Microbial Mediators of Trauma: The Gut-Brain Axis in Adverse Outcomes Following Blast Injury

Abstract

If you have felt “butterflies in your stomach” or had trouble going to the bathroom before an important meeting or event, you know that stress and the gut have a close relationship. Although much smaller than butterflies, the trillions of microbes that live in your gut (the gut microbiome) play an important role in this relationship. This bidirectional communication network, known as the microbiome-gut-brain axis (MGBA), is critical for maintaining health and wellness but is also vulnerable to trauma and injury. This dissertation zooms in on blast trauma, a full-body injury that results from exposure to overpressure waves, often emanating from high-order explosives or detonations. Thus, clinical studies and observations of this condition are often of veterans, although civilians in areas of military conflict suffer the same symptoms or worse. From clinical data, we see that individuals with a history of blast exposure often present with post-concussive symptoms, chronic pain, and post-traumatic stress disorder (PTSD). Gastrointestinal dysfunction is also comorbid with these disorders, yet the gut-brain connection has not been a focus of blast-related research. The overarching aim of this dissertation was to investigate the role of the MGBA in blast trauma in a translational mouse model. To do this, I first developed a novel fecal microbiota transplant (FMT) approach that limits extraneous stress for the mouse so that we can isolate the behavioral impact of the microbes and not the methods by which they are delivered (Chapter 2). I then applied this novel FMT approach to investigate whether changes to the microbiome after blast is a causal contributor to adverse blast outcomes (Chapter 3). Finally, I investigated the effects of vagus nerve stimulation (VNS), a neuromodulatory therapeutic targeting the gut-brain axis, as a potential treatment for adverse blast outcomes (Chapter 4). From refining animal models to testing therapeutic efficacy, this dissertation covers several steps in the preclinical stage of translational research and highlights the MGBA as a potential treatment target for blast trauma.