Date on Master's Thesis/Doctoral Dissertation

8-2022

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Anatomical Sciences and Neurobiology

Degree Program

Anatomical Sciences and Neurobiology, PhD

Committee Chair

Whittemore, Scott

Committee Co-Chair (if applicable)

Barve, Shirish

Committee Member

McClain, Craig

Committee Member

McGee, Aaron

Committee Member

Stirling, David

Author's Keywords

Neuropathology; CNS; targeting pathological

Abstract

There is growing evidence that the health of the gut microbiome (GM) has an important role on multiple host organ systems. Ethanol-related neuropathologies and Alzheimer’s disease (AD) currently have no effective clinical treatment. Therefore, we developed a novel mouse model of fecal matter transplantation (FMT) utilizing the microbiome from alcoholic hepatitis (AH) patients, characterized by a loss of butyrogenic potential. Minimal neuroinflammation occurred in AH-FMT mice, but significant increases in the endoplasmic reticulum stress response (ERSR) across the majority of neurons in the prefrontal cortex and hippocampus were observed. In the cerebellum, Purkinje cells were specifically affected. Targeting the loss of butyrate reduced the ERSR as well as low-grade inflammation. The AD 3xTg mouse model was assessed for the development of dysbiosis. At 12 months these mice developed dysbiosis, characterized by the loss of butyrate-producing bacteria. Butyrate supplementation did positively impact inflammation, oxidative stress, and neurofibrillary tangle formation. Functionally, cognitive decline was ameliorated in butyrate-supplemented mice. Aldose reductase (AR) is the rate-limiting enzyme in the polyol pathway. Biproducts of this pathway yield increases in inflammatory products and decreases in antioxidants. Lipopolysaccharide (LPS) was injected intraperitoneally in mice to mimic endotoxemia. The brains and livers of AR knock-out mice (ARKO) showed markedly reduced inflammation. While microglial activation remained the same, a significant reduction in macrophage-related cytokines was observed. Macrophages treated with Epalrastat, an AR inhibitor, showed reduced CNS inflammatory gene expression in response to LPS, indicating the role of AR in LPS-induced inflammation. These studies implicate the GM in the CNS pathology of neurological-related diseases. The loss of butyrate has a critical role in the health of neurons and targeting this loss reduced or prevented neuropathology. Finally, we identified AR as a critical mediator of LPS-induced inflammation indicating that Epalrastat may aid in the treatment of CNS disease driven by endotoxemia.

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