Huntington Disease (HD) is an autosomal dominant neurodegenerative disorder caused by a trinucleotide repeat expansion mutation in the huntingtin (HTT) gene. HD is characterized by neurological symptoms, including motor, cognitive, and psychiatric decline. A non-neurological symptom, metabolic dysfunction, is also common in HD and can cause weight change, a feature recapitulated in HD mice. There is a need for a better understanding of the weight changes associated with HD, because patients with a higher body mass index show slower disease progression. Our lab has shown that metabolic dysfunction in HD mice is the result of a disrupted circadian feeding rhythm but when HTT expression is suppressed in the brain, this is normalized. Additionally, when a normal circadian feeding rhythm is enforced, HTT protein in the brain is reduced. Together, this suggests that HTT is involved in gut-brain feedback. The gut brain axis (GBA) is the bidirectional communication pathway between the gut and central nervous system. One major component of the GBA is the gut microbiome, which has been implicated in neurological disorders. The microbiome interacts with the brain by producing short chain fatty acids, neurotransmitters, and metabolites. A plasma metabolomics study of HD mutation carriers revealed a reduction of Indole-3-propionic acid (IPA) in HD. IPA is a metabolite exclusively produced by bacteria and is a known antioxidant and anti-inflammatory. Inflammation and oxidative stress are features of HD and a reduction in circulating IPA may contribute to these aspects of the disease. This research was conducted to investigate the relationship between the relative abundance of IPA producing bacteria in the gut and the amount of plasma IPA in HD model mice. This will provide a basis for further investigation into the connection between the microbiome, bacterial metabolites, and the potential to target gut dysbiosis as a therapeutic outlet for HD.
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Master of Science (M.S.)
College of Medicine
Burnett School of Biomedical Sciences
Length of Campus-only Access
Masters Thesis (Open Access)
Millot, Christian, "Investigating the Relationship Between the Microbiome and Neuroactive Metabolites in Huntington Disease Model Mice" (2022). Electronic Theses and Dissertations, 2020-. 1414.