Sporadic colorectal cancer: microbial contributors to disease prevention, development and therapy

Abstract

The gut microbiota has been hailed as an accessory organ, with functions critical to the host including dietary metabolic activities and assistance in the development of a proper functioning immune system. However, an aberrant microbiota (dysbiosis) may influence disease processes such as colorectal cancer. In this review, we discuss recent advances in our understanding of the contributions of the microbiota to prevention, initiation/progression, and treatment of colorectal cancer, with a major focus on biofilms and the antimicrobial and antitumoural immune response.

Figure 1

Molecular features of the colon during homeostasis and carcinogenesis. (Top) General biological differences among healthy tissues along the colorectal axis are depicted in blue. (Bottom) Differences in the prevalence of genetic features and biofilms among tumours along the colorectal axis are summarised in orange and red. The dashed line represents the transition between right and left colon based on the overwhelming burden of biofilms in tumours proximal to the hepatic flexure as reported in Dejea et al (2014).

Figure 2

Roles of the microbiota in CRC prevention, initiation, progression, and therapy. Colonic epithelial cells are depicted with the mucus layer (dark yellow) facing the gut lumen. (Left) Bacteria have multiple protective roles against CRC, including production of anti-inflammatory metabolites and regulation of crypt epithelial cell proliferation. Most notably, bacteria have integral roles in the maintenance and repair of the colonic epithelial barrier, by triggering controlled innate immune responses through PRRs on host cells. Disruption of PRR signalling leads to breaches of the epithelial barrier and excessive inflammation that may instead promote tumorigenesis. (Middle) Multiple avenues by which bacteria may initiate or promote CRC tumorigenesis are also depicted, including the direct genotoxicity of specific bacteria, as well as the proinflammatory effects triggered by either specific microbes, a dysbiotic microbiota as a whole, and/or colonic biofilms. (Right) Immune responses to commensals have also been proposed to be essential for the efficacy of multiple chemotherapies and immunotherapies.