Manipulating the Microbiota-Immune Axis to Augment Recovery Following Spinal Cord Injury

• Author / Creator

  Doolin, Emma KA

• Spinal cord injury (SCI) not only leads to motor and sensory dysfunction, but just as debilitating are secondary consequences of SCI such as bowel disorders, neuroinflammation, immune suppression, pain and psychiatric disorders. In this thesis, I explore multiple aspects of recovery after SCI in an attempt to promote both physical and psychological well-being. In chapter 2, I show that an incomplete cervical SCI alters the composition of the gut microbiome (termed dysbiosis) and increases anxiety-like behaviour in rats. Using a fecal microbiota transplant (FMT) from uninjured donor rats to prevent SCI-induced dysbiosis also prevented the development of anxiety-like behaviour, suggesting a link between these two consequences of injury. I then wanted to determine whether optimal donor selection would influence the efficacy of FMT treatment for SCI. This was explored in chapter 3, where I show that FMT from uninjured rats with increased anxiety-like behaviour was unable to prevent SCI induced dysbiosis. Furthermore, recipients of this inferior FMT displayed increased anxiety-like behaviour, increased intestinal permeability, and long-term alterations in local and systemic inflammation. Independent of treatment group, this study showed a global downregulation of plasma cytokines and chemokines chronically after injury. I found in chapter 4 that treatment with the antibiotic and anti-inflammatory drug, minocycline, can prevent this SCI-induced suppression of systemic inflamma tory markers. In chapters 2, 3 and 4 we explore the complicated relationship between the microbiome, immune system and mental health after SCI. A potential link between these systems is through the bacterial endotoxin, lipopolysaccharide (LPS). LPS can enter circulation through a leaky intestinal barrier (which can be modulated by the microbiome as shown in chapter 3), where it induces an intense inflammatory response. Although increased inflammation is commonly associated with secondary damage following SCI, in certain circumstances inflammation can promote neural plasticity. I explore this dichotomous role of manipulating inflammation after SCI in chapter 5, where rats were given LPS in the subacute period following SCI. Although LPS significantly improved functional motor recovery of the ipsilesional forelimb, it also induced a chronic anxiety-like state. The results of this thesis show that manipulating the microbiome and inflammation following SCI may be a therapeutic tool to promote both physical and mental well-being, and that considering multiple aspects of recovery in preclinical models is imperative to determine potentially detrimental treatment side effects.

• Subjects / Keywords

  • Spinal cord injury
  • Microbiome
  • Anxiety

• Graduation date

  Fall 2021

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-dw9p-z408

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.