Doctoral Dissertations

Date of Award

5-2022

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Nutritional Sciences

Major Professor

Dallas Donohoe

Committee Members

Ahmed Bettaieb, Ling Zhao, Brynn Voy

Abstract

The host-microbiome interaction and the functions of microbial-derived metabolites, including butyrate, are important in colon health. Butyrate is the preferred energy source in colonocytes and has multiple physiological functions in the colon. A metabolic shift in colonocytes toward increased glucose utilization from butyrate oxidation is followed by several critical genetic modifications in cancerous colonocytes. Moreover, it has been suggested that the gut-microbiota composition is influenced by environmental factors, such as diets and the host's physiological status. Therefore, an understanding of the role of colonocyte metabolism toward impacting the host-microbiota commensal relationship would be an important step in understanding the functional importance of how diet, microbiome, and the host interact in colonic physiology.

This dissertation demonstrates that (1) colorectal cancer cells exhibit a metabolic shift from butyrate oxidation toward glycolysis; (2) the key factor in the metabolic shift is decreased pyruvate kinase M1 (PKM1), rather than increased pyruvate kinase M2 (PKM2); (3) an increase in HIF1⍺ through pyruvate metabolites reduction by a decrease in PKM1 is a critical mechanism to repress butyrate oxidation in colorectal cancer cells. Also, this dissertation explains that (1) a diminishment of short-chain acyl dehydrogenase (SCAD) in the non-disease mice model reduces butyrate oxidation in colonocytes and instead uses energy from glycolysis as a compensation mechanism; (2) the reduction of butyrate oxidation in SCAD-deficient mice causes a large diminishment in the butyrate-producing bacteria population; (3) these SCAD-deficient mice fail to respond in a prebiotic manner to dietary fiber.

These findings begin to characterize the different roles of the PKM isoforms in the cancerous colonocytes and show how these proteins change metabolism in a disease model. Also, the results allude to how colonocyte metabolism affects the population of gut microbiota in the gastrointestinal (GI) tract, which defines a significant relationship between butyrate metabolism in colonocyte and colonic gut microbiota homeostasis.

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