Linking Gut Microbiota to Colorectal Cancer

Abstract

Pre-clinical and clinical data produce mounting evidence that the microbiota is strongly associated with colorectal carcinogenesis. Dysbiosis may change the course of carcinogenesis as microbial actions seem to impact genetic and epigenetic alterations leading to dysplasia, clonal expansion and malignant transformation. Initiation and promotion of colorectal cancer may result from direct bacterial actions, bacterial metabolites and inflammatory pathways. Newer aspects of microbiota and colorectal cancer include quorum sensing, biofilm formation, sidedness and effects/countereffects of microbiota and probiotics on chemotherapy. In the future, targeting the microbiota will probably be a powerful weapon in the battle against CRC as gut microbiology, genomics and metabolomics promise to uncover important linkages between microbiota and intestinal health.

Keywords: carcinogenesis; colorectal cancer.; dysbiosis; inflammation; microbiota; mucosal defense mechanisms.

Figure 1

Biofilm formation. The structural components of the extracellular matrix is a highly hydrated, robust structure with high tensile strength and represents up to 90% of the biofilm mass keeping bacteria in close proximity, enabling intimate cell-to-cell interactions and DNA exchange while at the same time protecting the biomass from damaging agents. No copyright.

Figure 2

Adenoma-carcinoma sequence. CIS involves loss of APC function and KRAS, followed by loss of chromosome 18q with SMAD4 and mutation in TP53. MSI CRC is characterized by a deficiency of the MMR leading to slippage in microsatellites. CIN: chromosomal instability. From Walther & al. Nat Rev Cancer 2009;9:489-99. Permission from Macmillan Publishers Limited.

Figure 3

Mechanisms by which the bacterial microbiome modulates carcinogenesis. The microbiota promotes carcinogenesis through different mechanisms. A | Dysbiosis and inflammation induced by MAMP activating TLR and other PPR (e.g. NLR). B Detrimental effects are mediated by bacterial toxins such as colibactin and CDT: Cytolethal Distending Toxin, ROS, Reactive Nitrogen Species and H₂S. C Metabolic actions activating toxins such as acetaldehydes and nitrosamines. The microbiota mediates preventive effects (in green) through inactivation of carcinogens and production of SCFA: short chain fatty acids; such as butyrate and propionate. From Schwabe RF, Jobin C. Nature Reviews Cancer 2013;13:800-12. With permission from Macmillan Publishers Ltd.

Figure 4

Schematic presentation of bacterial gene regulation by Quorum sensing. No copyright.

Figure 5

Early stage of bacterial biofilm with visible intercellular polymeric matrix.