THERAPEUTIC IMPLICATIONS OF THE GUT-CNS AXIS IN PROMOTING RECOVERY FOLLOWING CERVICAL SPINAL CORD INJURY
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Year of Publication
Doctor of Philosophy (PhD)
Dr. Warren Alilain
Nearly 60% of all spinal cord injuries (SCI) occur at the cervical level. These high-level injuries can interrupt the descending respiratory pathways required for breathing. Indeed, therapies in animal studies have been successful at restoring breathing after SCI; however, these interventions appear to be more effective at chronic time points. One potential cause for this observation is the impact of the injury on the gut microbiome. Neurotrauma can induce gut dysbiosis, an imbalance of pathogenic and beneficial gut microbiota, which has previously been shown to negatively impact the central nervous system (CNS) and impair recovery. We aimed to build upon these findings and investigate 1.) the impact of cervical SCI (cSCI) on the gut microbiome and 2.) how treating the resulting gut dysbiosis may improve respiratory recovery after cSCI. We hypothesized that cSCI leads to dynamic changes in the gut microbiome, which aremost severe acutely after injury. Further, we hypothesized that this dysbiosis impedes functional recovery of breathing in the acute phase. As the dysbiosis resolves at chronic time points, treatments result in a more profound recovery.
To test our hypothesis, we performed a left C2 hemisection (LC2Hx) on adult female rats. We assessed the gut microbiome pre- and post-injury as well as the effects of treating gut dysbiosis following cSCI on respiratory outcomes. Our data suggest that LC2Hx results in transient changes in the gut microbiome that returns to preinjury levels over time. There were also inter-institutional differences in the Firmicutes-to-Bacteroidetes ratio when comparing animals that received cervical hemisection injuries at the University of Kentucky versus Drexel University. Further, gut tissue pathology indicated damage and dysregulation following LC2Hx. Performing a fecal matter transplant led to mixed results in functional outcomes. However, when we treated animals with high-dose probiotics following LC2Hx there were minimal deficits in minute ventilation when compared to vehicle. Additionally, the high-dose probiotic group also exhibited an increase in neurite sprouting and regenerative potential of neurons when compared to all other groups. Interestingly, we also observed a reduction in systemic TNF-alpha in all LC2Hx animals treated with probiotics, regardless of dose level, at 3dpi compared to vehicle. Our work suggests that treating gut dysbiosis in individuals with cSCI could improve functional outcomes and allow for interventions to be more efficacious at acute time points.
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This study was supported by: National Institute of Health R01 NS101105 (WJA), National Institute of Health R21 NS121966 (WJA), National Institute of Health Training Grant T32 NS077889 (JSN) 2020 - 2022
Wilson, Jessica, "THERAPEUTIC IMPLICATIONS OF THE GUT-CNS AXIS IN PROMOTING RECOVERY FOLLOWING CERVICAL SPINAL CORD INJURY" (2023). Theses and Dissertations--Neuroscience. 31.