Probiotics, Brain Structure and Psychological Variables

NCT03478527 | Completed

• 1 other identifier: ProBrain01
• Study Type: interventional
• Target: 59
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Depressive Symptoms; Anxiety; Stress

Keywords

Probiotics; Psychiatric Symptoms; Cognitive Function; Hippocampus; Oxytocin; Immunological Parameters

Outcome Measures

Primary Outcomes (10)

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

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

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

• Changes in functional brain activation during fMRI task

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

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

• Changes in depression

  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)

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

• Changes in spatial navigation

  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)

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

• Changes in Interleukin-6 (IL-6)

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

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

• Changes in IL-1ß

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

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

• Changes in Tumor Necrosis Factor alpha (TNF-alpha)

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

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

• Changes in Brain Derived Neurotrophic Factor (BDNF)

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

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

• Changes in verbal learning test performance

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

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

• Changes in pattern separation fMRI task

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

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

Other Outcomes (5)

• Changes in Oxytocin (OXT)

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

• Changes in Processing speed or performance IQ

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

• Changes in cognitive emotion regulation - functional emotion regulation

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

Study Arms (2)

verum condition probiotics

EXPERIMENTAL

The verum condition probiotics in the present study is a freely available product, Vivomixx® powder (dietary supplement). Each dose (4.4g) contains 450 billion bacteria, composed of eight bacterial strains: Lactobacilli (L. paracasei, L. plantarum, L. acidophilus, L.delbrueckii subsp. bulgaricus), Bifidobacteria (B. longum, B. infantis, B. breve), and Streptococcus thermophiles. 30 Participants will be randomly assigned to this condition. The intake period is 28 days, daily dose = 4.4g.

Dietary Supplement: Vivomixx® powder

placebo condition

PLACEBO COMPARATOR

In the placebo condition participants will receive a placebo powder (comparable in taste and consistency to Vivomixx® = verum condition probiotics) that contains no probiotic bacteria. 30 Participants will be randomly assigned to that condition. The intake period is 28 days, daily dose = 4.4g.

Other: Placebo powder

Interventions

Vivomixx® powder DIETARY_SUPPLEMENT

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

Also known as: probiotic dietary supplement

verum condition probiotics

Placebo powder OTHER

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

placebo condition

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• healthy participants
• age 18-40
• informed consent for all parts of the study (including MRT)

You may not qualify if:

• 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

Sponsors & Collaborators

• Universitätsklinikum Hamburg-Eppendorf: lead

Study Sites (1)

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

Hamburg, 20246, Germany

Location

Related Publications (8)

• Buffington SA, Di Prisco GV, Auchtung TA, Ajami NJ, Petrosino JF, Costa-Mattioli M. Microbial Reconstitution Reverses Maternal Diet-Induced Social and Synaptic Deficits in Offspring. Cell. 2016 Jun 16;165(7):1762-1775. doi: 10.1016/j.cell.2016.06.001.

  PMID: 27315483 BACKGROUND

• El Aidy S, Dinan TG, Cryan JF. Immune modulation of the brain-gut-microbe axis. Front Microbiol. 2014 Apr 7;5:146. doi: 10.3389/fmicb.2014.00146. eCollection 2014. No abstract available.

  PMID: 24778631 BACKGROUND

• Foster JA, McVey Neufeld KA. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013 May;36(5):305-12. doi: 10.1016/j.tins.2013.01.005. Epub 2013 Feb 4.

  PMID: 23384445 BACKGROUND

• Liu J, Sun J, Wang F, Yu X, Ling Z, Li H, Zhang H, Jin J, Chen W, Pang M, Yu J, He Y, Xu J. Neuroprotective Effects of Clostridium butyricum against Vascular Dementia in Mice via Metabolic Butyrate. Biomed Res Int. 2015;2015:412946. doi: 10.1155/2015/412946. Epub 2015 Oct 7.

  PMID: 26523278 BACKGROUND

• Liu WH, Chuang HL, Huang YT, Wu CC, Chou GT, Wang S, Tsai YC. Alteration of behavior and monoamine levels attributable to Lactobacillus plantarum PS128 in germ-free mice. Behav Brain Res. 2016 Feb 1;298(Pt B):202-9. doi: 10.1016/j.bbr.2015.10.046. Epub 2015 Oct 29.

  PMID: 26522841 BACKGROUND

• Mohle L, Mattei D, Heimesaat MM, Bereswill S, Fischer A, Alutis M, French T, Hambardzumyan D, Matzinger P, Dunay IR, Wolf SA. Ly6C(hi) Monocytes Provide a Link between Antibiotic-Induced Changes in Gut Microbiota and Adult Hippocampal Neurogenesis. Cell Rep. 2016 May 31;15(9):1945-56. doi: 10.1016/j.celrep.2016.04.074. Epub 2016 May 19.

  PMID: 27210745 BACKGROUND

• Wallace CJK, Milev R. The effects of probiotics on depressive symptoms in humans: a systematic review. Ann Gen Psychiatry. 2017 Feb 20;16:14. doi: 10.1186/s12991-017-0138-2. eCollection 2017.

  PMID: 28239408 BACKGROUND

• Wang H, Lee IS, Braun C, Enck P. Effect of Probiotics on Central Nervous System Functions in Animals and Humans: A Systematic Review. J Neurogastroenterol Motil. 2016 Oct 30;22(4):589-605. doi: 10.5056/jnm16018.

  PMID: 27413138 BACKGROUND

MeSH Terms

Conditions

Depression; Anxiety Disorders

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior; Mental Disorders

Study Officials

• Simone Kühn, Prof. Dr.

  Universitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für Psychiatrie und Psychotherapie, UKE Martinistraße 52, 20246 Hamburg, Germany

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: double blind
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 1 Verum group, receiving the probiotic Vivomixx® powder 1 Placebo group, receiving a placebo powder (similar taste and consistency as Vivomixx® powder)

Study Record Dates

• First Submitted: January 26, 2018
• First Posted: March 27, 2018
• Study Start: January 8, 2018
• Primary Completion: November 30, 2019
• Study Completion: January 28, 2021
• Last Updated: February 9, 2021

Record last verified: 2021-02

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)