Brain Responses to Short-Chain Fatty Acid Intervention

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.

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.

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")