Brain Responses to Short-Chain Fatty Acid Intervention (MoodBugs HDAC)

The Effect of a Short-Chain Fatty Acid Intervention on Affective Brain Circuits and Neuroepigenetics

A randomized, triple-blind, placebo-controlled study on the effect of colon-delivered short-chain fatty acids (SCFAs) on neural responses to stress and neuroepigenetics.

Study Overview

• Status: Not yet recruiting
• Conditions: Stress; Healthy Volunteers
• Intervention / Treatment: Other: Short-Chain Fatty Acids; Other: Placebo

Detailed Description

The goal of this interventional study is to study the underlying mechanism of the attenuating effect of colon-delivered SCFAs on the cortisol response to stress. Pre-clinical studies suggest that the histone-deacetylase (HDAC)-inhibiting properties of SCFAs are the main mechanism underlying SCFA-induced changes in stress, cognition and behavior.

Primary objective: to test the effect of colon-delivered SCFA intervention versus placebo on HDAC expression in the brain and neural responses to stress

Secondary objective: to determine the effects of colon-delivered SCFA administration versus placebo on inflammatory and autonomic responses to stress and to determine the mediating and/or moderating factors that potentially underlie SCFA-induced changes to stress responses (HDAC expression in stress-responsive regions, serum SCFA levels)

To this end, 32 participants will be asked to undergo a pre- and post-intervention visit, separated by one week intervention with either colon-delivered SCFAs or placebo (16 per group). During the study visits, participants undergo simultaneous PET-MR imaging with [11C]Martinostat. They undergo the Montreal Imaging Stress Test (MIST) and the Maastricht Acute Stress Test (MAST) at each visit.

• Study Type: Interventional
• Enrollment (Estimated): 32
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Lukas Van Oudenhove, MD, PhD; Phone Number: +32 16 33 01 47; Email: lukas.vanoudenhove@kuleuven.be

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • UZ/KU Leuven
    • Contact: Lukas Van Oudenhove, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Voluntary written informed consent of the participant or their legally authorized representative has been obtained prior to any screening procedures
2. Proficiency in English and/or Dutch
3. Access to a -18°C freezer (i.e. ordinary household freezer)
4. Male participants
5. Age 18-45 years
6. BMI 18.5-25 kg/m2

Exclusion Criteria:

1. Participant has a history of previous or current neurological, psychiatric, gastrointestinal or endocrine disorder
2. Any disorder, which in the Investigator's opinion might jeopardise the participant's safety or compliance with the protocol (as assessed by medical staff on the research team)
3. Any prior or concomitant treatment(s) that might jeopardise the participant's safety or that would compromise the integrity of the study
4. Participation in an interventional Trial with an investigational medicinal product (IMP) or device
5. Current or recent (3-month) medication use (especially antibiotics, cardiovascular drugs, steroids, non-steroid anti-inflammatory drugs, centrally effective drugs)
6. Current or recent (1-month) infection (e.g. common cold, influenza, COVID-19, etc.)
7. Recent (1-month) vaccination (e.g. flu shot, SARS-COV-2 vaccine, etc)
8. Smoking
9. Night-shift work
10. Adherence to special diets (e.g. vegan, vegetarian, weight-loss, lactose-free, gluten- free, etc.)
11. Use of pre- or probiotics within one month preceding the study
12. Previous experience with any of the tasks used in the study (not including questionnaires)
13. Neuroimaging contraindications
14. If the participant invokes that he does not want to be informed of eventual pathology that might be found during imaging (invokes the "right not to know")

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Short-Chain Fatty Acids; SCFAs will be delivered directly to the colon using pH-dependent colon delivery capsules	Other: Short-Chain Fatty Acids; Colon-delivery capsules of Short-Chain Fatty Acids will be administered in a ratio of 60:20:20, thus 150 mmol of acetate, 50 mmol of propionate and 50 mmol of butyrate equivalent to 20g of fibers, once daily, one week
Placebo Comparator: Placebo; Colon-delivery capsules of microcrystalline cellulose	Other: Placebo; Microcrystalline Cellulose will be used as placebo, one daily, one week

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HDAC expression	Brain HDAC expression will be quantified using the PET radiotracer [11C]Martinostat before and after the intervention	Throughout study completion, on average 2 years
Brain response to stress	Brain response (brain oxygenation level-dependent signals) to a fMRI-adapted stress task will be measured before and after intervention	Throughout study completion, on average 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain metabolite concentration	Relative quantification of brain metabolites (mmol/L) using 1H-Magnetic Resonance Spectroscopy before and after intervention	Throughout study completion, on average 2 years
Serum short-chain fatty acid levels	Quantification of serum SCFA (μM) before and after intervention	Throughout study completion, on average 2 years
Salivary cortisol response to stress	Biological stress sensitivity is measured by quantifying cortisol levels (ng/ml) from multiple saliva samples taken before, during, and after a stress task performed during the pre-intervention and post-intervention visit	Throughout study completion, on average 2 years
Cytokine levels	Quantification of inflammatory cytokines (pg/ml) before and after intervention	Throughout study completion, on average 2 years
C-reactive protein levels	Quantification of hs-C-reactive protein levels (ng/ml) before and after intervention	Throughout study completion, on average 2 years
Heart rate variability	Assessing heart rate variability (ms) with ECG before and after intervention	Throughout study completion, on average 2 years
Blood pressure	Assessing blood pressure (systolic/diastolic mmHg) with a blood pressure monitor before and after intervention	Throughout study completion, on average 2 years
Heartbeat	Assessing heartbeat (bpm) with a blood pressure monitor before and after intervention	Throughout study completion, on average 2 years
Self-reported stress	Psychological stress sensitivity is measured through stress reports of the participants using the visual analogue scale (VAS). VAS scorings are taken before, during, and after a stress task performed during the pre-intervention and post-intervention visit.	Throughout study completion, on average 2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fecal gut microbiota profile	Assessing gut microbiota profile before and after intervention	Throughout study completion, on average 2 years
Perceived Stress Scale (PSS)	Assessing ratings on PSS. PSS scores range between 0-40 with higher scores indicating worse outcome	Throughout study completion, on average 2 years
Gastrointestinal Symptom Rating Scale (GSRS)	Assessing ratings on the subscales of GSRS and its total score. It has 5 subscales (Reflux, Diarrhea, Constipation, Abdominal Pain, and Indigestion Syndrome). Subscale scores range from 1 to 7 and higher scores indicates a worse outcome.	Throughout study completion, on average 2 years
Big Five Inventory 10 (BFI-10)	Measuring the Big Five personality traits, including Extraversion, Agreeableness, Conscientiousness, Emotional Stability, and Openness.	Throughout study completion, on average 2 years
Generic Assessment of Side Effects	General side effects will be assessed and recorded in a structured, validated approach using the Generic Assessment of Side Effects (GASE)54. The GASE consists of 36 items asking for most frequently reported side effects for drugs based on the FDA adverse event reporting system database from all countries. Symptoms of all body parts during the last seven days will be self-reported and rated based on severity from 0 (not present) to 3 (severe).	Throughout study completion, on average 2 years
State-Trait-Anxiety Inventory (STAI)	Assessing momentary (state) anxiety during the pre- and post-intervention visit. This inventory is part of the State-Trait Anxiety Inventory (STAI) with 20 questions specifically for state anxiety, rated on a 4-point scale. State anxiety is rated with anxiety absent and anxiety present questions. Anxiety absent questions constitute the absence of anxiety in a statement like, "I feel secure." Anxiety present questions represent the presence of anxiety in a statement like "I feel worried." The 4-point scale are as follows: 1 'not at all', 2 'somewhat', 3 'moderately so', and 4 'very much so'.	Throughout study completion, on average 2 years
Emotion Regulation Questionnaire (ERQ)	designed to assess individual differences in the habitual use of two emotion regulation strategies: cognitive reappraisal and expressive suppression	Throughout study completion, on average 2 years
Pittsburgh Sleep Quality Index (PSQI)	an instrument to measure the quality and patterns of sleep in adults. . It differentiates "poor" from "good" sleep by measuring seven domains: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleep medication, and daytime dysfunction over the last month.	Throughout study completion, on average 2 years
The Cognitive Assessment Questionnaire (CAQ)	to assess the frequency with which people experience cognitive failures, such as absent-mindedness, in everyday life - slips and errors of perception, memory and motor functioning. The questionnaire has 25 items which are scored from Never (0), Very rarely (1), Occasionally (2), Quite often (3) to Very often (4). A total score as well as three subscales (Forgetfulness, Distractibility, False Triggering) can be calculated.	Throughout study completion, on average 2 years
Mainz Inventory for Microstressors (MIMIS)	retrospective assessment of microstressors over one week covering both stressor occurence and perceived stressor intensity	Throughout study completion, on average 2 years

Collaborators and Investigators

• Sponsor: Universitaire Ziekenhuizen KU Leuven
• Investigators: Principal Investigator: Lukas Van Oudenhove, MD, PhD, KU Leuven; Principal Investigator: Kristin Verbeke, Pharm, PhD, KU Leuven; Principal Investigator: Boushra Dalile, PhD, KU Leuven; Study Director: Annalena Fuchs, MSc, KU Leuven

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2024
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: August 6, 2024
• First Submitted That Met QC Criteria: August 6, 2024
• First Posted (Actual): August 9, 2024

Study Record Updates

• Last Update Posted (Actual): August 9, 2024
• Last Update Submitted That Met QC Criteria: August 6, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Functional magnetic resonance imaging; Short-Chain Fatty Acids; Acute Stress; Microbiota-Gut-Brain-Axis; Neuroepigenetics; [11C] Martinostat
• Other Study ID Numbers: S68154

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Time Frame: The data will become available upon publication with no time limitations.
• IPD Sharing Access Criteria: The data will be publicly available.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No