Author ORCID Identifier

https://orcid.org/0000-0002-5799-6561

Date Available

12-1-2024

Year of Publication

2024

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Medicine

Department/School/Program

Physiology

Advisor

Dr. John C. Gensel

Abstract

Most individuals who suffer a spinal cord injury (SCI) will experience some form of bowel dysfunction. Trauma to the spinal cord can result in severe constipation and/or incontinence, otherwise known as neurogenic bowel. Constipation requires extensive bowel routines typically involving the help of another person. Still, many living with SCI are hospitalized due to bowel complications such as fecal impaction. While neurogenic bowel has been well characterized in the clinic, pre-clinical models of neurogenic bowel after SCI are still in development. Most pre-clinical studies in bowel dysfunction after SCI are published in rat models. Studies existing in mice, to our best knowledge, have all been done in low level thoracic injuries (below T8). The highest incidence of constipation is found in humans with high thoracic and cervical level SCI. There remains a significant need to characterize a high-level thoracic SCI model of bowel dysfunction in mice to better mimic the clinical presentation.

For this reason, we have characterized a T3 transection (Tx) mouse model of bowel dysfunction using functional, histological, and molecular assays. We found that mice show acute [4 days post injury (dpi)] and chronic (21 dpi) constipation, measured by fecal output and retention. Specifically, using bead expulsion and ex vivo myography, there is evidence of decreased motility and increased contractility in the distal colon. This increased tone could play a role in the decreased output and increased retention of fecal pellets in animals with a T3 Tx. Molecularly, there is evidence of transient increases in inflammatory cytokine levels within the colon tissue itself. This was followed by an increase of collagen deposition chronically in the distal colon. Together, the acute presence of inflammatory cytokines could dictate the deposition of collagen at chronic timepoints.

We next sought to investigate sex dependent changes in bowel dysfunction. Historically, SCI research has leaned heavily on studies in female mice while the human population of SCI individuals remains predominantly male. Notably, we found a sex dependent response to injury in bowel function as measured by fecal output. Intestinal permeability after injury, however, was unaltered by injury or sex. These standard outcomes of bowel dysfunction had not been extensively investigated in mice up to this point. Thus, we sought to validate these outcomes in a T9 contusion (ct) SCI model in mice, commonly used in SCI research. As expected, the extent of bowel dysfunction was relatively mild in a T9 Ct model compared to T3. Transient changes in fecal output were detected. Interestingly, evidence of collagen deposition was found chronically in the colon tissue. This suggests collagen deposition could be independent of significant constipation. Taken together, these works have characterized a T3 Tx model of bowel dysfunction after SCI using both basic and advanced techniques. It was apparent that foundational techniques, such as fecal output and retention, were sensitive in only the high thoracic transection injury model versus the more commonly used lower-level thoracic contusion model.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2024.435

Funding Information

NINDS T32 Fellowship Neurobiology of CNS Injury & Repair (5T32 NS077889) 2022-2024

NIGMS T32 Fellowship in Physiology (GM118292) 2020-2021

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