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The Effect of Probiotic Supplementation on the Mental Status, Inflammation, and Intestinal Barrier in Major Depressive Disorder Patients Using Gluten-free or Gluten-containing Diet (SANGUT)

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ClinicalTrials.gov Identifier: NCT03877393
Recruitment Status : Recruiting
First Posted : March 15, 2019
Last Update Posted : March 15, 2019
Sponsor:
Collaborator:
Sanprobi Sp. z o.o., Sp. k., Szczecin, Poland
Information provided by (Responsible Party):
Medical University of Lublin

Brief Summary:
More and more evidence confirms the relationship between the gut-brain-microbiota axis and the symptoms of mood disorders. A potential pathway connecting the intestines and the brain in depression is inflammation. Interventions for reducing inflammation and restoring the integrity of the intestinal mucosa are promising approaches in patients with major depressive disorder (MDD). Gut dysbiosis and the diet containing gluten are potential factors may be factors that negatively affect the communication between intestinal and brain. Gluten has a high immunogenic potential and affinity for the intestinal mucosa layer. In patients with an abnormal reaction to gluten, the elimination diet led to improved mood symptoms. However, the relationship between gluten and depression is still poorly understood. Intestinal microbiota can affect the digestion of gluten and reduce its immunogenic potential. Studies have shown that probiotic supplementation has an anti-inflammatory effect, can lead to changes in intestinal permeability and alleviate the symptoms of depression. This evidence supports the need for co-therapy, including the elimination of gluten and the restoration of intestinal eubiosis to reduce inflammation and modulate the gut-brain-microbiota axis. The objective of the SANGUT study is to determine the impact of interventions concerning the gut-brain-microbiota axis (probiotic supplementation, gluten-free diet and their combination) on the mental state, markers of inflammation and markers of intestinal permeability in adult patients with MDD. The study will last 12 weeks and consist of four visits (V): V0 - Screening (Day 0), V1 - Baseline (up to 1 week after Screening), V2 (six weeks after Baseline), V3 - End of the study (12 weeks after Baseline). The main hypothesis is that probiotic supplementation and/or a gluten-free diet will reduce the symptoms of depression, lower the level of inflammatory markers and favourably affect the integrity of the intestinal mucosal barrier.

Condition or disease Intervention/treatment Phase
Depressive Disorder, Major Depression Combination Product: Probiotic supplementation + gluten-free diet Combination Product: Placebo supplementation + gluten-free diet Combination Product: Probiotic supplementation + gluten-containing diet Combination Product: Placebo supplementation + gluten-containing diet Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized, double-blind, and placebo-controlled study
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A 12-week, Randomized, Double-blind, and Placebo-controlled Study Evaluating the Effect of Probiotic Supplementation on the Mental Status, Inflammation, And Intestinal Barrier in Major Depressive Disorder Patients Using Gluten-free or Gluten-containing Diet
Estimated Study Start Date : April 2019
Estimated Primary Completion Date : July 2020
Estimated Study Completion Date : February 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: PRO-GFD
Probiotic supplementation + gluten-free diet
Combination Product: Probiotic supplementation + gluten-free diet
The probiotic and gluten-free diet group (PRO-GFD) will receive one capsule containing the probiotic mixture powder (Sanprobi Stress; Sanprobi sp. z o.o., sp.k., Szczecin, Poland) in the amount of 3 × 10^9 colony forming units (CFU) per day divided in two equal doses, comprising two bacteria strains: Lactobacillus helveticusRosell®-52, Bifidobacterium longumRosell®-175, and excipients: potato starch, magnesium stearate, and the capsule shell of hydroxypropyl methylcellulose. The participants will be asked to consume supplements before breakfast. The group will follow the elimination diet containing no gluten.

Placebo Comparator: PLA-GFD
Placebo supplementation + gluten-free diet
Combination Product: Placebo supplementation + gluten-free diet
The placebo and gluten-free diet group (PLA-GFD) will receive one capsule containing only the excipients, i.e. maize starch, maltodextrins, and the capsule shell. The participants will be asked to consume supplements before breakfast. The group will follow the elimination diet containing no gluten.

Experimental: PRO-GD
Probiotic supplementation + gluten-containing diet
Combination Product: Probiotic supplementation + gluten-containing diet
The probiotic and gluten-containing diet group (PRO-GD) will receive one capsule containing the probiotic mixture powder (Sanprobi Stress; Sanprobi sp. z o.o., sp.k., Szczecin, Poland) in the amount of 3 × 10^9 colony forming units (CFU) per day divided in two equal doses comprising two bacteria strains: Lactobacillus helveticusRosell®-52, Bifidobacterium longumRosell®-175 and excipients: potato starch, magnesium stearate, and the capsule shell of hydroxypropyl methylcellulose. The participants will be asked to consume supplements before breakfast. The group will stay with their current diet.

Placebo Comparator: PLA-GD
Placebo supplementation + gluten-containing diet
Combination Product: Placebo supplementation + gluten-containing diet
The placebo and gluten-containing diet group (PLA-GD) will receive one capsule containing only the excipients, i.e. maize starch, maltodextrins, and the capsule shell. The participants will be asked to consume supplements before breakfast. The group will stay with their current diet.




Primary Outcome Measures :
  1. The changes in Montgomery-Åsberg Depression Rating Scale(MADRS) total score to measure the severity of depression symptoms [ Time Frame: from the date of randomization until the end of the study up to 12 weeks ]

    A 10-item questionnaire to measure the severity of depressive symptoms in individuals with mood disorders. The assessment is performed by an experienced clinical psychiatrist. Each item yields a score of 0 to 6 (overall score ranges from 0 to 60). The higher score indicates a higher severity of the depressive episode.

    MADRS cut-off points include:

    • 0 to 6: symptom absent
    • 7 to 19: mild depression
    • 20 to 34: moderate depression
    • more than 34: severe depression

  2. The changes in Beck Depression Inventory (BDI) total score to measure the severity of depression symptoms [ Time Frame: from the date of randomization until the end of the study up to 12 weeks ]

    A 21-item multiple-choice self-report inventory to measure the severity of depression. Each item yields a score of 0 to 3 (overall score ranges from 0 to 63). The higher score indicates more severe depression symptoms.

    BDI cut-off points include:

    • 0 to 9: no/minimal depression
    • 10 to 18: mild depression
    • 19 to 29: moderate depression
    • 30 to 63: severe depression

  3. The changes in Symptom Checklist-90 (SCL-90) total score to measure the severity of psychopathological impairment [ Time Frame: from the date of randomization until the end of the study up to 12 weeks ]
    A 90-item self-reported inventory to evaluate a broad range of psychological problems and symptoms of psychopathology. The SCL-90 measure symptom intensity on nine different subscales: somatization, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, psychoticism. Each item yields a score of 0 to 4 (overall score ranges from 0 to 364). The higher score indicates more severity of symptoms.

  4. The changes in the 36-Item Short Form Survey (SF-36) total score to measure the quality of life [ Time Frame: from the date of randomization until the end of the study up to 12 weeks ]
    A 36-item self-reported survey to evaluate a health status including vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, and mental health. Raw scores are transforming to 0-100 scale. The higher score indicates a better health state.

  5. The changes in the Perceived Stress Scale (PSS-10) total score to measure the stress levels [ Time Frame: from the date of randomization until the end of the study up to 12 weeks ]
    A 10-item self-reported questionnaire to measure the perception of stress. Each item yields a score of 0 to 4 (overall score ranges from 0 to 40). The higher score indicates higher perceived stress.


Secondary Outcome Measures :
  1. Changes in serum levels of high-specific C-reactive protein (hs-CRP) [ Time Frame: from the date of randomization until the end of the study up to 12 weeks ]
  2. Changes in serum levels of interleukin 6 (Il-6) [ Time Frame: from the date of randomization until the end of the study up to 12 weeks ]
  3. Changes in serum levels of interleukin 1beta (Il-1beta) [ Time Frame: from the date of randomization until the end of the study up to 12 weeks ]
  4. Changes in serum levels of tumor necrosis factor alpha (TNF-alpha) [ Time Frame: from the date of randomization until the end of the study up to 12 weeks ]
  5. Changes in serum levels of anti-tissue transglutaminase (anti-TG2) IgG antibodies [ Time Frame: from the date of randomization until the end of the study up to 12 weeks ]
  6. Changes in serum levels of anti-gliadin (anti-AGA) IgG antibodies [ Time Frame: from the date of randomization until the end of the study up to 12 weeks ]
  7. Changes in serum levels of anti-gliadin (anti-AGA) IgA antibodies [ Time Frame: from the date of randomization until the end of the study up to 12 weeks ]
  8. Changes in serum levels of intestinal fatty acid-binding protein (I-FABP/FABP-2) [ Time Frame: from the date of randomization until the end of the study up to 12 weeks ]
  9. Changes in serum levels of lipopolysaccharide biding protein (LBP) [ Time Frame: from the date of randomization until the end of the study up to 12 weeks ]
  10. Changes in serum levels of total cholesterol [ Time Frame: from the date of randomization until the end of the study up to 12 weeks ]
  11. Changes in serum levels of low-density lipoprotein (LDL) cholesterol [ Time Frame: from the date of randomization until the end of the study up to 12 weeks ]
  12. Changes in serum levels of high-density lipoprotein (HDL) cholesterol [ Time Frame: from the date of randomization until the end of the study up to 12 weeks ]
  13. Changes in serum levels of triglycerides (TG) [ Time Frame: from the date of randomization until the end of the study up to 12 weeks ]
  14. Changes in serum levels of glucose [ Time Frame: from the date of randomization until the end of the study up to 12 weeks ]
  15. Changes in serum levels of insulin [ Time Frame: from the date of randomization until the end of the study up to 12 weeks ]
  16. Changes in serum levels of cortisol [ Time Frame: from the date of randomization until the end of the study up to 12 weeks ]
  17. Changes in serum levels of alanine aminotransferase (ALT) [ Time Frame: from the date of randomization until the end of the study up to 12 weeks ]
  18. Changes in serum levels of aspartate aminotransferase (AST) [ Time Frame: from the date of randomization until the end of the study up to 12 weeks ]
  19. Changes in diversity in microbial community in a single sample (alpha-diversity) [ Time Frame: from the date of randomization until the end of the study up to 12 weeks ]
  20. Changes in diversity in microbial community between samples (beta-diversity) [ Time Frame: from the date of randomization until the end of the study up to 12 weeks ]
  21. Changes in stool short-chain fatty acids (SCFAs) levels [ Time Frame: from the date of randomization until the end of the study up to 12 weeks ]
  22. Changes in electroencephalography (EEG) analysis to assess the functional connectivity (FC) [ Time Frame: from the date of randomization until the end of the study up to 12 weeks ]
    FC will be assessed, based on resting-state EEG-recordings, with the application of a Phase Lag Index (PLI), measuring connectivity strength between a given pair of cortical areas. The global neural network organization will be analyzed with Minimum Spanning Tree algorithm.

  23. Changes in Gastrointestinal Symptom Rating Scale (GSRS) total score to measure intensity of experienced gastrointestinal symptoms [ Time Frame: from the date of randomization until the end of the study up to 12 weeks ]
    A 15-item self-reported questionnaire to measure gastrointestinal symptoms in five clusters: reflux, abdominal pain, indigestion, diarrhoea and constipation. Each item yields a score of 0 to 3 (overall score ranges from 0 to 45). The higher score indicates a higher intensity of experienced symptoms.

  24. Changes in Trail Making Test (TMT) to measure the cognitive abilities [ Time Frame: from the date of randomization until the end of the study up to 12 weeks ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Outpatients aged 18-60 years old;
  2. Signed written Informed Consent Form;
  3. Meet the DSM-5 criteria for MDD;
  4. Body mass index (BMI) ≥18.5 kg/m2 and ≤30 kg/m2;
  5. MADRS (Montgomery-Asberg Depression Scale) total score at screening (V0) and at baseline (V1) of 20 points or more (moderate or severe depression);
  6. A willingness and motivation to follow the study protocol.

Exclusion Criteria:

  1. Diagnosis of autoimmune, neurological, immunocompromised, thyroid, inflammatory bowel diseases, diabetes, cancers, and/or IgE-dependent allergy;
  2. Psychiatric comorbidities (except specific personality disorder) including mental retardation, organic brain dysfunction, or addiction (except nicotine and caffeine);
  3. High risk of suicide in the investigator's opinion;
  4. An infection one month before the study baseline visit (V1);
  5. The use of antibiotics and/or probiotics three months prior to the study;
  6. Glucocorticosteroids and/or metformin treatment;
  7. Intake of any other drugs which in the investigator' opinion may affect the results of study;
  8. Intake of any dietary supplementation (except for vitamin D according to the "Vitamin D supplementation guidelines, 2018") which in the investigator' opinion may affect the results of the study;
  9. Changes in a pharmacotherapy and/or psychotherapy of MDD 2 weeks before the trial entry;
  10. Electroconvulsive therapy (ECT) 12 months before the trial entry;
  11. No specific diet (e.g., elimination, vegan, reduction) and changes in physical activity 4 weeks before the trial entry;
  12. Pregnancy or lactation.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03877393


Contacts
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Contact: Joanna Rog, MSc 0048817487307 joannarog@umlub.pl
Contact: Malgorzata Futyma-Jedrzejewska, MD 0048817487307 malgorzata.futyma-jedrzejewska@umlub.pl

Locations
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Poland
1st Department of Psychiatry, Psychotherapy and Early Intervention, Medical University of Lublin Recruiting
Lublin, Poland, 20439
Contact: Joanna Rog, MSc    0048817487307    joannarog@umlub.pl   
Contact: Malgorzata Futyma-Jedrzejewska, MD    0048817487307    malgorzata.futyma-jedrzejewska@umlub.pl   
Principal Investigator: Hanna Karakula-Juchnowicz, Prof, PhD, MD         
Principal Investigator: Joanna Rog, MSc         
Sub-Investigator: Dariusz Juchnowicz, PhD, MD         
Sub-Investigator: Malgorzata Futyma-Jedrzejewska, MD         
Sponsors and Collaborators
Medical University of Lublin
Sanprobi Sp. z o.o., Sp. k., Szczecin, Poland

Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Medical University of Lublin
ClinicalTrials.gov Identifier: NCT03877393     History of Changes
Other Study ID Numbers: DS192/2019
First Posted: March 15, 2019    Key Record Dates
Last Update Posted: March 15, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Medical University of Lublin:
Probiotics; dietary supplements
Diet, Gluten-Free
Inflammation
Gastrointestinal Microbiome
Intestinal mucosal permeability
Gut-brain axis
Gut permeability
EEG functional connectivity
Cortisol
Hypothalamic-pituitary-adrenal axis
Cognitive function
Additional relevant MeSH terms:
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Disease
Inflammation
Depression
Depressive Disorder
Depressive Disorder, Major
Pathologic Processes
Behavioral Symptoms
Mood Disorders
Mental Disorders