The Impact of Diet on the Gut-Microbiota-Brain Axis

Study Overview
=================
Brief Summary
-----------------
This study aims to investigate the effects of an 8-week dietary intervention on cognitive function, stress, and the gut microbiota in healthy adults with low fibre intake.

Detailed Description
-----------------
The gut microbiota communicates bidirectionally with the brain via the microbiota-gut-brain axis to influence various aspects of human physiology, including host metabolism, immune function, behaviour, and cognition. Diet is a key modulator of the microbial composition, suggesting that the microbiota could explain the association between poor nutrition and decreasing health of the population. Dietary fibre is the main energy source for the gut microbiota and fundamentally impacts its composition and function. The microbiota-gut-brain axis has been proposed to mediate some of the effects of dietary fibre on the brain, for example through microbial metabolites (e.g., short-chain fatty acids (SCFA)), regulation of the immune system, and the microbial impact on gut hormones and neurotransmitters. Similarly, intake of fermented foods is positively associated with cognitive health and has been shown to alter the microbiota composition and function and exert an anti-inflammatory effect. However, no studies to date have examined the singular and combined effects of fermented and fibrous foods on the gut microbiota, cognition, and emotion. The present study aims to determine the role of diet on the microbiota-gut-brain axis and mental health. Using a randomized-controlled, parallel, single-blinded design, participants consuming a habitually low fibre diet (N=200) will undergo an 8-week dietary intervention. Participants will receive one of four diets (n=50 in each group): high fibre (aim 24-35 grams/day), fermented foods (aim 4-6 portions/day), combined diet of fermented foods and high fibre (aim 25-30g/day of fibre and 3-4 servings/day of fermented foods) or control (dietary education according to national Irish guidelines). Cognitive, psychological, and biological measures will be compared at baseline and endpoint. During the intervention period, individuals will provide repeated faecal samples to assess temporal microbial changes.

Official Title
-----------------
An Interventional Study on the Association Between Diet, Cognitive Function, Stress and the Gut Microbiota in Healthy Volunteers.

Conditions
-----------------
Healthy

Intervention / Treatment
-----------------
* Other: Fermented Foods
* Other: High Fibre
* Other: Combined Diet
* Other: Control


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Be able to give written informed consent. Be between 18 and 50 years of age. Have a body mass index (BMI) between 18.5-29.9 Kg/m2. Be in generally good health as determined by the investigator. Exclusion Criteria: Are less than 18 and greater than 50 years of age. Have a BMI below 18.5 or above 29.9 Kg/m2. Have a significant acute or chronic coexisting illness [cardiovascular, gastrointestinal (GI) [to include functional GI disorders, inflammatory bowel disease, coeliac disease, lactose intolerance, food allergies], immunological, psychiatric [to include formal or as determined by MINI Psychiatric interview, diagnosis of current major depression, anxiety disorder, bipolar spectrum disorder, schizophrenia, other DSM-IV Axis I disorder], neurodevelopmental disorders, immunological, metabolic disorders [to include type I or II diabetes], or any condition which contraindicates, in the investigators judgement, entry to the study, Have a condition or taking a medication that the investigator believes would interfere with the objectives of the study, pose a safety risk, or confound the interpretation of the study results; all psychoactive medications [to include anxiolytics, antipsychotics, antidepressants, anticonvulsants, centrally acting corticosteroids, and opioid pain relievers), laxatives, enemas, antibiotics, anti-coagulants, over-the counter non-steroidal anti-inflammatories (NSAIDS). Subjects should have a wash-out period of 4 weeks. Current prebiotic or probiotic supplement use (a wash-out period of 4 weeks after cessation will allow entry to the study). Females who are peri-menopausal, menopausal or post-menopausal. Females who are pregnant or planning a pregnancy, or lactating. Participants who are not fluent in English. Are colour blind. Have dyslexia or dyscalculia. Are a current habitual daily smoker. Individuals who, in the opinion of the investigator, are considered to be poor attendees or unlikely for any reason to be able to comply with the trial. Subjects receiving treatment involving experimental drugs. If the subject has been in a recent experimental trial, these must have been completed not less than 30 days prior to this study. Have a malignant disease or any concomitant end-stage organ disease. Have completed a study in our laboratory in the past 4 years.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: Randomized-controlled, parallel, single-blinded design
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control<br>Participants will recieve dietary education based on the healthy eating guidleines provided by the Health Service Executive (HSE). | Other: Control<br>* Participants will recieve dietary education based on the Irish healthy food pyramid.<br>|
| Experimental: Fermented Foods<br>Fermented foods diet (4-6 portions/day) | Other: Fermented Foods<br>* Participants will recieve dietary education to include 4 to 6 portions of fermented foods to their normal diet.<br>|
| Experimental: High Fibre<br>High fibre diet (24-35 grams/day) | Other: High Fibre<br>* Participants will recieve dietary education to increase their fibre intake to 24-35g/day in their normal diet.<br>|
| Experimental: Combined Diet<br>Combined diet high in fibre and fermented foods (fibre aim 24-35 grams/day, fermented foods aim 4-6 portions/day) | Other: Combined Diet<br>* Participants will recieve dietary education to increase their fibre intake to 25-30g/day and include 3 to 4 portions of fermented foods to their normal diet.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trait stress/mood: self-report | self-report questionnaires | Change from baseline at 8 weeks | 
| Trait stress/mood: hypothalamic-pituitary-adrenal axis activity | Cortisol from saliva samples | Change from baseline at 8 weeks | 
| Responses to acute stress: self-report | Self-report questionnaires | Change from baseline at 8 weeks | 
| Responses to acute stress: sympathetic-adrenal-medullary pathway activity | Galvanic skin response taken from the skin on the hand | Change from baseline at 8 weeks | 
| Responses to acute stress: hypothalamic-pituitary-adrenal axis activity | Cortisol from saliva samples | Change from baseline at 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognitive performance: working memory | Spatial Working Memory | Change from baseline at 8 weeks | 
| Cognitive performance: episodic memory | Modified Rey Auditory Verbal Learning Test (ModRey) | Change from baseline at 8 weeks | 
| Cognitive performance: decision making | Iowa Gambling Task | Change from baseline at 8 weeks | 
| Cognitive performance: emotional inhibition | Emotional Stroop | Change from baseline at 8 weeks | 
| Cognitive performance: sustained attention | Rapid Visual Information Processing | Change from baseline at 8 weeks | 
| Cognitive performance: visual pattern recognition memory | Pattern Recognition Memory | Change from baseline at 8 weeks | 
| Cognitive performance: cognitive flexibility | Intra-Extra Dimensional Set Shifting | Change from baseline at 8 weeks | 
| Cognitive performance: social cognition | Emotion Recognition Task | Change from baseline at 8 weeks | 
| Cognitive performance: affective perceptual bias | Emotional Bias Task | Change from baseline at 8 weeks | 
| Microbiota composition and function | Shotgun metagenomics of fecal samples | Change from baseline at 8 weeks | 
| Microbial and host metabolomics | Untargeted metabolomics analysis | Change from baseline at 8 weeks | 
| Inflammation | Inflammatory markers in lipopolysaccharide stimulated and unstimulated bloods | Change from baseline at 8 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Microbiota-gut-brain axis, Diet, Cognition, Stress, Dietary Fibre, Fermented foods