Investigation of Spinal Cord Injury-Induced Gastrointestinal Dysfunction and Related Microbiota, Fungal, and Intestinal Alterations in a Rat Model and Humans with Spinal Cord Injury

Spinal cord injury (SCI) is a serious medical condition that can result in a spectrum of neurological impairments and physical disabilities. There is an average of 11-12,000 new injuries per year in the US alone, and no cure for either the paralysis, or other secondary effects. Although there have been significant strides made in the research of the pathophysiology of Spinal Cord Injury (SCI), there is still limited knowledge on the consequences of SCI in remote organs. SCI produces significant effects on the entire body including the gastrointestinal tract. Individuals with SCI often experience severe, debilitating bowel dysfunction in addition to their physical disabilities, which is of major concern due to the adverse effect on their quality of life. The aim of the studies reported in this thesis was to further understand the Gastrointestinal (GI) dysfunction in individuals with SCI and to start to identify the role and relationship of the gut microbiota, inflammation, fungi, and their associated signaling and small molecules. This project was developed based on the hypothesis that SCI causes both local and system inflammatory states which persist long-term, resulting in sustained disturbance of gut microbiota and fungi. This dysbiosis would include altered signaling and secretion of small molecules evidenced by a broad range of GI dysfunction and potentially contributing to other systemic dysfunctions such as autonomic and immune dysfunctions. The gut microbiome is now accepted as a determinant of human health and as such an area of intense research, especially in chronic diseases of the GI tract. However, so far there have been very limited research reports on bowel dysfunction in patients with SCI. In fact, only 1 study has been done in humans reporting alterations in gut microbial patterns in stool samples of adult chronic SCI patients. Further, another study has examined the effect of gut dysbiosis in a mouse model of SCI but only as it pertains to functional recovery of the cord injury, not systemic or secondary organ effects. In this thesis, by employing a SCI rat model of cervical and thoracic injury we examined the effects of SCI on gastrointestinal transit, permeability, and integrity, pro- inflammatory cytokines, and bacterial quorum sensing communication to characterize the state of the GI tract in an animal model. Then, preliminary results of a human study allowed for comparison with microbiota changes, analysis of inflammation, short chain fatty acids, and bacterial quorum sensing combined with fungal species. These data provide a greater understanding of the effects of SCI on the gastrointestinal tract, highlighting the need for further investigation to elucidate the mechanism underlying these effects. Further, this study demonstrates proof of concept of ability to reliably characterize GI dysfunction on multiple levels in individuals with SCI on a large scale by the creation of a biorepository of physiological samples from these patients, with the goal to understand the mechanism of the GI problems and explore non invasive microbiome-based interventions in this population