Gut Microbiome and Depression

Sponsor

Washington University School of Medicine (Other)

Overall Status

Recruiting

CT.gov ID

NCT05808101

Collaborator

University of Connecticut (Other), University of Texas (Other)

120

Enrollment

Location

32.1

Anticipated Duration (Months)

3.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this project is to determine if specific gut microbiome or gut-derived metabolites are associated with depression in patients with Multiple Sclerosis (pwMS). Mechanistically, the investigators further hypothesize that depression in pwMS is related to decreased abundance of gut bacteria with GABA-producing activities and/or with anti-inflammatory properties. To determine if the presence of depression in pwMS is associated with specific gut microbiome, gut-derived metabolites or peripheral blood immune profiles. The investigators will perform a cross-sectional study in clinically stable pwMS recruited at the John L. Trotter MS Center. The investigators will evaluate the presence of depression using the Quality of Life in Neurological Disorders (Neuro-Qol) depression scale, one of the 13 scales in the Neuro-Qol recently developed by the NIH using modern psychometric techniques and validated in pwMS.

A total of 120 pwMS will be recruited: 60 with and 60 without depression based on the Neuro-Qol depression scale. At the study visit each participant will be asked to provide a stool sample for microbiome analyses and a blood sample for peripheral blood immunophenotyping. Potential confounders will be collected and treated as covariates in the analyses. These include: 1) degree of disability (EDSS); 2) treatment with anti-depressants and DMTs; 3) a 4-days food diary to evaluate diet composition; 4) weight and height to calculate the BMI; 5) fatigue; 6) level of physical activity; 7) sleep quality.

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis Depression	Other: Neuro-QoL T-score determination

Detailed Description

Our overall hypothesis is that specific gut microbiome or gut-derived metabolites are associated with depression in pwMS. Mechanistically, the investigators further hypothesize that depression in pwMS is related to decreased abundance of gut bacteria with GABA-producing activities and/or with anti-inflammatory properties.

AIM 1. To determine if the presence of depression in pwMS is associated with specific gut microbiome, gut-derived metabolites or peripheral blood immune profiles.

The investigators will perform a cross-sectional study in clinically stable pwMS recruited at the John L. Trotter MS Center. The investigators will evaluate the presence of depression using the Quality of Life in Neurological Disorders (Neuro-Qol) depression scale, one of the 13 scales in the Neuro-Qol recently developed by the NIH using modern psychometric techniques and validated in pwMS. A total of 120 pwMS will be recruited: 60 with and 60 without depression based on the Neuro-Qol depression scale. At the study visit each participant will be asked to provide a stool sample for microbiome analyses and a blood sample for peripheral blood immunophenotyping. Potential confounders will be collected and treated as covariates in the analyses. These include: 1) degree of disability (EDSS); 2) treatment with anti-depressants and DMTs; 3) a 4-days food diary to evaluate diet composition; 4) the investigatorsight and height to calculate the BMI; 5) fatigue; 6) level of physical activity; 7) sleep quality.

AIM 1A. To determine if depression will correlate with specific gut microbiome or gut-derived metabolites profiles in pwMS.

Stool samples will be processed for microbiome sequencing and metabolome characterization.

AIM 1B. To determine if depression will correlate with a specific peripheral blood immune-inflammatory profile in pwMS.

A peripheral blood sample will be obtained from each participant to perform: 1) peripheral blood immune cell phenotyping to characterize the main immune cell subsets and their activation; 2) intracellular cytokine production to study cytokine production profiles of blood lymphocytes and monocytes.

AIM 2. To quantify GABA production in pwMS with or without depression and determine gut microbiome-immune system interaction in vitro.

In this aim the investigators will perform functional studies to evaluate the potential of gut microbiota from pwMS with or without depression to produce GABA and to modulate immune-inflammatory responses.

AIM 2A. To quantify GABA levels in whole stool, specific stool bacterial isolates and blood of pwMS with or without depression.

The investigators will evaluate GABA levels in the stool and blood of pwMS. In addition, the investigators will measure GABA production by Bacteroides ssp isolated from the gut microbiota of pwMS.

Aim 2B. To evaluate the effects of whole stool and specific bacterial species from pwMS on blood immune cell phenotype and cytokine production.

The investigators will test how whole gut microbiome or specific bacteria (identified in Aim 1 as associated with depression in pwMS) can modulate immune cell function. Peripheral blood mononuclear cells (PBMC) from healthy donors will be cultured in conditioning media from whole stool or bacteria of interest isolated from pwMS. PBMC phenotype and cytokine production after exposure in vitro will be characterized by flow cytometry.

Study Design

Study Type:

Observational

Anticipated Enrollment :

120 participants

Observational Model:

Cohort

Time Perspective:

Cross-Sectional

Official Title:

Role of the Gut Microbiome as Determinant of Depression in Multiple Sclerosis Subjects

Actual Study Start Date :

Jan 27, 2022

Anticipated Primary Completion Date :

Oct 1, 2023

Anticipated Study Completion Date :

Oct 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
With Neuro-QoL Depression scale T-score > 55 Collection of demographic and clinical data (age, gender, BMI, ethnicity, age of onset, number of relapses). Administration of the Neuro-QoL depression scale Neurological exam to evaluate disability and calculate the EDSS score (ranging from 0 to 10) Neurological cognitive and functional assessments: a 9-hole Peg Test and 25-ft Timed Walk from the Multiple Sclerosis Functional Composite (MSFC); the Symbol Digit Modality Test (SDMT) Administration of the Fatigue Severity Scale (FSS) Collection of a 4-days food diary to evaluate diet composition of enrolled pwMS Administration of the Stanford 7-day Physical Activity Recall Scale (PAR) Evaluation of sleep quality by administration of the Neuro-QoL sleep disturbance scale Collection of a stool sample for gut microbiome and metabolome analyses Collection of a saliva sample for microbiome and metabolome analyses	Other: Neuro-QoL T-score determination Neuro-Qol depression scale, using a T-score of 55 as a threshold
With Neuro-QoL Depression scale T-score < 55 Collection of demographic and clinical data (age, gender, BMI, ethnicity, age of onset, number of relapses). Administration of the Neuro-QoL depression scale Neurological exam to evaluate disability and calculate the EDSS score (ranging from 0 to 10) Neurological cognitive and functional assessments: a 9-hole Peg Test and 25-ft Timed Walk from the Multiple Sclerosis Functional Composite (MSFC); the Symbol Digit Modality Test (SDMT) Administration of the Fatigue Severity Scale (FSS) Collection of a 4-days food diary to evaluate diet composition of enrolled pwMS Administration of the Stanford 7-day Physical Activity Recall Scale (PAR) Evaluation of sleep quality by administration of the Neuro-QoL sleep disturbance scale Collection of a stool sample for gut microbiome and metabolome analyses Collection of a saliva sample for microbiome and metabolome analyses	Other: Neuro-QoL T-score determination Neuro-Qol depression scale, using a T-score of 55 as a threshold

Arm

Intervention/Treatment

With Neuro-QoL Depression scale T-score > 55

Collection of demographic and clinical data (age, gender, BMI, ethnicity, age of onset, number of relapses). Administration of the Neuro-QoL depression scale Neurological exam to evaluate disability and calculate the EDSS score (ranging from 0 to 10) Neurological cognitive and functional assessments: a 9-hole Peg Test and 25-ft Timed Walk from the Multiple Sclerosis Functional Composite (MSFC); the Symbol Digit Modality Test (SDMT) Administration of the Fatigue Severity Scale (FSS) Collection of a 4-days food diary to evaluate diet composition of enrolled pwMS Administration of the Stanford 7-day Physical Activity Recall Scale (PAR) Evaluation of sleep quality by administration of the Neuro-QoL sleep disturbance scale Collection of a stool sample for gut microbiome and metabolome analyses Collection of a saliva sample for microbiome and metabolome analyses

Other: Neuro-QoL T-score determination

Neuro-Qol depression scale, using a T-score of 55 as a threshold

With Neuro-QoL Depression scale T-score < 55

Other: Neuro-QoL T-score determination

Neuro-Qol depression scale, using a T-score of 55 as a threshold

Outcome Measures

Primary Outcome Measures

Gut microbiome, gut-derived metabolites and peripheral blood immune profiles [3 years]
Gut microbiome will be characterized by metagenomic sequencing. Untargeted metabolome analysis performed by LC-MS. Peripheral blood phenotyping performed by flow cytometry analysis
GABA levels in whole stool, specific stool bacteria isolates and blood [3 Years]
GABA levels in whole stool measured by targeted LC-MS Effects of whole stool and specific bacterial species from people with MS with or without depression on blood immune cell phenotype and cytokine production measured by flow cytometry.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Age ≥18 years
Diagnosis of RRMS or progressive MS based on the 2017 revised McDonald criteria
Untreated or on any of the MS DMTs as long as they have been stable clinically in the previous 3 months
No history of antibiotic treatment in the 3 months prior to study visit and sample collection
No other autoimmune diseases, chronic metabolic diseases (e.g. diabetes) or conditions (e.g. pregnancy) that would interfere with the parameters that we will be measuring in the stool and blood samples.