A Study of Healthy Microbiome, Healthy Mind

Mayo Clinic (Other)
Overall Status
Not yet recruiting
CT.gov ID

Study Details

Study Description

Brief Summary

Researchers are doing this study to find out if a high fermented food diet is tolerable, and if it will help improve quality of life after surviving a critical illness, including severe COVID-19, by promoting gut health recovery and decreasing gut inflammation.

Condition or Disease Intervention/Treatment Phase
  • Behavioral: Fermented Food Diet

Detailed Description

Critical illness, including severe COVID, often lead to long term cognitive and mental health complications. Current non-pharmacological interventions, including ABCDEF bundle, are of limited efficacy. The largest psychological intervention trial to date also demonstrated no beneficial effect. These impairments may persist for years and are associated with chronic pain, impaired physical functioning, decreased quality of life, increased use of psychotropic medications, opioid abuse, self-harm, and increased acute care service utilization. Half of previously employed critical illness survivors, including those with long COVID, are not able to return to work a year later resulting in loss of insurance and difficulty in seeking professional help.

Increasing recognition that the nervous system and the gastrointestinal tract are communicating through a bidirectional network of signaling pathways, collectively known as the gut-brain-axis, resulted in emergence of a novel discipline of "nutritional psychiatry" advocating that diet and nutrition may be central determinants of both physical and mental health. In the outpatient setting, fiber rich Mediterranean style diet has been linked to improvements in cognitive and mood symptoms possibly via its known anti-inflammatory effect whereby diets high in sugars and refined grains with high inflammatory potential have been linked to the development of depression.

Critical illness and associated interventions lead to the loss of normal gut bacteria, allowing overgrowth of disease-promoting pathogenic bacteria resulting in severe dysbiosis. During dysbiosis, gut-brain pathways are dysregulated resulting in neuroinflammation, anxiety and depressive-like behaviors as well as cognitive impairment. Dysbiosis can persist months after the resolution of critical illness. Restoration of healthy microbiome may thus be key to facilitating psychiatric and cognitive recovery after critical illness.

Can the Mediterranean diet be used to restore microbiome diversity in this population? Perhaps not right away, as critical illness survivors have significant decrease in fiber degrading bacterial organisms. Others demonstrated that high-fiber diet alone does not result in increased microbial community diversity. What about probiotics? In patients with antibiotics-associated dysbiosis, probiotics induced a persistently incomplete indigenous stool microbiome recovery. How can microbiome diversity be restored? Fermented foods may be the most promising approach. Consumption of fermented milk facilitated restoration of gut homeostasis in patients with irritable bowel syndrome and increased their "feeling good" scores. Other human intervention studies using fermented tea, sauerkraut, fermented plant extract, kimchi, and fermented soybean milk reported increased presence of bacteria in the gut known for their health promoting properties. Consumption of fermented foods was associated with positive modulation in brain activity and fewer symptoms of social anxiety. A 10-week high fermented food diet intervention demonstrated increased microbiota diversity and decreased inflammatory markers among healthy volunteers. Can it be applied to survivors of critical illness including COVID to help them recover from dysbiosis and inflammation, and improve their mental health and other outcomes?

Specific Aim #1: to evaluate feasibility of high fermented food diet among critical illness survivors and its effect on microbiome diversity Hypothesis 1a: critical illness survivors will tolerate high fermented food diet Hypothesis 1b: high fermented food diet will increase microbiome diversity in critical illness survivors.

Specific Aim #2: to evaluate the effect of high fermented food diet on immune system performance and recovery, mental health, cognition, and quality of life of critical illness survivors.

Hypothesis 2a: high fermented food diet will improve immune system performance among critical illness survivors.

Hypothesis 2b: critical illness survivors treated with fermented food diet for 3 months will have a reduction in symptoms of anxiety, depression and acute stress/PTSD Hypothesis 2c: critical illness survivors treated with fermented food diet for 3 months will have improvement in cognition.

Hypothesis 2c: critical illness survivors treated with fermented food diet for 3 months will have improvement in quality of life.

Study Design

Study Type:
Anticipated Enrollment :
40 participants
Intervention Model:
Parallel Assignment
None (Open Label)
Primary Purpose:
Official Title:
Healthy Microbiome, Healthy Mind: Using Gut-brain Axis for Improving Psychocognitive Health Outcomes of Critical Illness Survivors
Anticipated Study Start Date :
Oct 2, 2023
Anticipated Primary Completion Date :
Apr 30, 2025
Anticipated Study Completion Date :
Jun 30, 2025

Arms and Interventions

Arm Intervention/Treatment
Experimental: Fermented Foods Diet

Subjects will incorporate fermented food into their diet.

Behavioral: Fermented Food Diet
Subjects will incorporate 1 serving of fermented food a day and increase to 6 more each day as tolerated for 4 weeks. After the initial 4 weeks, subjects will eat 6 or more servings of fermented foods each day for 8 weeks.

No Intervention: Normal Diet

Subjects will continue their regular diet.

Outcome Measures

Primary Outcome Measures

  1. Feasibility of high fermented food diet among critical illness survivors [12 weeks]

    20 critical illness survivors assigned to the intervention arm will tolerate high fermented food diet on 75% of the study days or more

  2. gut microbiome diversity [Baseline, 12 weeks]

    assessed using Shannon index

Secondary Outcome Measures

  1. Change in inflammatory cytokines [Baseline, 12 weeks]

    Targeted analyses will be performed to compare the values of inflammatory markers such as tumor necrosis factor-alpha, interleukin-2, interleukin-2 soluble receptor, interleukin-4, interleukin-5, interleukin-6, interleukin-8, interleukin-10, interleukin-12 interleukin-13, interleukin-17, interferon-gamma and interferon-1beta.

  2. Symptoms of anxiety and depression [Baseline, 12 weeks]

    Measured using the self-reported Hospital Anxiety and Depression Scale (HADS). Total questions: 14. Anxiety 7, Depression 7. Each item is rated on a 4-point scale from 0 "absence" to 3 "extreme presence". Total score is 21 per subscale: 0 - 7: Normal levels of anxiety/depression; 8-10: Borderline abnormal; > 11: Abnormal

  3. Cognitive Assessment [Baseline, 12 weeks]

    Measured using the Montreal Cognitive Assessment (MoCA-BLIND). Total questions:13. Memory 3 Attention 4 Language 3 Abstraction 2 Orientation 1. Subscores for each of the 5 sections are calculated. The total score is summed from the subscores, with a maximum score of 22. A score equal > 18 is considered normal cognition

  4. Self-Reported quality of life [Baseline, 12 weeks]

    Measured using the self-reported EuroQol-5D-3L questionnaire. Total questions: 6. Mobility: 1, Self-Care: 1, Usual Activities: 1, Pain/discomfort: 1, Anxiety/depression: 1, Health State - Visual Analog Scale: 1. 3L - 3 levels of severity: no problems, some problems, extreme problems. The visual analog scale ranges from 0 to 100 with higher scores reflecting better perceived current health-related quality of life state.

  5. symptoms of acute stress/PTSD [Baseline, 12 weeks]

    Measured using Impact of Events-revised (IES-r). Total questions: 22. Intrusion 7, Avoidance 8, Hyperarousal 7. Items are rated on a 5-point scale ranging from 0 ("not at all") to 4 ("extremely"). Total scores are summed with higher scores indicating greater distress with regards to a specific event. Orientation 1

Eligibility Criteria


Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
Accepts Healthy Volunteers:
Inclusion Criteria:
  • Patients who survived critical illness and are at risk for mental health morbidity/long COVID (spent > 48 hours in the ICU or had COVID requiring ICU stay) who have a smartphone.
Exclusion Criteria:
  • History of dementia, mental retardation, psychotic disorders such as schizophrenia, patients not expected to survive the hospital stay or non-English speaking, participants not able to tolerate foods by mouth or those with potential contraindications to such diet (chronically immunosuppressed including organ transplant recipients; those with neutropenia or currently undergoing chemotherapy, those taking Monoamine oxidase inhibitors).

Contacts and Locations


Site City State Country Postal Code
1 Mayo Clinic Minnesota Rochester Minnesota United States 55905

Sponsors and Collaborators

  • Mayo Clinic


  • Principal Investigator: Lioudmila Karnatovskaia, MD, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Additional Information:


None provided.
Responsible Party:
Lioudmila Karnatovskaia, Principal Investigator, Mayo Clinic
ClinicalTrials.gov Identifier:
Other Study ID Numbers:
  • 23-005057
First Posted:
Sep 1, 2023
Last Update Posted:
Sep 1, 2023
Last Verified:
Aug 1, 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:
Studies a U.S. FDA-regulated Drug Product:
Studies a U.S. FDA-regulated Device Product:
Additional relevant MeSH terms:

Study Results

No Results Posted as of Sep 1, 2023