Biological Signatures, Probiotic Among Those With mTBI and PTSD

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.

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