Microbes, microbiota, and colon cancer

Abstract

Colorectal cancer (CRC) presents a considerable disease burden worldwide. The human colon is also an anatomical location with the largest number of microbes. It is natural, therefore, to anticipate a role for microbes, particularly bacteria, in colorectal carcinogenesis. The increasing accessibility of microbial meta'omics is fueling a surge in our understanding of the role that microbes and the microbiota play in CRC. In this review, we will discuss recent insights into contributions of the microbiota to CRC and explore conceptual frameworks for evaluating the role of microbes in cancer causation. We also highlight new findings on candidate CRC-potentiating species and current knowledge gaps. Finally, we explore the roles of microbial metabolism as it relates to bile acids, xenobiotics, and diet in the etiology and therapeutics of CRC.

Figure 1. Genetic alterations and the progression of CRC (Vogelgram)

The major signaling pathways that drive the development of CRC are shown at the transitions between each tumor stage. One of several driver genes in each signaling pathway can be altered in an individual tumor. Patient age indicates the time interval during which the driver genes are usually mutated. The classic ‘vogelgram’ shown in the upper panel is adapted from Vogelstein et al. (2013). A map of genes mutated in CRC is shown in the lower panel with peak height indicating that a large percentage of human colorectal tumors harbor such mutations (adapted from Wood et al. 2007).

Figure 2. Microbial contributions to the pathogenesis of colorectal cancer

Complex microbiota:host interactions are considered probable primary or secondary contributors to the pathogenesis of colorectal cancer. From the microbiota perspective, several hypotheses are actively under investigation including disease instigation or promotion through individual microbes (Model 1), the collective microbiota (Model 2) or an interactive model in which single microbes drive the emergence of a modified, disease-generating microbiota (Model 3). From the host perspective, the microbiota may alter tumor-associated inflammation with consequences for tumor biology or, conversely, the tumor microenvironment or associated inflammation may induce microbiota shifts with the potential to further inhibit or promote tumor biology. Host genetic polymorphisms that modify immune and metabolic responses are predicted to play a key role in host:microbiota interactions during colonic carcinogenesis. See text for details.

Figure 3. Host and microbial metabolism affect CRC risk

Host and microbiota co-metabolism influence colonic bile pool exposure, drug metabolism, and the breakdown of ingested foodstuffs with significant consequences for CRC. The enterohepatic circulation of bile acids is shown from the generation of the primary bile acids from cholesterol in the liver to the generation of secondary bile acids by the intestinal microbiota. Bile acids linked to decreased or increased colorectal cancer risk are highlighted. Both the liver and the gut microbiota play critical roles in drug metabolism with significant effects on drug toxicity and response in CRC. Specific dietary components have been implicated in increasing or decreasing CRC risk, e.g. saturated fats, red and processed meats, and polyphenols. An individual’s gut microbial metabolism may play a role in the beneficial or detrimental effects of certain foods.