Probiotic Effects on the Microbe-brain-gut Interaction and Brain Activity During Stress Tasks in Healthy Subjects

The aim of this study is to determine if and how the "Probiotic Product" affects functional brain responses in healthy subjects during an emotional- and arithmetic stress task, respectively and in terms of microbe-brain-gut interactions.

Study Overview

• Status: Completed
• Conditions: Probiotics; Magnetic Resonance Imaging; Emotional Stress; Gut Microbiota
• Intervention / Treatment: Other: Placebo; Dietary supplement: Probiotic

Detailed Description

The aim of this study is to determine if and how the "Probiotic Product" affects functional brain responses in healthy subjects during an emotional- and arithmetic stress task, respectively and in terms of microbe-brain-gut interactions.

In this randomized double-blind placebo-controlled study, n=22 healthy subjects will receive the following interventions in a crossover fashion, separated by a 4-week wash-out period: 1) Probiotic Formula, 2) placebo. After baseline assessments, study participants will start with a 4-week intervention with the study product or the placebo, followed by a 4-week wash-out period and a subsequent 4-week intervention period (placebo or study product, respectively). fMRI (functional magnetic resonance imaging) scanning during two validated stress tasks will be performed after each of the intervention periods (week 4 and week 12). At the same time points and in addition on the days before the 1st and 2nd intervention (baseline 1 and 2), saliva, blood and faecal samples will be collected. Questionnaire data will be collected and psychological tests and instruments will be performed. For one week at baseline and during the intervention periods (last week), subjects will wear actigraphs to record their physical activity and help assess sleep quality. At baseline, subjects will undergo a carbon dioxide (CO2) challenge test as well as a food diary to record dietary habits.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Sweden
  • Örebro, Sweden, 70182
    • Örebro University, Campus USÖ, Örebro University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age: Age: 18-65 years, males/females.
2. Signed informed consent -

Exclusion Criteria:

1. Concurrent or recent treatment with drugs affecting intestinal function or mood, e.g., antidepressants (< 12 weeks) or antibiotics (< 12 weeks).
2. Concurrent or recent (< 4 weeks) use of nutritional supplements or herb products affecting intestinal function or mood (e.g. aloe vera, St. John´s Wort, fibers, prebiotics and probiotics).
3. Diagnosis of major psychiatric or somatic disease. 4) Abuse of alcohol or drugs. 5) Recent (< 4 weeks) intake of proton pump inhibitors, proton pump inhibitors, PPIs (e.g., omeprazole).

6) Asthma. 7) Cardiovascular diseases. 8) Epilepsy. 9) Renal failure. 10) Cerebral bleeding or history of cerebral bleeding. 11) Allergic to latex. 12) Pregnancy (assessed by urine test) or breastfeeding. 13) Claustrophobia. 14) Smoking or using tobacco including snuff. 15) Inability to maintain exercise routine and dietary pattern during the study.

16) Consumption of more than 6 cups of coffee/caffeine-containing beverages per day.

17) Professional athlete. 18) Dominant left-hand. 19) Medical implant (e.g., pacemaker). 20) Aneurysm clips in the head. 21) Shunts in the head. 22) Grenade-splinter or metal-splinter in the body (e.g., eyes). 23) Metal or electrodes in the body (e.g., temp-catheter, aorta stent, cochlea implant).

24) Comprehensive tooth-implants or prothesis. 25) Operated in the head. 26) Operated in the heart. 27) Swallowed a video-capsule. 28) Non-corrected astigmatism. 29) Regular intake of systemic corticosteroids and anti-inflammatory medication (including NSAIDs) during the last three months.

30) Visual defect without possibility to use lenses during MRI scanning. 31) Known allergy to milk or soy. 32) Any other reason the investigator feels the subject is not suitable for participation in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo; All study participants will receive the study product and the placebo in a randomized, double-blind crossover fashion. Probiotic and placebo products have similar appearance and taste.	Other: Placebo; Placebo intervention.
EXPERIMENTAL: Probiotic; All study participants will receive the study product and the placebo in a randomized, double-blind crossover fashion. Probiotic and placebo products have similar appearance and taste.	Dietary supplement: Probiotic; The Probiotic Formula is commercially available and contains a combination of 3 probiotic strains in addition to other nutrients. The total daily amount of probiotic strain in the product will be no less than 3 billion colony-forming units (CFU) per 3 g powder sachet.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in brain response to validated emotional challenge task (EAT) during functional brain imaging	Comparing week 4 and 12

Secondary Outcome Measures

Outcome Measure	Time Frame
Change in brain response to a cognitive challenge task (MIST) during functional brain imaging	Comparing week 4 and 12

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in physical activity assessed by an actigraphy watch (actiwatch)	Actigraph data regarding physical activity	Comparing the change in week 0 compared to 4, and 8 compared to 12 (before and in the end of the two intervention periods)
Change in sleep quality assessed by an actigraphy watch (actiwatch)	Actigraph data regarding sleep quality	Comparing the change in week 0 compared to 4, and 8 compared to 12 (before and in the end of the two intervention periods)
Change in daily stress levels assessed by an actigraphy watch (actiwatch)	Actigraph data regarding daily stress levels	Comparing the change in week 0 compared to 4, and 8 compared to 12 (before and in the end of the two intervention periods)
Autonomous Nervous System (ANS) Activity, Biopac	ANS activity is measures during stressful tasks.	Comparing the change in week 0 compared to 4, and 8 compared to 12 (before and in the end of the two intervention periods)
Stroop test	The Stroop test is performed for stress induction	Comparing the change in week 0 compared to 4, and 8 compared to 12 (before and in the end of the two intervention periods)
HADS (Hospital Anxiety and Depression Scale)	Hospital Anxiety and Depression Scale, min score 0, max score 3, total score max 42, subscale anxiety max 21, subscale depression max 21	Measured weekly, week 1-12
STAI (State and Trait Anxiety Inventory for Adults)	State and Trait Anxiety Inventory for Adults	Measured weekly, week 1-12
PSS (Perceived Stress Scale)	Perceived Stress Scale, min score 0, max score 40	Measured weekly, week 1-12
Euro-QoL	Euro Qol- Health-related Quality of Life 5Q-5D-5L, min score 0, max score 20, subscale 0-100	Measured weekly, week 1-12
Karolinska Sleep Diary (KSD)	KSD measures sleep quality in the morning	Measured daily, week 1-4 and 8-12
Karolinska Diary of Workload (KDW)	KDW measures workload daily in the evening	Measured daily, week 1-4 and 8-12
Cortisol levels during fMRI tasks (Saliva)	Saliva samples are collected during fMRI to assess cortisol levels	Comparing week 4 and 12
Cortisol awakening rhythm (saliva)	Saliva samples are collected at home (3 days á 5 samples) to assess cortisol levels	Comparing the change in week 0 compared to 4, and 8 compared to 12 (before and in the end of the two intervention periods)
Faecal samples	Faecal samples will be analyzed for quantitative and qualitative microbial composition by 16S rRNA-based next generation sequencing (NGS)	Comparing the change in week 0 compared to 4, and 8 compared to 12 (before and in the end of the two intervention periods)
Change in inflammatory markers	Blood samples will be collected after each intervention period to assess inflammatory markers using Enzyme-Linked Immunosorbent Assays (ELISA)s	Comparing the change in week 0 compared to 4, and 8 compared to 12 (before and in the end of the two intervention periods)

Collaborators and Investigators

• Sponsor: Örebro University, Sweden
• Collaborators: Pfizer
• Investigators: Principal Investigator: Robert Brummer, Prof, Örebro University, Sweden

Publications and helpful links

General Publications

• Rode J, Edebol Carlman HMT, Konig J, Repsilber D, Hutchinson AN, Thunberg P, Andersson P, Persson J, Kiselev A, Lathrop Stern L, Salomon B, Mohammed AA, Labus JS, Brummer RJ. Probiotic Mixture Containing Lactobacillus helveticus, Bifidobacterium longum and Lactiplantibacillus plantarum Affects Brain Responses Toward an Emotional Task in Healthy Subjects: A Randomized Clinical Trial. Front Nutr. 2022 Apr 29;9:827182. doi: 10.3389/fnut.2022.827182. eCollection 2022.

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 22, 2018
• Primary Completion (ACTUAL): June 16, 2018
• Study Completion (ACTUAL): June 16, 2018

Study Registration Dates

• First Submitted: June 8, 2018
• First Submitted That Met QC Criteria: July 30, 2018
• First Posted (ACTUAL): August 6, 2018

Study Record Updates

• Last Update Posted (ACTUAL): August 6, 2018
• Last Update Submitted That Met QC Criteria: July 30, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Other Study ID Numbers: 2017/398

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