Doctoral Dissertations

Date of Award

12-2023

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Nutritional Sciences

Major Professor

Dallas R. Donohoe

Committee Members

Dallas R. Donohoe, Jay Whelan, Ahmed Bettaieb, Jeremiah Gene Johnson

Abstract

Gastrointestinal diseases, including colorectal cancer and inflammatory bowel disease, continue to pose significant challenges due to our incomplete understanding of their etiology. Chronic inflammation and alterations in colonocyte metabolism have been implicated in the development of colorectal cancer and inflammatory bowel disease. Moreover, an abnormal immune response to gut microbiota in inflammatory bowel disease can lead to an imbalance of the gut microbiota, specifically decreased butyrate-producing bacteria. Therefore, understanding the role of inflammation in regulating colonocyte metabolism and in contributing to butyrate producing bacteria in gastrointestinal disease is crucial for elucidating the underlying mechanisms contributing to the pathogenesis of these diseases. For example, how do cytokines regulate colorectal cancer cell metabolism to promote progression? Are changes in butyrate-producing bacteria occurring before disease onset or after?

This dissertation shows (1) interleukin-1beta promotes a metabolic shift from butyrate oxidation towards glycolysis in colorectal cancer cells; (2) interleukin-1beta elevates glycolysis through increasing hypoxia-inducible factor 1-alpha through AKT activation in colorectal cancer cells; (4) interleukin-1beta effects mitochondrial function in a hypoxia-inducible factor 1-alpha-dependent way (4) tumor necrosis alpha shares a similar mechanism using AKT and hypoxia-inducible factor 1-alpha in colorectal cancer cells. Furthermore, this dissertation demonstrates that (5) pre-colitis mouse model 9-week interleukin-10 knockout mice shows a noticeable increase in inflammation, decreased butyrate oxidation and increased glycolysis in their colonocytes; (6) a significant increase in butyrate kinase is associated with increased abundance of Coprococcus comes that use butyrate kinase for butyrate production in 9-week interleukin-10 knockout mice; (7) a significant decrease in butyrate transferase aligns with the reduced level of Faecalibacterium prausnitzii, which use butyryl-CoA:acetate-CoA transferase for butyrate production, along with the decreased acetate levels in 9-week IL-10 knockout mice.

These findings contribute to our understanding of how two prominent proinflammatory cytokines, interleukin1-beta and tumor necrosis factor-alpha, shift colonocyte metabolism in colorectal cancer cells. Also, the results provide the exploration of changes in butyrate-producing bacteria in inflammatory bowel disease. Taken together, the data derived from this dissertation advances our understanding of the interplay between inflammation, colonocytes metabolism and butyrate producing bacteria during the development of gastrointestinal disease.

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