Bacterial oncogenesis in the colon

Abstract

The human colon plays host to a diverse and metabolically complex community of microorganisms. While the colonic microbiome has been suggested to contribute to the development of colorectal cancer (CRC), a definitive link has not been made. The role in which the colon microflora could contribute to the initiation and/or progression of CRC is explored in this review. Potential mechanisms of bacterial oncogenesis are presented, along with lines of evidence derived from animal models of microbially induced CRC. Particular focus is given to the oncogenic capabilities of enterotoxigenic Bacteroides fragilis. Recent progress in defining the microbiome of CRC in the human population is evaluated, and the future challenges of linking specific etiologic agents to CRC are emphasized.

Figure 1. Overview of tissue- and cell-level mechanisms of bacterial oncogenesis

(A) In the healthy human colon, the inner mucus layer serves as a physical barrier separating the mucosal epithelium from luminal contents. The mucus layer is further protected through epithelial cell secretion of antimicrobial peptides and plasma cell secretion of IgA. This spatial segregation largely maintains the host–microbe homeostasis; nevertheless, bacterial invasion of the inner mucus layer does occur. (B) It is this perturbation that facilitates direct interactions between microbes and host cells, resulting in pathology. The precise mechanisms by which the bacterial community may induce oncogenesis when invading the inner mucus layer are, as yet, uncertain. (C & D) By contrast, for select bacteria for which preliminary epidemiologic data suggest an association with some human colorectal cancer, linkages between the mechanism of action of secreted toxins and colorectal cancer are shown. (C) Genotoxin colibactin secreted by Escherichia coli harboring the PKS island damages DNA. DNA damage by colibactin can be direct and/or through as yet unidentified colonic epithelial and/or other mechanisms. (D) Steps supported by experimental data regarding the action of BFT secreted by ETBF. See text for details. DC: Dendritic cell; ETBF: Enterotoxigenic Bacteroides fragilis; Mφ: Macrophage; MDSC: Myeloid-derived suppressor cell; NOS: Nitric oxide synthase; PMN: Polymorphonuclear cell; ROS: Reactive oxygen species.