Mild Traumatic Brain Injury, Post Traumatic Stress Disorder
Conditions
Keywords
PTSD, Mild TBI, Probiotic, Inflammation
Brief summary
Exaggerated inflammation in the body and brain is thought to play a role in the vulnerability to and aggravation and perpetuation of adverse consequences among those with co-occurring mild TBI (mTBI) and post-traumatic stress disorder (PTSD). The proposed study begins the process of investigating the use of a natural immunoregulatory/anti-inflammatory probiotic to treat chronic symptoms associated with co-occurring mTBI and PTSD among Veterans. By looking at the impact of probiotic supplementation on biological signatures of increased inflammation, as reflected by the gut microbiota, gut permeability, and biomarkers of peripheral inflammation, this study may lead to the identification of a novel intervention for the treatment of symptoms associated with these frequently co-occurring conditions.
Detailed description
United States military Veterans from recent conflicts are coping with symptoms related to mild traumatic brain injury (mTBI), persistent post concussive (PPC) symptoms, and posttraumatic stress disorder (PTSD). Many Veterans are resistant to conventional health and mental health interventions (e.g., medication, psychotherapy), and often symptoms are not significantly improved by traditional treatments. Moreover, there are limited treatments for symptoms associated with both conditions, which frequently co-occur. Alternative treatment methods are needed. One potential common underlying feature of both mTBI and PTSD is exaggerated inflammation, both peripherally and in the central nervous system, which is thought to play an important role in the vulnerability to, aggravation of, and perpetuation of adverse consequences of these often co-occurring conditions. Therefore, a novel intervention strategy would be the use of immunoregulatory/anti-inflammatory probiotics to reduce inflammation. In this study, the investigators will investigate the effects of an immunoregulatory probiotic on both biological signatures of systemic inflammatory processes and proximal signatures of probiotic administration. Lactobacillus reuteri (L. reuteri), a commensal organism that colonizes the human gut mucosa, suppresses mucosal inflammation via inhibition of the production of proinflammatory cytokines, and is the probiotic of interest. Specific aims of the study are to determine the: 1) effects of L. reuteri on biological signatures of gut microbiota, gut permeability, systemic inflammation processes, and stress responses; 2) feasibility of L. reuteri supplementation; 3) acceptability of L. reuteri supplementation; and 4) tolerability and safety of L. reuteri supplementation. Project aims will be assessed using a longitudinal, double blind, randomized placebo-controlled design. Participants will be Veterans with PPC symptoms, PTSD, and evidence of elevated systemic inflammation (based on high baseline plasma C-reactive protein \[CRP\] concentrations). After initial evaluation procedures, 20 participants will be randomized to probiotic supplementation and 20 will be randomized to placebo supplementation. The proposed line of research addresses the Office of Rehabilitation Research and Development (RR&D) Service's goal of identifying means of intervening to increase function among those with mTBI and co-occurring psychiatric conditions. Long-term, this study may lead to a paradigm shift in the manner by which the investigators target clinical symptoms associated with PPC and PTSD symptoms, by beginning the process of supporting a multitargeted, neuroprotective approach.
Interventions
DIETARY_SUPPLEMENTof Lactobacillus reuteri (L. reuteri; DSM 17938)
Commercially available L. reuteri (deposited in the Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ) and referenced as DSM 17938; Gerber Soothe Colic Drops, 100 million CFU/5 drops; formerly known as L. reuteri ATCC 55730) will be used in the proposed study. L. reuteri (phylum Firmicutes) is a gram-positive anaerobic commensal bacteria found in the gut microbiome of humans. Independent testing of the viability of the commercial product will be conducted in our laboratories by diluting drops, plating on agar in triplicate, and anaerobic culturing at 37 oC. The commercial strain (DSM 17938) has been used to improve intestinal functions in infants and reduce symptoms of infantile colic.
OTHERSunflower and medium chain triglyceride oils
Placebo
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Biologic
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* History of at least one deployment in support of Operation Enduring Freedom (OEF)/Operation Iraqi Freedom (OIF)/Operation New Dawn (OND) * History of mTBI per the Ohio State University (OSU) TBI-ID85 with any endorsement of post concussive symptoms (PCS) associated with an mTBI, which occurred at least 6 months prior to the baseline assessment * Current symptoms in 3 or more of the following ICD-10 Post Concussive Symptom86 categories as measured by the Rivermead Post Concussive Symptom Questionnaire (RPCSQ87; score of 2 or greater per symptom to qualify): * headache * dizziness * malaise * fatigue * noise intolerance * irritability * depression * anxiety * emotional lability * subjective concentration * memory * intellectual difficulties * and/or insomnia * Current diagnosis of PTSD per the Clinician Administered PTSD Scale-5 (CAPS-5)88 * Medical clearance by study physicians to participate in the protocol * Age between 18 and 50 * Ability to provide informed consent * Willingness not to take probiotic supplements (pills, tablets, oils, etc.) other than the product provided in the clinical study until all study procedures are completed * Willingness to provide blood, as well as stool samples
Exclusion criteria
* Inability to adequately respond to questions regarding the informed consent procedure * Currently involved in the criminal justice system as a prisoner or ward of the state * Non-English speaking * Current (past month) alcohol or substance abuse or dependence * Lifetime history of bipolar disorder or psychosis or anxiety disorders (excluding PTSD) * Current major depressive disorder (MDD) * Consistent (e.g., 5x/week or greater) probiotic supplementation within the last month, including probiotic food products such as yogurt, as determined by phone screen interview and Probiotic Food Check List * Receiving antibiotics within the last month; use of topical antibiotics or topical steroids on the face, scalp, or neck or on arms, forearms, or hands within the previous 7 days * Receiving medications that interfere with gut motility (opiates, loperamide, stool softeners) * Presence of central venous catheters (CVCs) * Gastrointestinal (GI) barriers as identified by the 2-week run-in period as determined by the study team (e.g., daily GI discomfort with frequent diarrhea prior to supplementation) * Participation in conflicting interventional research protocol * Body mass index (BMI) greater than or equal to 35 or less than or equal to 18 * Vital signs outside of acceptable range, i.e., blood pressure \>160/100, oral temperature \>100 F, pulse \>100 * Use of any of the following drugs within the last 6 months: * systemic antibiotics * antifungals * antivirals or antiparasitics (intravenous, intramuscular, or oral) * oral * intravenous * intramuscular * nasal or inhaled corticosteroids * cytokines or cytokine inhibitors * methotrexate or immunosuppressive cytotoxic agents * Acute disease at the time of enrollment (defer sampling until subject recovers) * Acute disease is defined as the presence of a moderate or severe illness with or without fever * Chronic, clinically significant (unresolved, requiring on-going medical management or medication) pulmonary, cardiovascular, gastrointestinal, hepatic or renal functional abnormality, as determined by medical history or physical examination other than irritable bowel syndrome (IBS) * History of cancer except for squamous or basal cell carcinomas of the skin that have been medically managed by local excision * Unstable dietary history as defined by major changes in diet during the previous month, where the subject has eliminated or significantly increased a major food group in the diet * Positive test for human immunodeficiency virus (HIV), Hepatitis B virus, or Hepatitis C virus * Any confirmed or suspected condition/state of immunosuppression or immunodeficiency (primary or acquired) including HIV infection * Major surgery of the GI tract, with the exception of cholecystectomy and appendectomy, in the past five years. Any major bowel resection at any time * Regular urinary incontinence necessitating use of incontinence protection garments * Female who is pregnant or lactating * Treatment for or suspicion of ever having had toxic shock syndrome * Those receiving immunosuppressive drugs or treatment including antineoplastic therapy, post-transplantation immunosuppressive therapy, and/or radiation therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| C-Reactive Protein Change | Baseline and approximately 10 weeks | Inflammation - Biological Signature (Blood) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Necrosis Factor Change | 2 weeks and approximately 10 weeks | Inflammation - Biological Signature (Blood) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Interleukin 10 Change | 2 weeks and approximately 10 weeks | Inflammation - Biological Signature (Blood) |
| Intestinal Fatty Acid Binding Protein (IFABP) Change | 2 weeks and approximately 10 weeks | Gut Permeability (Blood) - IFABP, measured by ELISA |
| Visual Analog Scale | Approximately 10 weeks | The VAS was administered during the Trier Social Stress Task (TSST). The VAS is self-reported stress response on a Likert scale (1-10). A higher score indicates greater perceived stress. In the TSST, participants are asked to give a 5-minute speech and perform a math task. The VAS was administered at the baseline of the TSST, after the Speech Task, and after the Math Task. |
| Generic Assessment of Side Effects-Probiotics (GASE-P) | Time 1 (Baseline), Time 2 (2 weeks), and Time 3 (10 weeks) | This measure of tolerability consists of 36 symptom descriptions organized by body parts. Participants are asked to rate if these symptoms were either not present, mild, moderate, or severe in the past week related to supplementation. Total severity scores range 0-108. A higher severity score indicates more symptom severity. Total symptom scores range 0-36. A higher symptom score indicates more symptoms. |
| D-amino Acid Oxidase (DAO) Change | 2 weeks and approximately 10 weeks | Gut Permeability (Blood) - DAO, measured by ELISA |
| Interleukin 6 Change | 2 weeks and approximately 10 weeks | Inflammation - Biological Signature (Blood) |
Countries
United States
Participant flow
Recruitment details
Although 75 participants were consented and enrolled in the study, 31 participants met inclusion criteria and continued participation.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Sham Probiotic | 15 |
| L Reuteri Probiotic | 16 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 4 |
Baseline characteristics
| Characteristic | L Reuteri | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 37.9 years STANDARD_DEVIATION 7.3 | 37.4 years STANDARD_DEVIATION 6.7 | 36.7 years STANDARD_DEVIATION 6.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) White | 11 Participants | 21 Participants | 10 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 16 Participants | 31 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 16 |
| other Total, other adverse events | 0 / 15 | 0 / 16 |
| serious Total, serious adverse events | 0 / 15 | 0 / 16 |
Outcome results
Primary
C-Reactive Protein Change
Inflammation - Biological Signature (Blood)
Time frame: Baseline and approximately 10 weeks
Population: A sufficient amount of plasma was not available to run CRP on 1 participant in the placebo group and 2 participants in the L reuteri group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | C-Reactive Protein Change | 0.113 mg/L | Standard Deviation 1.2 |
| L Reuteri | C-Reactive Protein Change | -0.625 mg/L | Standard Deviation 1.1 |
p-value: 0.056Wilcoxon-rank sum
Secondary
Tumor Necrosis Factor Change
Inflammation - Biological Signature (Blood)
Time frame: 2 weeks and approximately 10 weeks
Population: A sufficient amount of plasma was not available to run TNF on 1 participant in the placebo group and 3 participants in the L reuteri group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Tumor Necrosis Factor Change | -0.62 pg/ml | Standard Deviation 1.4 |
| L Reuteri | Tumor Necrosis Factor Change | -2.1 pg/ml | Standard Deviation 8.2 |
p-value: 0.26Wilcoxon (Mann-Whitney)
Other Pre-specified
D-amino Acid Oxidase (DAO) Change
Gut Permeability (Blood) - DAO, measured by ELISA
Time frame: 2 weeks and approximately 10 weeks
Population: A sufficient amount of plasma was not available to run DAO on 5 participants in the placebo group and 4 participants in the L reuteri group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | D-amino Acid Oxidase (DAO) Change | -0.11 pg/ml | Standard Deviation 0.24 |
| L Reuteri | D-amino Acid Oxidase (DAO) Change | 0.03 pg/ml | Standard Deviation 0.12 |
Other Pre-specified
Generic Assessment of Side Effects-Probiotics (GASE-P)
This measure of tolerability consists of 36 symptom descriptions organized by body parts. Participants are asked to rate if these symptoms were either not present, mild, moderate, or severe in the past week related to supplementation. Total severity scores range 0-108. A higher severity score indicates more symptom severity. Total symptom scores range 0-36. A higher symptom score indicates more symptoms.
Time frame: Time 1 (Baseline), Time 2 (2 weeks), and Time 3 (10 weeks)
Population: 2 participants in the L reuteri group were lost to follow at Time 2, and then 2 more participants were lost to follow at Time 3.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Generic Assessment of Side Effects-Probiotics (GASE-P) | Time 1 - Severity | 25.6 score on a scale | Standard Deviation 13.9 |
| Placebo | Generic Assessment of Side Effects-Probiotics (GASE-P) | Time 1 - Symptom Count | 14.4 score on a scale | Standard Deviation 5.5 |
| Placebo | Generic Assessment of Side Effects-Probiotics (GASE-P) | Time 2 - Severity | 22.1 score on a scale | Standard Deviation 13.2 |
| Placebo | Generic Assessment of Side Effects-Probiotics (GASE-P) | Time 2 - Symptom Count | 12.4 score on a scale | Standard Deviation 6.4 |
| Placebo | Generic Assessment of Side Effects-Probiotics (GASE-P) | Time 3 - Severity | 11.7 score on a scale | Standard Deviation 11.3 |
| Placebo | Generic Assessment of Side Effects-Probiotics (GASE-P) | Time 3 - Symptom Count | 6.5 score on a scale | Standard Deviation 4.5 |
| L Reuteri | Generic Assessment of Side Effects-Probiotics (GASE-P) | Time 3 - Severity | 14.3 score on a scale | Standard Deviation 12 |
| L Reuteri | Generic Assessment of Side Effects-Probiotics (GASE-P) | Time 1 - Severity | 28.1 score on a scale | Standard Deviation 12.7 |
| L Reuteri | Generic Assessment of Side Effects-Probiotics (GASE-P) | Time 2 - Symptom Count | 15.6 score on a scale | Standard Deviation 4.8 |
| L Reuteri | Generic Assessment of Side Effects-Probiotics (GASE-P) | Time 1 - Symptom Count | 15.9 score on a scale | Standard Deviation 6.4 |
| L Reuteri | Generic Assessment of Side Effects-Probiotics (GASE-P) | Time 3 - Symptom Count | 9.8 score on a scale | Standard Deviation 8.5 |
| L Reuteri | Generic Assessment of Side Effects-Probiotics (GASE-P) | Time 2 - Severity | 23.7 score on a scale | Standard Deviation 8.8 |
Other Pre-specified
Interleukin 10 Change
Inflammation - Biological Signature (Blood)
Time frame: 2 weeks and approximately 10 weeks
Population: A sufficient amount of plasma was not available to run IL10 on 1 participant in the placebo group and 3 participants in the L reuteri group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Interleukin 10 Change | 0.15 pg/ml | Standard Deviation 0.85 |
| L Reuteri | Interleukin 10 Change | -0.23 pg/ml | Standard Deviation 2 |
Other Pre-specified
Interleukin 6 Change
Inflammation - Biological Signature (Blood)
Time frame: 2 weeks and approximately 10 weeks
Population: A sufficient amount of plasma was not available to run IL6 on 1 participant in the placebo group and 3 participants in the L reuteri group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Interleukin 6 Change | .22 pg/ml | Standard Deviation 2.4 |
| L Reuteri | Interleukin 6 Change | -.07 pg/ml | Standard Deviation 7.7 |
p-value: 0.64Wilcoxon Rank-Sum
Other Pre-specified
Intestinal Fatty Acid Binding Protein (IFABP) Change
Gut Permeability (Blood) - IFABP, measured by ELISA
Time frame: 2 weeks and approximately 10 weeks
Population: A sufficient amount of plasma was not available to run IFABP on 3 participants in the placebo group and 2 participants in the L reuteri group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Intestinal Fatty Acid Binding Protein (IFABP) Change | -0.09 pg/ml | Standard Deviation 0.45 |
| L Reuteri | Intestinal Fatty Acid Binding Protein (IFABP) Change | -0.04 pg/ml | Standard Deviation 0.16 |
Other Pre-specified
Visual Analog Scale
The VAS was administered during the Trier Social Stress Task (TSST). The VAS is self-reported stress response on a Likert scale (1-10). A higher score indicates greater perceived stress. In the TSST, participants are asked to give a 5-minute speech and perform a math task. The VAS was administered at the baseline of the TSST, after the Speech Task, and after the Math Task.
Time frame: Approximately 10 weeks
Population: VAS was administered at T3 therefore data was only available on participants who completed the study.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Placebo | Visual Analog Scale | TSST Baseline | 4.13 score on a scale |
| Placebo | Visual Analog Scale | TSST After Speech | 5.29 score on a scale |
| Placebo | Visual Analog Scale | TSST After Math | 6.44 score on a scale |
| L Reuteri | Visual Analog Scale | TSST Baseline | 5.38 score on a scale |
| L Reuteri | Visual Analog Scale | TSST After Speech | 6.25 score on a scale |
| L Reuteri | Visual Analog Scale | TSST After Math | 7.13 score on a scale |