The Effects of Short-Chain Fatty Acids in Psychosocial Stress-Induced Impairment on Core Executive Functions

The Effects of Gut Bacterial Metabolites Short-Chain Fatty Acids on Stress-Induced Impairment in Core Executive Functions

The aim of the present trial is to examine core executive functions (EFs) as a functional outcome of attenuating the cortisol response to acute laboratory stress through colonic delivery of an Short Chain Fatty Acids (SCFAs) mix (acetate, propionate, butyrate).

A triple-blind randomized placebo-controlled parallel group trial will be conducted to compare the effects of SCFAs vs. placebo on core EFs (working memory [WM], cognitive flexibility [CF], response inhibition [RI]) under stress vs. no-stress conditions, after one week of SCFA vs. placebo treatment.

First, the effects of SCFAs on stress-induced changes in core executive functions, with WM as the primary outcome, and CF and RI as secondary outcomes will be tested. Second, interindividual differences in microbiota composition (particularly abundance of SCFA-producers), saliva cortisol and serum SCFA levels will be explored to assess whether they are associated with interindividual differences in core EFs at baseline or following acute stress.

Each participant will undergo 2 study visits: one will involve a stress condition and the other will involve a no-stress condition. Each study visit is preceded by a 1-week intervention or placebo period and separated by a 3-4 week washout period. To induce stress, participants will perform the Maastricht Acute Stress Task (MAST) or sham MAST as the control condition. To assess EF performance, three cognitive tasks will be performed 15 minutes after task offset: n-back task for WM; Stop Signal Task for RI; and Wisconsin Card Sorting Test for CF. Saliva samples will be collected before, during and after the (sham) MAST to assess the cortisol response. Blood samples will be collected throughout all study visits to quantify serum SCFAs, inflammatory markers and ACTH. Additionally, cardiovascular variables will be measured, and self-report questionnaires will be completed to evaluate autonomic response to the condition and subjective stress responses, respectively

Inclusion Criteria:

• Voluntary written informed consent of the participant or their legally authorized representative has been obtained prior to any screening procedures
• Proficiency in English and/or Dutch
• Healthy with no intestinal and/or psychological complaints
• Access to a -18°C freezer (i.e. ordinary household freezer)
• Male participants
• Age 20-40 years
• BMI 18.5-25 kg/m2

Exclusion Criteria:

• Participant has a history of previous or current neurological, psychiatric, gastrointestinal or endocrine disorder
• Any disorder, which in the Investigator's opinion might jeopardise the participant's safety or compliance with the protocol
• Any prior or concomitant treatment(s) that might jeopardise the participant's safety or that would compromise the integrity of the study
• Participation in an interventional Trial with an investigational medicinal product (IMP) or device
• Current or recent (over the past month) medication use as a (prescribed) medical treatment. This does not include isolated intakes of 'over the counter' medication (e.g. ibuprofen, paracetamol).
• Use of antibiotics within three months preceding the study.
• Current or recent (1-month) infection (e.g. common cold, influenza, COVID-19, etc.)
• Recent (1-month) vaccination (e.g. flu shot, SARS-COV-2 vaccine, etc)
• Previous or current substance/alcohol dependence or abuse (>2 units per day or 14 units per week).
• One or more diagnoses based on the Mini International Neuropsychiatric Interview.
• One or more diagnoses based on ROME-IV for gastrointestinal disorders.
• Smoking.
• Night-shift work.
• Adherence to special diets (e.g. vegan, vegetarian, weight-loss, lactose-free, gluten-free, etc.).
• Use of pre- or probiotics within one month preceding the study.
• Previous experience with or knowledge of any of the tasks used in the study (not including questionnaires).