Colorectal cancer: The epigenetic role of microbiome

Abstract

Colorectal cancer (CRC) is the third most common cancer in men (746000 cases per year) and the second most common cancer in women globally (614000 cases per year). The incidence rate of CRC in developed countries (737000 cases per year) is higher than that in less developed countries (624000 cases per year). CRC can arise from genetic causes such as chromosomal instability and microsatellite instability. Several etiologic factors underlie CRC including age, diet, and lifestyle. Gut microbiota represent a proven cause of the disease, where they play pivotal roles in modulating and reshaping the host epigenome. Several active microbial metabolites have been found to drive carcinogenesis, invasion, and metastasis via modifying both the methylation landscape along with histone structure in intestinal cells. Gut microbiota, in response to diet, can exert both beneficial and harmful functions in humans, according to the intestinal balance of number and types of these bacteria. Although the intestinal microbial community is diverse among individuals, these microbes cumulatively produce 100-fold more proteins than the human genome itself, which calls for further studies to elaborate on the complicated interaction between these microorganisms and intestinal cells. Therefore, understanding the exact role that gut microbiota play in inducing CRC will help attain reliable strategies to precisely diagnose and treat this fatal disease.

Keywords: Cancer; Colorectal; Colorectal cancer; Epigenetics; Gut; Microbiota.

Figure 1

The way gut microbiota induces CRC. Several factors affecting the normal behavior of microbiota such as low fiber and high-fat diets. This change might affect the number/types of gut bacteria or cause them to express different kinds of proteins and metabolites. A category of these metabolites could be oncogenic (oncometabolites) and trigger inflammation in gut epithelial cells leading to cancer initiation. Bacterial metabolites also could enhance cancer spreading and metastasis. CRC: Colorectal cancer.

Figure 2

Different pathways through which CRC develops. CRC: Colorectal cancer.

Figure 3

Different functions of butyrate in protecting against CRC. CRC: Colorectal cancer; HDAC: Histone deacetylase.

Figure 4

Different gut microbiota generate different oncometabolites. Bacteroides expresses specific signaling substances to activate toll-like receptor 2 (TLR 2), which functions in two different ways; activation of FOX3 to trigger Treg activation leading to inflammation. The other way is the activation of T helper 17 cells that also triggers inflammation. Flagellin, a product of flagellated bacteria, activates also TLR 5 to activate innate lymphoid cells 3 and then IL 17 and 22 that initiate inflammation. TLR 5 also works on nuclear factor κB to activate miR-21 that has a role in initiating cancer carcinogenesis (CRC). Meanwhile, Fusobacteria can stimulate a specific type of TLR that activates nuclear factor of activated T cell via calmodulin-based calcineurin to initiate CRC. CRC: Colorectal cancer; IL: Interleukin; ILC: lymphoid cells; NF-κB: Nuclear factor-κB; NFAT: Nuclear factor of activated T cell; TLR: Toll-like receptor; Treg: T regulatory cell.