nicola Filippini, MD, PhD - Principal Investigator

• Director of Neuroimaging, IRCCS San Camillo
• Expert in MRI biomarkers for neurodegenerative disease
• Published extensively on gut-brain axis imaging

Institutional Resources

The participating institutions bring complementary expertise:

• IRCCS San Camillo: Neuroimaging and clinical neuroscience
• IRCCS Fatebenefratelli: Alzheimer's disease research and biomarkers
• Università Ca' Foscari Venezia: Bioinformatics and statistical analysis

Future Directions

Planned Sub-Studies

Collaborative Network

The study aims to establish:

• International gut-brain axis consortium
• Shared data repository for cross-study validation
• Standardized protocols for microbiome-neuroimaging studies

References