Bowel Cancer and the Microbiome

By Daniella Gimbosh

Cancer is an extremely broad category of diseases caused by the uncontrollable growth of dividing cells, and novel treatment therapies are constantly being investigated by scientists around the world. One of these novel areas of research focuses on the microbiome – a field that is rapidly gaining momentum for its complexity and therapeutic potential. 

The microbiome is the entire collection of genes found in all the microbes associated with a particular host, including bacteria, archaea, protists, fungi and viruses (Amon & Sanderson, 2017). The thousands of microorganisms present on the human body are vital in maintaining gut health, developing the immune system and have been implicated in a myriad of diseases including cancer. Bowel or colorectal cancer specifically has been implicated, however, the question of how the microbiome affects the risk of bowel cancer remains largely unanswered (Gunjur, 2020). 

Specific bacterial strains seem to be linked to colorectal cancer. Through metagenomic faecal analysis of colorectal cancer patients, bacteria specific to this cancer were identified, including Bacteroides fragilis, Fusobacterium nucleatum and Porphyromonas asaccharolytica, to name a few (Cheng, Wu & Yu, 2020). These species could therefore potentially serve as diagnostic markers for bowel cancer. 

Moreover, these bacterial species, among others, have been associated with an increase in various biochemical pathways, including energy and lipopolysaccharide synthesis, catabolism of proteins and mucin, as well as destruction of carbohydrates. The relevance of this information is that the upregulation of these pathways could potentially lead to cancer. For example, Dai et al. found that the Krebs cycle was significantly enriched in colorectal cancer patients; this type of increase in bioenergetics is typical of cancer cells, which quickly outgrow their blood supply and begin to take up huge amounts of glucose and glutamine even at normal oxygen levels (Dai et al., 2018). Glutamine, for example, provides intermediates for the TCA cycle through anaplerosis, and is also converted to alpha keto-glutarate as a precursor for biomolecules by entering the TCA cycle. This process is called glutaminolysis and is usually heavily favoured in cancer cells. 

Furthermore, these specific microbiota had a significant upregulation in lipopolysaccharide (LPS) synthesis (Hersoug, Møller & Loft, 2015). LPS, a gram-negative bacterial antigen, can enhance cell survival and proliferation in bowel cancer through signalling via toll-like receptor 4. Furthermore, oesophageal cancer cell migration has been seen to increase when stimulated with LPS (Rousseau et al., 2013). The upregulation of this pathway, which is linked to bowel cancer-enriched bacteria, possibly implicates it in bowel cancer. 

However, it is worth focusing on a single, specific bacterial strain to get a more detailed understanding on the impact of the microbiome on bowel cancer. Although thousands of species of bacteria are found in the human gut, by analysing the microbiome of healthy subjects and of patients with bowel cancer, it was found that a specific E. coli strain called pks+ E. coli was present in much higher quantities in the bowel cancer patients. This strain is present in approximately 20% of healthy individuals, 40% of patients with inflammatory bowel disease, and 60% of patients with familial adenomatous polyposis or colorectal cancer (Pleguezuelos-Manzano et al., 2020). This strain has been termed “genotoxic” as the island pks (or the polyketide-nonribosomal peptide synthase operon) codes for enzymes that are responsible for the synthesis of colibactin, a molecule that causes DNA damage (Xue et al., 2019). However, the link between this DNA damage and bowel cancer remaind to be unearthed.

In one study, intestinal organoids, which replicate the intestinal environment, were exposed both to this genotoxic strain of E.coli as well as non colibactin-producing E.coli for 5 months, and the organoids exposed to the genotoxic E.coli had double the DNA damage of organoids exposed to non colibactin-producing E.coli (Pleguezuelos-Manzano et al., 2020). Furthermore, the colibactin-induced DNA damage consisted of 2 unique “patterns” that were denoted as “fingerprints” that would identify colibactin-specific effects. 

This pattern presents an invaluable tool; by investigating tumours from cancer patients, the presence of this fingerprint could confirm a link between this bacterial strain and cancer. This could be investigated since any mutations acquired by a cancer cell at its primary site are preserved even during later metastases, thus providing information about the previous mutations in a tumour. Multiple other studies conducted found that there was a much higher frequency of the fingerprints in bowel cancers when compared to other cancers (Wirbel et al., 2019).

Although much more research needs to be done to fully implicate specific bacterial strains of the microbiome in bowel cancer, and to find out the exact details of how their specific pathways could lead to cancer, these findings could be revolutionary for the early diagnosis of bowel cancer. If specific bacterial strains possibly trigger the disease, we could carry out analysis on intestinal cells looking for specific bacterial fingerprints, such as the colibactin fingerprint, and we could therefore identify people who have a higher chance of developing the cancer. By recognizing and targeting cancer-related bacteria carrying such toxins before they are able to cause a significant amount of damage in the body, bowel cancer could be completely avoided in some people. In the future, finding as many microbiota as possible that could be implicated in cancer could greatly improve diagnosis and possibly even treatment of cancers such as colorectal cancer. 

There are many other areas which suggest the involvement of the microbiome in cancer. Notably, resistance to chemotherapy as well as to immune checkpoint inhibitors has been associated with a shift in the microbiota profile (Galluzzi et al., 2020). Therefore, research is being done to investigate if controlling the microbiota with antibiotics, faecal transplants and other nanotechnological methods could promote the destruction of tumours with chemotherapy and immune checkpoint inhibitors by overcoming this resistance. Clearly, much is still to be discovered about the mysterious microbiome, and the therapeutic potential that it holds is undeniable and invigorating for the scientific community. 

References

Amon, P. & Sanderson, I. (2017) What is the microbiome? Archives of disease in childhood – Education & practice edition. [Online] 102 (5), 257–260. Available from: doi:10.1136/archdischild-2016-311643 [Accessed: 14 June 2021].

Gunjur, A. (2020) Cancer and the microbiome. The Lancet Oncology. [Online] 21 (7), 888. Available from: doi:10.1016/s1470-2045(20)30351-x [Accessed: 20 February 2021].

Cheng, W.Y., Wu, C.-Y. & Yu, J. (2020) The role of gut microbiota in cancer treatment: friend or foe? BMJ. [Online] 69 (10), 1867–1876. Available from: doi:10.1136/gutjnl-2020-321153 [Accessed: 20 February 2021].

Dai, Z., Coker, O.O., Nakatsu, G., Wu, W.K.K., et al. (2018) Multi-cohort analysis of colorectal cancer metagenome identified altered bacteria across populations and universal bacterial markers. Microbiome. [Online] 6 (1). Available from: doi:10.1186/s40168-018-0451-2 [Accessed: 20 February 2021].

Hersoug, L.-G. ., Møller, P. & Loft, S. (2015) Gut microbiota-derived lipopolysaccharide uptake and trafficking to adipose tissue: implications for inflammation and obesity. Obesity Reviews. [Online] 17 (4), 297–312. Available from: doi:10.1111/obr.12370 [Accessed: 14 June 2021].

Rousseau, M.C., Hsu, R.Y.C., Spicer, J.D., McDonald, B., et al. (2013) Lipopolysaccharide-induced toll-like receptor 4 signaling enhances the migratory ability of human esophageal cancer cells in a selectin-dependent manner. Surgery. [Online] 154 (1), 69–77. Available from: doi:10.1016/j.surg.2013.03.006 [Accessed: 14 June 2021].

Pleguezuelos-Manzano, C., Puschhof, J., Huber, A.R., van Hoeck, A., et al. (2020) Mutational signature in colorectal cancer caused by genotoxic pks + E. coli. Nature. [Online] 580, 1–5. Available from: doi:10.1038/s41586-020-2080-8 [Accessed: 19 February 2021].

Xue, M., Kim, C.S., Healy, A.R., Wernke, K.M., et al. (2019) Structure elucidation of colibactin and its DNA cross-links. Science. [Online] 365 (6457), eaax2685. Available from: doi:10.1126/science.aax2685 [Accessed: 1 March 2021].

Wirbel, J., Pyl, P.T., Kartal, E., Zych, K., et al. (2019) Meta-analysis of fecal metagenomes reveals global microbial signatures that are specific for colorectal cancer. Nature Medicine. [Online] 25 (4), 679–689. Available from: doi:10.1038/s41591-019-0406-6 [Accessed: 21 February 2021].

Galluzzi, L., Humeau, J., Buqué, A., Zitvogel, L., et al. (2020) Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nature Reviews Clinical Oncology. [Online] 17 (12), 725–741. Available from: doi:10.1038/s41571-020-0413-z [Accessed: 3 March 2021].

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