The gut microbiome and colorectal cancer

By Kai Yee Eng

The human microbiome consists of a complex range of microorganisms, ranging from bacteria, to viruses, archaea, and other eukaryotic microbes. These microorganisms play a huge role in modulating metabolism, maintaining immune health and many other functions to an extend that it has been regard as “the hidden organ”. (Guinane and Cotter, 2013) Extensive studies have been carried out to understand the role of these little organisms in regulating health and how the interaction between them and the host leads to the cause and development of diseases. The largest microbial population identified in our body, would be the gut microbiome, with more than 95% colonising the large intestine. (Galland, 2014)The gut microbiome composition changes as the environment of the gastrointestinal tracts change. With that being said, the microbial community in the small intestine differs from the colon, which the latter is dominated by microbes who are the producers of short chain fatty acids (SCFA) such as butyrate and propionate. The SCFA are a major component of the host-microbe interactions, for instance, butyrate is the main source of metabolism of colonocytes. (Parada Venegas et al., 2019)

As the gut microbiome plays a significant function in the human body, the gut microbiome has been found to have an association to several diseases. Colorectal cancer (CRC) was one of them. The dysbiosis, a shift of the microbial community was observed in these patients. Although the changes have not been consistent across patients, (Cheng, Ling & Li, 2020) it was found that the patients have reduced diversity in their gut microbiome, via analysis from the stool samples, with a significant decrease of butyrate-producer, the Faecaelibacterium sp. and the Roseburia sp. (Kho and Lal, 2018). Microbial diversity in tumour tissue in CRC has also experienced changes.  Other bacteria which is identified to have an association with CRC includes enterotoxigenic Bacteroides fragilis which was observed in 90% of CRC patients and Enterococcus faecalis. Both are observed to have a higher proportion in CRC cases as compared to the normal control. (Mima et al., 2017; Cheng, Ling & Li, 2020)The changes in the microbial community also provides insights of how the patients progressed, an increase of Fusobacterium nucleautum isnormally linked to a worse prognosis. (Cheng et al., 2020) Furthermore, fungal composition has also changed in the CRC patients. Although there is no new species or loss of a species observed, 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.

We have now known that the gut microbiome changes drastically in CRC patients. However, there is currently no known correlation between these changes and the initiation, development or metastasis of CRC. Several mechanisms were suggested. Firstly, inflammation. The gut microbiome itself has been found to relate with inflammatory diseases, such as Crohn’s disease and ulcerative colitis which are two major inflammatory bowel diseases. (Shreiner et al., 2015; Anon, n.d.) Chronic inflammation was thought to be one of the reasons to the initiation of cancer due to the increased risk of developing colorectal adenomas. (Lucas, Barnich and Nguyen, 2017) From the above, it is known that the gut microbiota is involved in shaping and building the immune system. The changes in the gut environment due to inflammation may lead to increased signalling by the microorganisms, forming a positive loop to enhance the immune signalling. (Wong & Yu, 2019) Butyrate was shown to act in anti-inflammation, by reducing inflammatory cytokines such as nuclear factor-κB. It is a transcription factor which further regulates other signalling molecules of the immune reaction TNF-α, IL-1b and T cell receptor-α and MHC class II molecules. (Canani et al., 2011)Butyrate can also binds with some G-protein coupled receptors which can be found on immune cells and thus may be able to activate leucocytes. (Canani et al., 2011) Animal studies has shown that the production of SCFA of obese mice differs from lean mice or germ-free mice, with an increased production of butyrate and acetate. (Davis, 2016)

Next, obesity, which has led to change in the gut microbiota composition. Obesity is classified as a low grade inflammation and a common risk factor across many cancers.(Wong & Yu, 2019) In human study, it is found that there is an increase proportion of Firmicutes and a huge decreased of Bacteroides.(Davis, 2016)The changes in microbiome is thought to contribute to the impact of immune health due to dysbiosis of gut microbiota. Moving on from that, in obese patients, their metabolism has been greatly affected. The gut microbiota plays an undeniable role in digestion and metabolism. The metabolites of gut microbiota can provide energy and acts as core element for other biochemical reactions such as acetate in gluconeogenesis and lipogenesis in liver which is by-product of fermentation of gut microbiota. Furthermore, several bacteria species can induce the immune reaction, for instance, enterotoxigenic Bacteroides fragilis produces toxin and trigger nuclear factor-κB signalling and IL-17 signalling.(Wu et al., 2009), Escherichia and Campylobacter spp. produce cytolethal distending toxin and interfere with cell division, inducing double stranded DNA breaks, contributing to genomic instability. (Wong and Yu, 2019)

Studies on gut microbiome and CRC have been challenging as it is very difficult to replicate the microbiome environment as well as the tumour environment in vitro or in animal models.  Some of the key reasons are due to the diversity of the gut microbiome and the complex interactions within the gut environment and tumour microenvironment which changes drastically overtime. With the advancement of sequencing technology such as 16s ribosomal RNA sequencing and 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) scientists are keen to learn the role of gut microbiome in CRC and how can the findings translate into clinical diagnosis, prognosis and most importantly, treatment of CRC to improve the survival rate and life quality of the patients.

References:

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