Qi Zhang

Date of Award

Fall 2020

Document Type

Open Access Dissertation

Department

Pharmacology, Physiology and Neuroscience

First Advisor

Lorne J. Hofseth

Abstract

Early-onset colorectal cancer (EOCRC) is the second most common cancer and the third leading cause of cancer mortality in people under 50 years old in the United States. Our hypothesis is that a high-fat diet (HFD), Allura Red AC, and/or psychological stress causes distal and rectal colon inflammation, which are associated with dysbiosis. Furthermore, chronic exposure to one or more of these elements increases the risk of EOCRC. A/J inbred mice were utilized in this study. The results are consistent with our hypothesis.

Overall findings are the following: (1) An HFD increased inflammatory scores and polyps’ burden in the distal and rectal colon. (2) An HFD increased gut microbiota Firmicutes/Bacteroidetes ratio causes dysbiosis. (3) An HFD depleted beneficial microbiota S24-7 at the family level and enriched colorectal cancer (CRC) biological marker Allobaculum at the genera level. (4) An HFD caused Apc mutations in colonic stem cells. (5) Psychological stress increased inflammatory scores and polyps’ burden in the distal and rectal colon. (6) Psychological stress enriched the CRC biological marker Allobaculum in gut microbiota at the genera level. (7) Allura Red AC led to elevated IL-6 levels in the serum and elevated p53 mutations in colonic stem cells. (8) Allura Red AC increased polyps’ burden and colitis in the distal and rectal colon when overlaid with the HFD. (9) Allura Red AC decreased overall survival when overlaid with the HFD. (10) Allura Red AC decreased microbial diversity and richness when overlaid with the HFD. (11) Allura Red AC enriched CRC-related microbiota Erysipelotrichaceaeat the family level when overlaid with the HFD. (12) Allura Red AC resulted in metabolic changes by depleting the microbial phylum Verrucomicrobia. (13) Allura Red AC overlaid with HFD induced reproductive toxicity in A/J mice.

Our future directions are the following: (1) Identify the developmental window of susceptibility to HFD, psychological stress, and Allura Red AC on EOCRC. (2) Test the effects of HFD, psychological stress, and Allura Red AC in the A/J mouse with AOM to determine any impact on tumorigenesis. (3) Test the effects of the HFD, psychological stress, and Allura Red AC in other EOCRC animal models, e.g., ApcΔ14/+ (truncated Apc) mice. (4) Perform the fecal microbiota transplantation into germ-free mice, e.g., transfer the fecal sample from stressed human patients into germ-free A/J mice with AOM, to determine stressed microbiota and carcinogen-induced EOCRC in mice.

Rights

© 2020, Qi Zhang

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