The gut microbiome and colorectal cancer

By Kai Yee Eng

The human microbiome consists of a diverse set of microorganisms, from bacteria, to viruses, archaea, and other eukaryotic microbes. These microorganisms play a huge role in maintaining immune health – to the extent that they are regarded as “the hidden organ” (Guinane and Cotter, 2013). The largest portion of the human microbiome is in the gut. This gut microbiome has been found to have an association to several diseases – one of which is colorectal cancer (CRC).

In CRC patients, a shift of the gut microbial community (or dysbiosis) has been observed. Although the changes have not been consistent across patients, it was found that the patients have reduced diversity in their gut microbiome (Cheng, Ling & Li, 2020). In particular, a significant decrease of the Faecaelibacterium sp. and the Roseburia sp. was seen (Kho and Lal, 2018). Other bacteria identified to have an association with CRC include the enterotoxigenic Bacteroides fragilis (which was observed in 90% of CRC patients) and Enterococcus faecalis. Both are over-represented in CRC cases as compared to the normal control (Mima et al., 2017; Cheng, Ling & Li, 2020). Changes in the microbial community also seem to be linked to CRC progression. For example, an increase of Fusobacterium nucleautum is normally linked to a worse prognosis (Cheng et al., 2020).

In addition, fungal composition seems to be linked to CRC. Although there is no observed loss or gain of a species, the abundance of the individual fungal species has changed, with an increased ratio of Basidiomycota to Ascomycota in CRC patients (Oluwabukola Coker et al., 2019). The same study has also shown an increase of fungal class Malasseziomycetes and decrease of both fungal classes Saccharomycetes and Pneumocystidomycetes abundance in CRC patients (Oluwabukola Coker et al., 2019).

Whilst there seems to be a relationship between the gut microbiota and CRC, its exact involvement in the initiation, development or metastasis of CRC is not understood. However, several theories have been suggested.

One of the most prominent theories relates to inflammation – with changes in the gut environment due to inflammation increasing signalling by microorganisms and enhance immune signalling (Wong & Yu, 2019).  There is some evidence for this – a product of the gut microbiome, butyrate, was shown to act in anti-inflammation, by reducing inflammatory cytokines such as nuclear factor-κB. This is a transcription factor which further regulates other signalling molecules of the immune system (such as TNF-α, IL-1b, T cell receptor-α and MHC class II) (Canani et al., 2011). Butyrate can also bind with some G-protein coupled receptors which can be found on immune cells and thus may be able to activate leucocytes (colloquially known as white blood cells) (Canani et al., 2011). Animal studies have shown that the production of butyrate in obese mice differs from lean mice or germ-free mice, with an increased production of butyrate and other short chain fatty acids (Davis, 2016). This may be significant in the context of CRC – inflammation increases the risk of developing colorectal adenomas, and so is thought to be linked to CRC development (Lucas, Barnich and Nguyen, 2017).

Improving understanding of how CRC is linked to the gut microbiota may be possible through research into other diseases – such as obesity. Obesity is classified as a low-grade inflammation and a common risk factor across many cancers (Wong & Yu, 2019). In one human study, it was found that there is an increase proportion of Firmicutes and a huge decrease of Bacteroides in cases of obesity (Davis, 2016). Such changes in the microbiome are thought to contribute to the impact of immune health due to dysbiosis of gut microbiota. Determining the microbiome differences in various diseases can allow characterisation of the roles of components of the gut microbiome.

Studies on gut microbiome and CRC have been challenging as it is very difficult to replicate the microbiome environment.  Some of the key reasons for this are the diversity of the gut microbiome and the complex interactions within the gut environment that change drastically over time. With the advancement of sequencing technology such as 16s ribosomal RNA sequencing, the building of cloud data from researchers (i.e., European Metagenomics of the Human Intestinal Tract (MetaHIT) and the NIH-funded Human Microbiome Project (HMP)) (Shreiner et al., 2015), research into the role of the gut microbiome in CRC is seeing huge interest. This research may translate into improved clinical diagnosis, prognosis and most importantly, treatment of CRC to increase the survival rate and life quality of CRC patients.

References:

Canani, R.B., Costanzo, M. Di, Leone, L., Pedata, M., et al. (2011) Potential beneficial effects of butyrate in intestinal and extraintestinal diseases. World Journal of Gastroenterology : WJG. [Online] 17 (12), 1519. Available from: doi:10.3748/WJG.V17.I12.1519 [Accessed: 5 October 2021].

Cheng, Y., Ling, Z. & Li, L. (2020) The Intestinal Microbiota and Colorectal Cancer. Frontiers in Immunology. [Online] 0, 3100. Available from: doi:10.3389/FIMMU.2020.615056.

Davis, C.D. (2016) The Gut Microbiome and Its Role in Obesity. Nutrition today. [Online] 51 (4), 167. Available from: doi:10.1097/NT.0000000000000167 [Accessed: 5 October 2021].

Guinane, C.M. & Cotter, P.D. (2013) Role of the gut microbiota in health and chronic gastrointestinal disease: understanding a hidden metabolic organ. Therapeutic Advances in Gastroenterology. [Online] 6 (4), 295. Available from: doi:10.1177/1756283X13482996 [Accessed: 3 October 2021].

Kho, Z.Y. & Lal, S.K. (2018) The Human Gut Microbiome – A Potential Controller of Wellness and Disease. Frontiers in Microbiology. [Online] 0 (AUG), 1835. Available from: doi:10.3389/FMICB.2018.01835.

Lucas, C., Barnich, N. & Nguyen, H.T.T. (2017) Microbiota, Inflammation and Colorectal Cancer. International Journal of Molecular Sciences. [Online] 18 (6). Available from: doi:10.3390/IJMS18061310 [Accessed: 5 October 2021].

Mima, K., Ogino, S., Nakagawa, S., Sawayama, H., et al. (2017) The role of intestinal bacteria in the development and progression of gastrointestinal tract neoplasms. Surgical Oncology. [Online] 26 (4), 368–376. Available from: doi:10.1016/J.SURONC.2017.07.011.

Oluwabukola Coker, O., Nakatsu, G., Dai, Z., Ka, W., et al. (2019) Gut microbiota Enteric fungal microbiota dysbiosis and ecological alterations in colorectal cancer. Gut. [Online] 68, 654–662. Available from: doi:10.1136/gutjnl-2018-317178 [Accessed: 4 October 2021].

Shreiner, A.B., Kao, J.Y. & Young, V.B. (2015) The gut microbiome in health and in disease. Current opinion in gastroenterology. [Online] 31 (1), 69. Available from: doi:10.1097/MOG.0000000000000139 [Accessed: 3 October 2021].

Wong, S.H. & Yu, J. (2019) Gut microbiota in colorectal cancer: mechanisms of action and clinical applications. Nature Reviews Gastroenterology & Hepatology 2019 16:11. [Online] 16 (11), 690–704. Available from: doi:10.1038/s41575-019-0209-8 [Accessed: 5 October 2021].

Wu, S., Rhee, K.-J., Albesiano, E., Rabizadeh, S., et al. (2009) A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nature Medicine 2009 15:9. [Online] 15 (9), 1016–1022. Available from: doi:10.1038/nm.2015 [Accessed: 5 October 2021].

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