The Interplay Between the Gut Microbiome and Enteric Nervous System after Spinal Cord Injury Restricted; Files Only
Hamilton, Adam (Summer 2024)
Abstract
One of the most debilitating outcomes of spinal cord injury (SCI) is dysregulation of the gastrointestinal tract, known as neurogenic bowel dysfunction (NBD). NBD most often presents as severe constipation and can occur regardless of lesion location or severity. It is thought that a number of factors contribute to the impairment of gut function after injury, however, the exact etiology is currently unknown. Recent investigation has revealed that SCI not only influences the gut itself, but also the gut’s microbial inhabitants, with the most significant dysbiosis associated with the most severe cases of NBD. In this dissertation I review the current literature regarding the physiology of the gut in the presence and absence of SCI and highlight how injury-associated changes in the nervous system, immune system, and gut microbiome influence one another and contribute to NBD. To determine if SCI induces any characteristic changes to the microbiome, we conducted a systematic review of existing human and animal post-injury microbiome datasets. Our analysis revealed a consistent loss of microbes that produce short-chain fatty acids (SCFAs), a byproduct of microbial fermentation of dietary fiber. Using a severe thoracic model of SCI, we found that providing injured mice with inulin, a dietary fiber, immediately after SCI significantly reduced the severity of gut dysbiosis and dysmotility, and improved locomotor outcomes. Further investigation revealed that inulin-mediated improvements to gut and locomotor outcomes are dependent on the anti-inflammatory cytokine IL-10, which is increased in response to butyrate, a microbially-produced SCFA. We next sought to determine if the SCI-associated microbiome was inherently detrimental to host health, even outside of the context of SCI. Using gnotobiotic models, we found that injury-associated microbes do influence intestinal and metabolic function, even in injury-naïve mice. Our findings reveal a microbiome-based pathway that can be targeted to improve health after SCI. NBD is most often associated with SCI but is also a component of numerous diseases and disorders of the nervous system and often comorbid with changes in the gut microbiome, suggesting that the findings presented herein could have wide reaching implications for treating aspects of various nervous system disorders.
Table of Contents
Table of Contents.
Chapter 1: Introduction. 1
1.1 Brief overview of the branches of the nervous system. 2
1.2 Anatomy of the spinal cord. 3
1.3 The gastrointestinal tract and the enteric nervous system. 4
1.4 Overview of the gut microbiome in health and disease. 9
1.5 The gut microbiome, fiber, & short-chain fatty acids. 11
1.6 A brief introduction to spinal cord injury. 12
1.7 Physiological changes associated with spinal cord injury. 13
1.8 Gastrointestinal motility dysfunction after spinal cord injury. 14
1.9 The role of extrinsic neurons in neurogenic bowel. 15
1.10 Intrinsic changes involved in neurogenic bowel. 17
1.11 Current therapeutics and unmet need. 18
1.12 Fiber, SCFAs, and SCI. 18
1.13 Figures. 20
Chapter 2: Traumatic spinal cord injury and the contributions of the post-injury microbiome. 26
2.1 Abstract. 27
2.2 Introduction. 27
2.3 Remodeling of the gut microbiome after SCI. 29
2.4 Interactions between the gut microbiome and SCI-induced neurogenic bowel. 32
2.5 SCI-triggered local and systemic immune responses. 34
2.6 Contributions of the microbiome to SCI-associated inflammation in humans. 36
2.7 Microbiome contributions to SCI-associated inflammation in experimental models. 38
2.8 SCI microbiome association with gut permeability after injury. 41
2.9 Microbiome manipulations with therapeutic potential for SCI recovery. 43
2.9.1 Fecal microbiome transplants. 44
2.9.2 Probiotic therapeutics. 45
2.9.3 Selective antibiotic treatment. 46
2.9.4 Beneficial microbiome-related metabolites. 48
2.10 Looking broadly into the future at microbiome effects on SCI. 52
2.11 Acknowledgments. 53
2.12 Tables. 54
Chapter 3: Diet-microbiome interactions promote enteric nervous system resilience following spinal cord injury. 56
3.1 Abstract. 57
3.2 Introduction. 57
3.3 Results. 59
3.3.1 Inulin limits NBD pathology following mid-thoracic SCI in mice. 59
3.3.2 Dietary inulin prevents SCI-triggered gut dysbiosis. 61
3.3.3 Injury and diet-associated gut microbiomes are not sufficient to induce or prevent NBD. 62
3.3.4 IL-10 signaling is necessary to limit intestinal dysmotility post-SCI. 64
3.3.5 SCFA signaling is sufficient to improve SCI-induced dysmotility. 65
3.4 Discussion. 67
3.5 Methods. 70
3.5.1 Animals. 70
3.5.2 Spinal cord injury. 71
3.5.3 Total gastrointestinal transit. 72
3.5.4 Ex vivo colonic contractility recordings. 73
3.5.5 Microbiome sequencing. 74
3.5.6 SCFA analysis. 75
3.5.7 Western blots. 76
3.5.8 Multiplexed ELISAs. 77
3.5.9 Immunofluorescence imaging. 77
3.5.10 Bacterial manipulations and colonization. 78
3.6 Author contributions. 78
3.7 Acknowledgements. 79
3.8 Figures. 80
3.9 Tables. 94
Chapter 4: Discussion. 102
4.1 SCFA-producing bacteria are diminished after SCI. 103
4.2 Inulin fiber increases SCFAs and improves outcomes after SCI. 103
4.3 The role of IL-10 in recovery from SCI. 105
4.4 Inulin and SCFA-triglycerides prevent atrophy of ENS neurons. 109
4.5 The influence of inulin outside of the GI tract. 110
4.6 The influence of the SCI-associated microbiome on host health. 112
4.7 Comparing microbiome-based therapeutic options. 114
4.8 Potential risks associated with inulin and SCFAs. 117
4.9 Direct comparison of inulin and tributyrin. 118
4.10 Future directions & concluding remarks. 121
4.11 Figures. 123
References. 133
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File download under embargo until 21 August 2025 | 2024-07-02 12:05:20 -0400 | File download under embargo until 21 August 2025 |
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