Effect of Probiotics on Central Nervous System Functions in Humans
Condition: Social Stress
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      The gut-brain axis is described as being important in both, gut functions and central nervous
      system (CNS) functions. The microbiota in the gut plays an important role in this axis
      through neural, immune and endocrine systems. Previous studies have found altered gut
      microbiota (GM) composition could change the CNS functions in animals and humans. Probiotics
      were shown having positive effect on improving stress response in animals and stress related
      psychiatry in humans. The current study will investigate if probiotics can improve response
      to social stress in healthy participants and patients with irritable bowel syndrome (IBS),
      which is a stress-related disease, and whether this probiotic action can be counteracted by
      the locally acting antibiotic, Rifaximin. The investigators will use the Cyberball paradigram
      to induce social stress and magnetoencephalography (MEG) to record neural responses related
      to the social stress. The administration of the probiotics will be a new strategy for both
      the mental health management and treatment of gastrointestinal (GI) disorders in the future.
    

Detailed description: 
      Understanding the neural mechanisms underlying the experience of social stress may help to
      prevent the development of IBS and to help people to maintain their mental health. Social
      distress has been examined with the Cyberball paradigm in developing peers and children with
      autism spectrum disorders, people with social anxiety disorder and with borderline
      personality disorder. These studies provided researchers the clinical evidence and validity
      of the paradigm in patients . Here the investigators will examine the neural response of
      healthy volunteers to acute stress induced by the Cyberball game and if acute intervention
      with probiotics for 4 weeks can alleviate the stress response. The study will be firstly
      conducted on healthy volunteers whose GM will be disturbed by an antibiotic Rifaximin as to
      simulate IBS patients, to see their neural response to the social exclusion (Study 1). The
      second study will be conducted as a clinical trial in healthy volunteers to investigate the
      effect of the probiotic Bifidobacterium longum 1714 (Study 2).

      Study 1 & 2 will be a randomized, double blind, double dummy design, during which the
      participants will visit the laboratory for 2 times (M1, M2,): measurement at baseline and
      after intervention. Intervention period lasts for 1 week in study 1 and 4 weeks in study 2.

      In study 1, Group 1 will take Rifaximin for 1 week Group 2 will take Placebo for 1 week

      In study 2, Group 1 will take B.longum 1714 for 4 weeks Group 2 will take Placebo for for 4
      weeks

      Participants will be not allowed to eat certain kinds of food. As mentioned in the exclusion
      criteria, participants will not eat probiotic/prebiotic containing food supplements, or
      potentially immune-enhancing dietary supplements either. The food to be avoided will be
      summarized on a list of probiotic/prebiotic containing food. Also, participants will be asked
      to record the food they take on each day during the intervention, by taking photos.
      Nutritional information about the food taken by the participants will be analyzed by using an
      online tool http://nutritiondata.self.com/.

      Before the intervention period, each participant will need to complete questionnaires
      including a demographic questionnaire, the Patient Health Questionnaire (PHQ) and the
      Hospital Anxiety and Depression Scale (HADS). The PHQ is for excluding those healthy
      participants who suffer from psychiatry disorder(s) and for further analysis. The HADS, which
      will also be completed after each intervention period, aims to study the effect of the
      probiotic on anxiety and depression level in healthy participants and especially in IBS
      patients. Also, participants will receive a daily online questionnaire via email, including
      the Positive Affect and Negative Affect Scales, and questions about their level of stress,
      consumption of the study capsules, hours of sleep, IBS symptom and quality of life (QoL) (the
      last two are only for patients), etc. Through questionnaires, the investigators will record
      menstruation information of female participants for controlling confounders. Also, gender and
      age between healthy and patient groups will be matched as much as possible, since these
      factors could have an effect on the GM composition and the CNS functions.

      Stool samples will be collected on the day participants come to a lab visit for measurements.
      The stool sample should be as fresh as possible, ideally collected in the morning of the
      visiting day. Fresh samples will be stored in RNA synthesis stabilization buffer at the time
      of collection. A centrifuged fecal pellet will be stored at -80°.

      During the Magnetoencephalography measuring, before the Cyberball game, there will be a
      resting state session for 5 minutes. In this session participants will be studied in supine
      position. Participants will be instructed to move as little as possible and remain awake,
      while keeping their eyes closed. After the resting state recording the Cyberball game will
      start. The task of the game will be projected on a screen and participants will be asked to
      fixate the screen and hold a response box to get ready for the task. Magnetic fields will be
      measured with a 275-channel whole head magnetometer at a sampling rate of 1200 Hz. In order
      to overlay the brain activity derived from MEG on anatomical scans, a high-resolution (1 mm,
      isotropic) T1-weighted structural MR image will be acquired with an MPRAGE sequence with a
      3-T MR scanner (University Hospital Tübingen, Tübingen, Germany).

      7 participants will be needed in each experimental group in study 1, resulting in at least 14
      in study 1. 20 participants will be needed in each experimental group in study 2, resulting
      in at least 40 in study 2. The recruitment of participants will be organized by the MEG
      center under the responsibility of Prof. Dr. Christoph Braun. The study will be announced on
      black boards in the Tübingen University Clinic and the campus of the University. Further
      announcements will be done via the University mailing list and the local newspaper. Each
      participant will be provided with detailed information about the aims of the investigation,
      the tasks and measurements. Participants will be informed about the possibility to cancel the
      examination at any time without cause or prejudice for her person. Investigation will be
      carried out only when written consent from the participants is obtained.
    

Intervention name(s): Probiotic; Placebo for antibiotic; Antibiotic; Placebo for probiotic
Intervention type(s): Dietary Supplement; Dietary Supplement; Drug; Dietary Supplement
Intervention description(s): Probiotic B.longum 1714 will be donated by Alimentary Health Ltd. (Cork, Ireland) and each sachet contains 10 billion CFU; The placebo supplementation is identical-looking to the antibiotic Xifaxan ®; Antibiotic Xifaxan ® will be 200mg per tablet; The placebo identical-looking to the probiotic B.longum 1714
Intervention MeSH terms: Anti-Bacterial Agents; Antibiotics, Antitubercular
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment