Dissertation
METABOLOME-MICROBIOME INTERRELATIONSHIPS IN THE PATHOPHYSIOLOGY OF SUCCINIC SEMIALDEHYDE DEHYDROGENASE DEFICIENCY, A DEFECT OF GABA METABOLISM
Washington State University
Doctor of Philosophy (PhD), Washington State University
01/2022
DOI:
https://doi.org/10.7273/000004362
Handle:
https://hdl.handle.net/2376/122748
Abstract
Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare, autosomal recessive, inherited disorder of γ-aminobutyric acid (GABA) metabolism. Individuals with this disorder manifest a neurological phenotype that includes global developmental delay, ataxia, hypotonia, neuropsychological morbidity (obsessive-compulsive disorder, attention deficit hyperactivity disorder), and epilepsy. Symptomatology associates with extensive metabolic dysregulation of GABA and GABA-related metabolic pathways in all the tissues and biological fluids of patients. Metabolic dysfunction and disease presentation were postulated to act synergistically to induce intestinal dysbiosis. This hypothesis was tested by conducting an extensive and unique characterization of metabolic dysfunction in post-mortem human brain tissue, analyzing the SSADHD metabolome in dried bloodspots obtained from patients and healthy individuals, and characterizing the SSADHD intestinal microbiome using stool samples collected from patients enrolled in an ongoing natural history study. These human studies were guided by the results of preceding work showing significant intestinal dysbiosis in a mouse model of the disease (aldh5a1-/-). Collectively, results demonstrate a significant impact of SSADHD on the intestinal microbiota and suggest that intestinal dysbiosis may be related to metabolic markers of the disease in tissues and biological fluids. Additional studies of the intestinal microbiome in humans and animals further aided in a more robust analysis of metabolome-microbiome interrelationships in SSADHD. This work significantly expands the understanding of the gut microbiota-disease relationship in various disease conditions.
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Details
- Title
- METABOLOME-MICROBIOME INTERRELATIONSHIPS IN THE PATHOPHYSIOLOGY OF SUCCINIC SEMIALDEHYDE DEHYDROGENASE DEFICIENCY, A DEFECT OF GABA METABOLISM
- Creators
- Trevor Owen Kirby
- Contributors
- K. Michael Gibson (Advisor)Jean-Baptiste Roullet (Committee Member)Mary F. Paine (Committee Member)Jonathan Wisor (Committee Member)Nancy Potter (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Pharmacy and Pharmaceutical Sciences, College of
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 162
- Identifiers
- OCLC#: 1363848289; 99900883036301842
- Language
- English
- Resource Type
- Dissertation