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Completed

NCT Number: NCT03478527

Probiotics, Brain Structure and Psychological Variables

Theory and research on the gut-brain-axis emphasize complex interactions between the gut microbiota, immunological and hormonal responses, brain function, brain structure, as well as resulting behavioral manifestations, such as cognitive functions and mental illness. Probiotics are living micro-organisms that change the composition of the gut microbiota and hypothetically have a positive effect on the host's general health and well-being. Probiotic bacteria naturally occur in foods such as Sauerkraut, olives, and dark chocolate, and are currently also added to industrial products such as yogurt.

Regarding the effect of probiotics on brain structure and function, animal studies have shown that the administration of probiotics in mice and rats was linked to neurogenesis in the hippocampus and an improvement of associated cognitive functions. The majority of these studies applied probiotics for 4 weeks. The substances used in these studies were often composed of several bacterial strains, suggesting that the neurogenic effect may not be reducible to a specific type of probiotic bacteria.

Probiotics seem to be effective in improving memory abilities, including spatial and non-spatial memory, both in rodents and humans. Moreover, specifically regarding the beneficial effect of probiotics on anxiety, depression and stress, preliminary evidence in humans is compelling. However methodologically sound (randomized-controlled trial [RCT], 'blind') studies are still lacking.

To sum up, the present study is going to be the first RCT with human participants that investigates structural and functional changes of the hippocampus through probiotic bacteria, using Magnet Resonance Imaging (MRI). In addition, the study aims at advancing research in the field by investigating the effects of probiotics on a broad spectrum of cognitive functions, particularly those associated with hippocampal activity (e.g. spatial memory, verbal memory). Furthermore, effects on several types of mental illness (e.g. anxiety, depression, stress) will be studied. Potential translatory mechanisms that may promote the aforementioned effects will be examined, i.e. changes in immunological parameters, 'brain derived neurotrophic factor' (BDNF), and oxytocin.

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Key information

Conditions

Depressive Symptoms Anxiety Anxiety Disorders Behavior Behavioral Symptoms Depression Mental Disorders Stress

Age range

18 year–40 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Universitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für Psychiatrie und Psychotherapie

Hamburg, 20246, Germany

About this study

A double-blind RCT intervention study will be conducted to investigate the effect of a probiotic dietary supplement vs. a placebo, taken by healthy human participants (N = 60) for 28 consecutive days. Both substances are administered in doses of 4.4g (powder) per day.

The probiotic dietary supplement used in the present study is a freely available product (in powder form) sold under the name of Vivomixx®. Per 4.4g the powder contains 450 billion bacteria, composed of eight bacterial strains: Lactobacilli (L. paracasei, L. plantarum, L. acidophilus and L.delbrueckii subsp. bulgaricus), Bifidobacteria (B. longum, B. infantis, B. breve), and Streptococcus thermophiles.

This product was chosen, because a similar supplement with an identical composition of bacteria as Vivomixx® was found to be linked to hippocampal neurogenesis in mice. The placebo powder has a similar taste and consistency as the verum (Vivomixx®) powder, but contains no probiotic bacteria.

First, participants will be screened online for eligibility (T0). Before and after the 28-day intake period, participants are asked to perform several cognitive tests and fill out questionnaires (T1, T2) at our laboratory (ca. 2 - 2.5 hours). Afterwards, blood samples will be drawn (ca. 5 minutes) and a magnet resonance tomography (MRT) session (ca. 1 - 1.5 hours) will be conducted, where participants will perform an object pattern separation task in the scanner (T1, T2). Furthermore, a follow-up after 2 months (T3), including the same assessments as at T1 and T2, will be conducted.

During the intake period participants will fill out a brief questionnaire on a weekly basis, which includes an assessment of state depression and anxiety, defecation (control item to rule out adverse effects), recent (start of) intake of medication, recent (onset of) intake of antibiotics, and recent inter-current illness (e.g. influenza). In addition, participants will record their food intake (protocol) for one week (7 consecutive days) during the intake period.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • healthy participants
  • age 18-40
  • informed consent for all parts of the study (including MRT)
  • none of the exclusion criteria (see below) fulfilled

Exclusion criteria

  • age < 18 or > 40 years
  • pregnancy or breastfeeding
  • left-handedness
  • degenerative or inflammatory diseases of the central nervous system
  • severe cognitive/ neuropsychological impairment
  • severe pain syndrome or other severe organic diseases
  • epilepsy
  • (past or present) psychiatric disorders
  • neurological disorder
  • severe diabetic polyneuropathy
  • malignancies/ cancer
  • cardiac insufficiency
  • arterial hypertension
  • heart attack/ stroke
  • severe hepatic or renal insufficiency
  • diseases of the hemopoietic system
  • alcoholism/ drug addiction
  • medical history of severe allergic or toxic reactions
  • current participation in drug trial
  • doubts about legal capacity/ capability of understanding
  • referral to institutions based on court/ official order
  • treatment with centrally acting medication (e.g. antipsychotics, antiepileptics, antidepressants, etc.)
  • non-removable metal pieces (aneurysm clips, artificial limbs, etc.) or implanted electronic devices (pacemaker, osmotic or other implanted pumps, cochlear implants, etc.)
  • claustrophobia
  • acute (respiratory) infection, physical uneasiness
  • tattoos in the head region, permanent make-up
  • non-removable piercings
  • chronic/ acute gastrointestinal diseases
  • vegetarianism, veganism
  • current intake of antibiotics or intake of antibiotics at any time point during the last 2 months
  • lactose intolerance
  • general focus on probiotic diet

Treatment and study plan

Vivomixx® powder

Dietary Supplement

Participants will take in a daily dose of 4.4g for 28 consecutive days

Other names: probiotic dietary supplement

Placebo Powder

Other

Participants will take in a daily dose of 4.4g for 28 consecutive days

Primary outcomes

  1. Changes in hippocampal volume, assessed via Magnet Resonance Imaging (MRI)

    Time frame: at baseline (day 0) after intake period (day 28+) and at follow up (day 84+)

    changes in hippocampal volume in verum experimental group (in comparison to placebo control)

  2. Changes in functional brain activation during fMRI task

    Time frame: at baseline (day 0) after intake period (day 28+) and at follow up (day 84+)

    changes in functional connectivity (using BOLD signal) in hippocampal regions in verum experimental group (in comparison to placebo control) during pattern separation fMRI task

  3. Changes in depression

    Time frame: at baseline (day 0) after intake period (day 28+) and at follow up (day 84+)

    changes in levels of depression, assessed with Beck's Depression Inventory - II Revised (BDI-II-R) sum score in verum experimental group (in comparison to placebo control)

  4. Changes in spatial navigation

    Time frame: at baseline (day 0) after intake period (day 28+) and at follow up (day 84+)

    changes in test performance scores (number of correct responses, degree of accuracy measured as position hits) in the Tunnel task in verum experimental group (in comparison to placebo control)

  5. Changes in Interleukin-6 (IL-6)

    Time frame: at baseline (day 0) after intake period (day 28+) and at follow up (day 84+)

    changes in IL-6 blood serum concentration levels in verum experimental group (in comparison to placebo control)

  6. Changes in IL-1ß

    Time frame: at baseline (day 0) after intake period (day 28+) and at follow up (day 84+)

    changes in IL-1ß blood serum concentration levels in verum experimental group (in comparison to placebo control)

  7. Changes in Tumor Necrosis Factor alpha (TNF-alpha)

    Time frame: at baseline (day 0) after intake period (day 28+) and at follow up (day 84+)

    changes in TNF-alpha blood serum concentration levels in verum experimental group (in comparison to placebo control)

  8. Changes in Brain Derived Neurotrophic Factor (BDNF)

    Time frame: at baseline (day 0) after intake period (day 28+) and at follow up (day 84+)

    changes in blood serum level concentration of BDNF in verum experimental group (in comparison to placebo control)

  9. Changes in verbal learning test performance

    Time frame: at baseline (day 0) after intake period (day 28+) and at follow up (day 84+)

    changes in verbal learning performance score, assessed with the Verbal Learning Memory Test (VLMT) in verum experimental group (in comparison to placebo control)

  10. Changes in pattern separation fMRI task

    Time frame: at baseline (day 0) after intake period (day 28+) and at follow up (day 84+)

    changes in the pattern separation task performance (no. of correct responses to picture stimuli) in in verum experimental group (in comparison to placebo control)

Other outcomes

  1. Changes in Oxytocin (OXT)

    Time frame: at baseline (day 0) after intake period (day 28+) and at follow up (day 84+)

    changes in blood serum concentration levels of OXT in verum experimental group (in comparison to placebo control)

  2. Changes in Processing speed or performance IQ

    Time frame: at baseline (day 0) after intake period (day 28+) and at follow up (day 84+)

    changes in processing speed assessed by a digit-symbol test (BIS; Berliner Intelligenzskala) in verum experimental group (as compared to placebo control)

  3. Changes in cognitive emotion regulation - functional emotion regulation

    Time frame: at baseline (day 0) after intake period (day 28+) and at follow up (day 84+)

    changes in functional emotion regulation questionnaire sum score (as assessed with the Cognitive Emotion Regulation Questionnaire; CERQ) in verum experimental group (as compared to placebo control)

  4. Changes in Sleepiness

    Time frame: at baseline (day 0) after intake period (day 28+) and at follow up (day 84+)

    changes in sleepiness questionnaire sum score (ESS; Epworth Sleepiness Scale) scores in verum experimental group (as compared to placebo control)

  5. Changes in cognitive emotion regulation - dysfunctional emotion regulation

    Time frame: at baseline (day 0) after intake period (day 28+) and at follow up (day 84+)

    changes in dysfunctional emotion regulation questionnaire sum score (as assessed with the Cognitive Emotion Regulation Questionnaire; CERQ) in verum experimental group (as compared to placebo control)

Sponsors and collaborators

Lead sponsor

Universitätsklinikum Hamburg-Eppendorf

Other

Registry information

Official study title

Effects of Probiotic Bacteria on Brain Structure and Function and on Psychological Variables

Acronym: ProBrain01

Important dates

Study start
2018
Primary completion
2019
Study completion
2021
First posted
Mar 27, 2018
Registry last updated
Feb 9, 2021

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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