Date of Award
Fall 2023
Document Type
Open Access Thesis
Department
Biological Sciences
First Advisor
Marj Pena
Abstract
Early onset colorectal cancer (EOCRC) is an aggressive form of colorectal cancer diagnosed before the age of 50. While colorectal cancer cases in patients 50 years and older have been declining, EOCRC cases have been steadily increasing globally in the last few decades, and the cause is unknown. Many agents, called exposomes, have been associated with EOCRC based on their emergence and prevalence prior to and in parallel with the rise in EOCRC cases. Among these are antibiotics (Abx). Abx are indispensable in our fight against infectious diseases, however their overuse is becoming a global epidemic. They are prescribed globally, and their use has increased prior to and in tandem with EOCRC cohorts. While effective against bacterial infections, they also affect the gut microbiome, a protector of colonic health, and they are often prescribed early in life, which impacts proper development of the immune system and may predispose patients to inflammatory diseases and maybe cancer later in life. In this study, we will test the hypothesis that exposure to Abx early in life will cause dysbiosis leading to inflammation in the colon, thereby increasing risk for EOCRC. To determine if Abx are contributing factors to EOCRC, A/J mice were given repeated exposures to two common pediatric Abx, amoxicillin and azithromycin, via oral gavage. One group of mice was sacrificed immediately after completing the Abx treatment to determine their effect on the colon microenvironment, while the other was given several doses of azoxymethane (AOM), a carcinogen, via intraperitoneal injection and later sacrificed to determine their impact on tumor development. Fecal pellets were collected at critical times to assess the impact of Abx on the gut microbiome composition. In this study, we specifically examine the effect of Abx exposure on immune cell infiltration as an indicator of inflammation in the colon. Fixed colon tissues were rolled into “swiss rolls” and colon slices were stained with antibodies against different immune cell-specific markers to examine immune cell infiltration in treated mice versus control mice, and quantified. The results showed gut dysbiosis and increased tumor burden in Abx-treated mice. Of the immune cells studied, there was a significant increase in F4/80+ cells in azithromycin treated mice as compared to control mice and in CD4+FoxP3+ T regulatory (Treg) cells in mice treated with both Abx as compared to controls. In mice that were further treated with AOM, there was a corresponding significant difference in macrophages and Tregs in Abx-treated mice compared to control mice. These results indicate that the immune response is altered in response to prolonged gut microbiome dysbiosis, and that macrophages and Tregs could directly contribute to tumor development in EOCRC.
Rights
© 2024, Valerie Hinsch
Recommended Citation
Hinsch, V.(2023). The Effect of Antibiotics on Immune Cell Infiltration of Colon in a Mouse Model of Early Onset Colorectal Cancer. (Master's thesis). Retrieved from https://scholarcommons.sc.edu/etd/7557