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Microbial Interactions and Interventions in Colorectal Cancer

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  • Authors: Terence Van Raay1, Emma Allen-Vercoe2
  • Editors: Robert Allen Britton3, Patrice D. Cani4
    Affiliations: 1: Molecular and Cellular Biology, University of Guelph, 50 Stone Road East, Guelph, Ontario, N1G 2W1, Canada; 2: Molecular and Cellular Biology, University of Guelph, 50 Stone Road East, Guelph, Ontario, N1G 2W1, Canada; 3: Université catholique de Louvain, Brussels, Belgium; 4: Baylor College of Medicine, Houston, TX
  • Source: microbiolspec June 2017 vol. 5 no. 3 doi:10.1128/microbiolspec.BAD-0004-2016
  • Received 05 September 2016 Accepted 14 October 2016 Published 23 June 2017
  • Emma Allen-Vercoe, eav@uoguelph.ca
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  • Abstract:

    Recently, several lines of evidence that indicate a strong link between the development of colorectal cancer (CRC) and aspects of the gut microbiota have become apparent. However, it remains unclear how changes in the gut microbiota might influence carcinogenesis or how regional organization of the gut might influence the microbiota. In this review, we discuss several leading theories that connect gut microbial dysbiosis with CRC and set this against a backdrop of what is known about proximal-distal gut physiology and the pathways of CRC development and progression. Finally, we discuss the potential for gut microbial modulation therapies, for example, probiotics, antibiotics, and others, to target and improve gut microbial dysbiosis as a strategy for the prevention or treatment of CRC.

  • Citation: Van Raay T, Allen-Vercoe E. 2017. Microbial Interactions and Interventions in Colorectal Cancer. Microbiol Spectrum 5(3):BAD-0004-2016. doi:10.1128/microbiolspec.BAD-0004-2016.

Key Concept Ranking

Tumor Necrosis Factor alpha


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Recently, several lines of evidence that indicate a strong link between the development of colorectal cancer (CRC) and aspects of the gut microbiota have become apparent. However, it remains unclear how changes in the gut microbiota might influence carcinogenesis or how regional organization of the gut might influence the microbiota. In this review, we discuss several leading theories that connect gut microbial dysbiosis with CRC and set this against a backdrop of what is known about proximal-distal gut physiology and the pathways of CRC development and progression. Finally, we discuss the potential for gut microbial modulation therapies, for example, probiotics, antibiotics, and others, to target and improve gut microbial dysbiosis as a strategy for the prevention or treatment of CRC.

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Image of FIGURE 1a

Schematic of the anatomy of the human colon, indicating right/proximal and left/distal regions and their designations.

Source: microbiolspec June 2017 vol. 5 no. 3 doi:10.1128/microbiolspec.BAD-0004-2016
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Image of FIGURE 1b

Depiction of the overlap between development, innervation, vascularization, and tumorigenesis of the human colon. Abbreviations: superscript c, chick; superscript m, mouse; superscript z, zebrafish; PMF, parasympathetic motor fibers; SMF, sympathetic motor fibers; SF, sensory fibers.

Source: microbiolspec June 2017 vol. 5 no. 3 doi:10.1128/microbiolspec.BAD-0004-2016
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Image of FIGURE 2

Colonic crypt and aberrant Wnt signaling. Model of Wnt signaling. In the absence of Wnt-ligand stimulation, the central signaling molecule β-catenin is degraded and Wnt target genes remain silent (left). In the presence of Wnt ligand-mediated signaling, β-catenin becomes stabilized, resulting in cytoplasmic and nuclear accumulation and active transcription of Wnt target genes (center). APC mutations disrupt the destruction complex resulting in constitutively active Wnt signaling (right). Under normal circumstances, β-catenin-E-cadherin-mediated cell adhesion is not thought to have a role in Wnt signaling. The left side of the crypt depicts normal development. Black nuclei represent β-catenin-positive stem cells, with varying gray scale levels representing decreasing Wnt signaling, which is shut down (white nuclei) as the precursor cells differentiate. Colors represent the four major lineages of the colonic epithelium, with lighter colors representing less differentiated forms in the colonic crypt. On the right side, a mutation in APC renders the Wnt signaling pathway constitutively active, resulting in the proliferation of stem cells that become hyperplastic, eventually forming polyps on the luminal surface. Wnt signaling inhibits mucin-2 synthesis, possibly generating the nonmucinous phenotype characteristic of distal cancers. It is expected that cells in the polyp would consist of a heterogenous mixture of cells, some more differentiated (with less nuclear β-catenin) than others. The selection of APC alleles to generate the just-right amount of Wnt signaling results in the elimination of cells with too much or too little β-catenin signaling. The loss of E-cadherin (E-CAD) could have a role in generating this “just-right” amount of signaling.

Source: microbiolspec June 2017 vol. 5 no. 3 doi:10.1128/microbiolspec.BAD-0004-2016
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Image of FIGURE 3

Schematic detailing microbiome changes that can lead to the development of CRC. In the normal, healthy state (normal tissue), the gut microbiota is diverse and in balance within the host. The mucosal layer of the gut is intact, and microbes are not found directly in the vicinity of the colonic cells. In the alpha-bug model, certain pathobionts within the microbiome obtain entry to host tissues, e.g., by interfering with mucus secretion or by penetrating the mucus layer, and directly secrete metabolites and/or virulence determinants such as toxins to modulate host cells. Colonization by alpha-bugs in this way can also directly modulate the composition of the local microbiota. The driver-passenger model suggests that the major CRC-promoting factors come from colonization by passenger microbes that can settle within a niche prepared for them by the driver species. The biofilm model indicates that certain colonizing microbes, particularly in the proximal colon, can form aggregates, perhaps with cooperating species, that are able to persist in the niche and to secrete factors (including, in particular, polyamines) that potentiate CRC development. In the intestinal microbiota adaptations model, exogenous factors, such as diet, as well as endogenous factors, such as immune system function, behave as forces that shape the overall balance of cancer-promoting versus cancer-protective microbiota compositions. Finally, the bystander-effect model proposes that certain superoxides produced by the metabolism of certain microbial species can stimulate stromal macrophages to produce clastogens, which in turn have a directly carcinogenic effect on host cells.

Source: microbiolspec June 2017 vol. 5 no. 3 doi:10.1128/microbiolspec.BAD-0004-2016
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Comparison of characteristics across regions of the colon

Source: microbiolspec June 2017 vol. 5 no. 3 doi:10.1128/microbiolspec.BAD-0004-2016
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Common elements that distinguish proximal from distal colorectal cancers

Source: microbiolspec June 2017 vol. 5 no. 3 doi:10.1128/microbiolspec.BAD-0004-2016

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