The Microbial Etiology of Colorectal Cancer

Abstract

The microbiome of the Gastro-Intestinal tract is estimated at 100 trillion organisms which act in a symbiotic relationship with the surrounding tissue cells to maintain homeostasis. However, alterations in the gut microbiota caused by genetics or environmental factors can disturb this relationship and promote diseases such as colorectal cancer (CRC). CRC is the third most common form of cancer in both men and women and the second leading cause of cancer-related death worldwide, presenting a considerable disease burden. The intimate association between the microbiota and the cells of the colon sets the stage for a number of interactions that may contribute to carcinogenesis. While only a few specific commensal species may play a direct causal role in CRC, more general shifts in the composition may promote local inflammation through engagement of innate immune receptors encoded within the colonic tissue. Changes in gene expression within the microbiota may also be important by altering virulence factors and producing metabolites that may have detrimental effects on the tissue. In the first chapter of this Thesis, we explore the conceptual frameworks through which certain members of the microbiota are believed to cause CRC, the sensing of microbiota associated molecular patterns by innate immune receptors known as Toll-Like-receptors (TLRs) and the various strategies aimed at manipulating the microbiota and targeting the TLRs, in the hopes of developing new treatment approaches. In the second chapter of this body of Research, we focus on Bacteroides fragilis, a particular bacterial commensal species that has been correlated to CRC development in human studies. Mouse models have also shown that B. fragilis is capable of remodeling the mucosal immune response and colonic bacterial community to promote oncogenic changes in the epithelium. In our study, we analyzed the mucosal microbiome of patients undergoing CRC screening and noted a high prevalence of B. fragilis in patients with early CRC lesions. We isolated B. fragilis from mucosal biopsy samples for deeper characterization and showed that they phenotypically differed according to their geographical location in the colon and the presence of pre-cancerous lesions in the microenvironment they were isolated from. The results we gathered explore the relationship between B. fragilis and early-stage CRC and provide biological framework for microbiota-based biomarkers and therapeutic targets. This study shows that the pre-cancerous mucosal environment alters the immunogenicity of a gut commensal. Environmental factors that influence the gut microbiota are then further explored in the context of individual species in Chapter 3 using Matrix-Assisted Laser Desorption Ionization Time of Flight Mass Spectrometry (MALDI TOF MS) technology. Another factor influencing the gut microbiota and, therefore the host immune response, is genetics. Development of the human immune system depends on various receptors capable of recognizing and responding to pathogens and commensals. As mentioned in Chapter 1, these receptors include toll-like receptors (TLRs) found on macrophages, dendritic cells, and intestinal epithelial cells. Using TLR6 knockout mice in chapter 4, our study aimed to understand how disruption in host recognition of the microbiota can exacerbate disease. Defective TLR6 signaling was shown to worsen the host susceptibility to inflammation associated colorectal cancer. Within the same study, analysis of the microbiota revealed a therapeutic potential by restoring microbial ecology. By better understanding how the gut microbiome influences the development of colorectal cancer, we can begin to think in terms of innovative therapies to approach the treatment of this disease that continues to be challenge for healthcare professionals and patients in the clinic.