Modulation of the Gut-brain Axis by Cranberries: Impact on University Students' Mental Wellbeing (CM)

In this work, the investigators will assess whether cranberry (poly)phenols improve mood disorders including stress, anxiety and depression via the gut-brain axis in university students. The investigators will evaluate whether the effects observed are related to an improvement in gut microbiome diversity and function, and whether the mechanism of action may be mediated by a decrease in inflammatory markers, modulation of neurotransmitters or via an alteration of BDNF levels. The investigators will also quantify the most comprehensive panel of cranberry (poly)phenol metabolites. A double-blind, randomized placebo controlled 2-arm parallel study will be conducted in the Metabolic Research Unit (MRU, Department of Nutritional Sciences at KCL).

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Dietary supplement: Placebo; Dietary supplement: Cranberry juice

Detailed Description

The study population will be final year BSc and MSc university students between 20-25 years old (n=60), who are generally healthy and not taking any medication. The study will be conducted during the period prior to their final exams (January until September). The intervention will be cranberry and placebo juice, consumed daily for 12 weeks, and will be provided free of cost by the Cranberry Institute. After a screening visit to evaluate inclusion and exclusion criteria, informed consent will be obtained, and subjects will be randomized to the treatments.

The study will consist in a total of 4 visits, one visit every 4 weeks over a total of 12 weeks intervention. Volunteers will consume a cranberry or a control drink every day for 12 weeks. The day before each visit (pre-visit), volunteers will self-collect a total of 6 saliva samples throughout the day to measure cortisol levels as a biomarker of stress. Mental health, cognitive function, diet and physical activity will also be assessed using self-reported questionnaires, an online cognitive battery test and an online 24 h dietary recall. In addition, on the day before visits 1 and 4 (baseline and 12 weeks), a stool sample will be self-collected to assess changes in gut microbiome diversity and composition. On the day of each visit, a spot urine sample will be self-collected after waking up and before breakfast. During each visit, volunteers will drop the self-collected samples, and will collect new kits for the next visit. Visits 1 and 4 will last approximately 20 min, while visits 2 and 3 will last approximately 5 minutes. In addition, during visits 1 and 4, blood samples will be taken to investigate changes in gut-brain axis and cranberry related metabolites. Blood samples will also be collected at baseline to assess general health status of participants (blood lipids, markers of liver and kidney function, urea, uric acid, creatinine, and glucose).

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • England
    • London, England, United Kingdom, SE1 9NH
      • King's College London

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 25 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy men and women aged 20-25 years old.
• Final year BSc or MSc university students.
• Subjects are willing to maintain their normal eating/drinking habits and exercise habits to avoid changes in body weight over the duration of the study.
• Able to understand the nature of the study.
• Able and willing to give signed written informed consent.
• Comply with all study protocol procedures.

Exclusion Criteria:

• Subjects taking regular prescribed medication (including iron for anemia).
• Grade 1 hypertensive or above, as defined as SBP superior or equal to 140 mmHg or DBP superior or equal to 90 mmHg.
• Obese participants, defined as BMI superior or equal to 30.
• Diabetes mellitus and metabolic syndrome.
• Chronic and acute disease.
• Terminal renal failure and other kidney abnormalities.
• Malignancies.
• Allergies to berries or other significant food allergy.
• Subjects who took food supplements, dietary supplement or herbal remedies within 1 month of study start.
• Subjects who have lost more than 10% of their weight in the past 6 months or are currently in a diet.
• Subjects with allergies to berries or other relevant/related food.
• Subjects who reported participant in another study within one month before the study start.
• Subjects who smoke an irregular number of cigarettes per day or plan quitting smoking in the next 3 months.
• Subjects who require chronic antimicrobial or antiviral treatment
• Subjects with unstable psychological condition (diagnosed with mental health disorders).
• Subjects with history of cancer, myocardial infarction, cerebrovascular incident
• Pregnant, lactating or planning to become pregnant, as well as pre-menopausal women who do not have a regular menstrual cycle and do not adequate method of contraception.
• Any reason or condition that in the judgement of the clinical investigator(s) may put the subject at unacceptable risk or that may preclude the subject from understanding or complying with the study's requirements.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Cranberry flavored drink, once daily, in a 8fl oz bottle. Identical in appearance and taste compared with the treatment.	Dietary supplement: Placebo; composition: Water, dextrose, citric acid, malic acid, fumaric acid, colorants, xanthan gum, natural flavor, emulsion
Active Comparator: Cranberry juice; 100% cranberry juice, once daily, in a 8fl oz bottle.	Dietary supplement: Cranberry juice; composition: Water, cranberry juice concentrate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in mood	Mood measured as the Total Mood Disturbance (TMD), using the Profile of Mood States (POMS) questionnaire. The POMS assessment has six scales of measure: Anger-Hostility, Confusion-Bewilderment, Depression-Dejection, Fatigue-Inertia, Tension-Anxiety, and Vigor-Activity. Scores on these items are added together to determine a Total Mood Disturbance score. Additionally, there is a measure of Friendliness which is scored separately. The POMS2 is an adjective checklist with instructions to respond "How have you been feeling over the PAST WEEK, INCLUDING TODAY" on a 5- point Likert response scale ranging from 0 = Not at all to 4 = Extremely. If one changes the instructions to "how you feel RIGHT NOW" then the instrument measures emotional states. This it is adaptable to both state and trait forms of affect. Higher scores mean a worse outcome.	Baseline and 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mental Health outcomes: stress levels	Mental Health outcomes including changes in stress levels, measured as salivary and blood cortisol and the Perceived Stress Scale (PSS) questionnaire. The questions in the PSS ask about feelings and thoughts during the last month. In each case, respondents are asked how often they felt a certain way. It consists of 10 questions, takes 5-10 minutes to complete and is for individual or group administration. Higher scores indicate higher levels of perceived stress.	Baseline and 12 weeks
Mental Health outcomes: anxiety	Mental Health outcomes including changes in anxiety and depression symptoms, measured with the Hospital Anxiety and Depression Scale (HADS) questionnaire. The questionnaire comprises seven questions for anxiety and seven questions for depression, and takes 2-5min to complete. For both scales (anxiety and depression), higher scores mean a worse outcome.	Baseline and 12 weeks
Changes in cognitive function and performance	Measured using the Online General Cognitive Assessment Battery (CogniFit) using established procedures. The cognitive score is an aggregate measure of the current cognitive strength of different cognitive skills. The minimum cognitive score is 0 and the maximum is 800. A higher score means higher cognitive abilities.	Baseline and 12 weeks
Changes in plasma gut-brain-axis metabolites	Serotonin and kynurenine pathway will be measured using targeted metabolomics	Baseline and 12 weeks
Changes in brain-derived neurotrophic factor	Brain-derived neurotrophic factor (BDNF) will be measured using established procedures	Baseline and 12 weeks
Changes in inflammatory markers	Inflammatory markers, including blood cytokines (IL1β, IL2, IL4, IL6, IL8, IL10, IL12, IL13, MIF, IFN-γ, and TNF-α), will be measured using established procedures	Baseline and 12 weeks
Changes in plasma and faecal short chain fatty acids	Measured using gas chromatography according to established procedures	Baseline and 12 weeks
Changes in plasma and urinary cranberry polyphenol metabolites	Measured using a validated targeted metabolomics method	Baseline and 12 weeks
Assessment of habitual diet	Diet will be assessed using 7-day food diaries (from the European Prospective Investigation into Cancer and Nutrition) at baseline and after 12 weeks.	Baseline and 12 weeks
Assessment of physical activity	The international physical activity questionnaire (IPAQ) will also be used to assess physical activity. IPAQ assesses physical activity undertaken across a comprehensive set of domains including leisure time, domestic and gardening (yard) activities, work-related and transport-related activity. The higher the score, the higher the physical activity level.	Baseline and 12 weeks
Changes in gut microbiome diversity and composition.	Faecal samples will be collected at baseline and 12 weeks after consumption of cranberry or placebo drinks. Gut microbiome diversity and composition will be analysed using 16s mRNA sequencing at the Genome Centre of Queen Mary University (London, UK).	Baseline and 12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in plasma metabolome	Measured via untargeted metabolomics using liquid chromatography mass spectrometry	Baseline and 12 weeks
Changes in urinary metabolome	Measured via untargeted metabolomics using liquid chromatography mass spectrometry	Baseline and 12 weeks
Changes in gene expression	Measured using microarray hybridization and data analyses on Affymetrix CEL files using GeneSpring GX software	Baseline and 12 weeks
Changes in DNA methylation	Measured using the Illumina Infinium HD Methylation Assay	Baseline and 12 weeks
Changes in blood pressure	Blood pressure measured as systolic and diastolic blood pressure after 12-week daily consumption of cranberry	Baseline and 12 weeks
Changes in sleep patterns	Measured as bedtime and sleep duration.	Baseline and 12 weeks

Collaborators and Investigators

• Sponsor: King's College London
• Collaborators: The Cranberry Institute

Study record dates

Study Major Dates

• Study Start (Actual): January 10, 2022
• Primary Completion (Actual): August 22, 2022
• Study Completion (Actual): August 22, 2022

Study Registration Dates

• First Submitted: January 13, 2022
• First Submitted That Met QC Criteria: February 18, 2022
• First Posted (Actual): March 2, 2022

Study Record Updates

• Last Update Posted (Actual): November 22, 2022
• Last Update Submitted That Met QC Criteria: November 21, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Other Study ID Numbers: CRANMOOD study

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes