Healthy Volunteers, Stress
Conditions
Keywords
Short-Chain Fatty Acids, Acute Stress, Microbiota-Gut-Brain-Axis, Neuroepigenetics, [11C] Martinostat, Functional magnetic resonance imaging
Brief summary
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.
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.
Interventions
OTHERPlacebo
Microcrystalline Cellulose will be used as placebo, one daily, one week
OTHERShort-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
Sponsors
Universitaire Ziekenhuizen KU Leuven
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
Participants, investigators, and personnel involved in data analyses are blinded to the intervention. Unblinding occurs after all data has been collected and analysed.
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HDAC expression | Throughout study completion, on average 2 years | Brain HDAC expression will be quantified using the PET radiotracer \[11C\]Martinostat before and after the intervention |
| Brain response to stress | Throughout study completion, on average 2 years | Brain response (brain oxygenation level-dependent signals) to a fMRI-adapted stress task will be measured before and after intervention |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Heartbeat | Throughout study completion, on average 2 years | Assessing heartbeat (bpm) with a blood pressure monitor before and after intervention |
| Self-reported stress | Throughout study completion, on average 2 years | 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. |
| Brain metabolite concentration | Throughout study completion, on average 2 years | Relative quantification of brain metabolites (mmol/L) using 1H-Magnetic Resonance Spectroscopy before and after intervention |
| Serum short-chain fatty acid levels | Throughout study completion, on average 2 years | Quantification of serum SCFA (μM) before and after intervention |
| Salivary cortisol response to stress | Throughout study completion, on average 2 years | 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 |
| Cytokine levels | Throughout study completion, on average 2 years | Quantification of inflammatory cytokines (pg/ml) before and after intervention |
| C-reactive protein levels | Throughout study completion, on average 2 years | Quantification of hs-C-reactive protein levels (ng/ml) before and after intervention |
| Heart rate variability | Throughout study completion, on average 2 years | Assessing heart rate variability (ms) with ECG before and after intervention |
| Blood pressure | Throughout study completion, on average 2 years | Assessing blood pressure (systolic/diastolic mmHg) with a blood pressure monitor before and after intervention |
Other
| Measure | Time frame | Description |
|---|---|---|
| Gastrointestinal Symptom Rating Scale (GSRS) | Throughout study completion, on average 2 years | 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. |
| Perceived Stress Scale (PSS) | Throughout study completion, on average 2 years | Assessing ratings on PSS. PSS scores range between 0-40 with higher scores indicating worse outcome |
| Big Five Inventory 10 (BFI-10) | Throughout study completion, on average 2 years | Measuring the Big Five personality traits, including Extraversion, Agreeableness, Conscientiousness, Emotional Stability, and Openness. |
| Generic Assessment of Side Effects | Throughout study completion, on average 2 years | 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). |
| State-Trait-Anxiety Inventory (STAI) | Throughout study completion, on average 2 years | 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'. |
| Emotion Regulation Questionnaire (ERQ) | Throughout study completion, on average 2 years | designed to assess individual differences in the habitual use of two emotion regulation strategies: cognitive reappraisal and expressive suppression |
| Pittsburgh Sleep Quality Index (PSQI) | Throughout study completion, on average 2 years | 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. |
| The Cognitive Assessment Questionnaire (CAQ) | Throughout study completion, on average 2 years | 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. |
| Mainz Inventory for Microstressors (MIMIS) | Throughout study completion, on average 2 years | retrospective assessment of microstressors over one week covering both stressor occurence and perceived stressor intensity |
| Fecal gut microbiota profile | Throughout study completion, on average 2 years | Assessing gut microbiota profile before and after intervention |
Countries
Belgium
Contacts
Primary ContactLukas Van Oudenhove, MD, PhD
Outcome results
None listed