The Potential of Gut Microbiota in Early Colorectal Cancer Detection

The human body, and particularly the gut, is home to over a thousand species of bacteria, fungi and viruses. While microbes in general often have a bad reputation for causing sickness and disease in humans, the many species residing in the gut — particularly the large intestine — have a symbiotic relationship with and play important, beneficial roles in the human body.

The gut microbiota, sometimes referred to as gut flora, gut microbiome, or colloquially ‘gut bacteria’ (despite the presence of non-bacterial species), is also regarded collectively as an oft-neglected endocrine organ. With the endocrine system’s responsibility of regulating cellular growth and repair, researchers considered that it is possible that the gut microbiota could have an influence on colorectal cancer development and growth.

What do we currently know about the relationship between our gut flora and colorectal cancer, and what are the possible applications in early cancer detection? Besides applications in cancer screening, we also explore the possibilities of restoring the balance of gut microbiota through dietary supplements, and if it has any cancer prevention benefits.

While different gut flora species may perform different functions, the microbiota collectively plays an important metabolic role, particularly in the fermentation of dietary fiber into short-chain fatty acids. These fatty acids are absorbed by the body to produce vitamin B and vitamin K, which are essential for maintaining the body’s energy levels and blood coagulation and wound healing respectively.

In the colon itself, the microbiota protects the large intestine’s epithelial lining from infection and inflammation. It also has immunologic effects — it stimulates immunoglobulin A (IgA) production, an antibody found in mucous secretions. IgA is the mucous tissue’s first line of defense against pro-inflammatory activity of commensal and pathogenic bacteria.

The microbiota also promotes anti-inflammatory cytokines and down-regulates proinflammatory cytokines, induces regulatory T cells that suppress immune responses, and are important in maintaining homeostasis, self-tolerance and preventing autoimmunity.

Because the gut microbiome is a key player in preventing inflammation in the colon, dysregulation of the gut flora population can weaken the protective layer and increase the likelihood of infection and inflammation in the colon, creating an environment that favors cancerous growth.

While ongoing research continues to investigate whether a causal relationship exists between the presence of certain gut microbiota species and colorectal cancer, multiple studies so far have at least established a correlation.

For instance, after comparing stool samples from colorectal cancer patients and healthy individuals, researchers have found that cancer patients not only have a lower microbiota diversity, but also a high abundance of Fusobacterium and Porphyromonas bacteria species. Beneficial microbe species such as Bifidobacterium, Faecalibacterium and Blautia also had reduced populations.

Of the different bacteria species, two in particular stand out in terms of their association with colorectal cancer.

Fusobacterium nucletum is a Gram-negative anaerobic bacteria that has been found to be highly expressed in colorectal cancer tissue, and has been associated with high microsatellite instability — one of the types of gene mutations that is known to cause colorectal cancer. The bacteria also correlates with lymph node metastasis in colorectal cancer patients.

Another well-known bacteria, Escherichia coli, or E. coli for short, is associated with the colon mucosa and is found to be more prevalent in colorectal cancer tissue. E. coli also encodes cyclomodulins, bacterial toxins that are able to regulate the eukaryotic cell cycle by inhibiting or promoting cell division and proliferation. Clinical studies have also shown that advance-stage colorectal cancer patients have a higher E. coli load, while experiments on mice have shown that the resultant tumor load in mice incubated with E. coli is higher.

While more evidence is needed to establish a causal relationship between gut microbiota and colorectal cancer, the known correlations do point to a possibility of using gut microbiota as colorectal cancer biomarkers.

For instance, microbiota could be used as a fecal marker for detecting colorectal cancer, such as by combining conventional fecal immunochemical tests (FITs) with fecal microbial markers for greater accuracy and testing sensitivity. One of the ways this can be done is by capitalizing on the abundance of F. nucletum and other bacteria to create a multitarget test, which has been shown in one particular study to increase the FIT sensitivity in detecting adenomas (benign colorectal tumors) from 73.1% to 92.3%.

If a microbiota imbalance skewed towards pathogenic microbes plays a part in promoting cancerous growth, it’s reasonable to guess that the opposite — increasing the populations of good bacteria — may help prevent it.

To date, many studies have found that introducing probiotics into the gastrointestinal system has several health benefits, though the mechanisms specific to colorectal cancer prevention are still unclear.

Probiotics, as defined by the International Scientific Association for Probiotics and Prebiotics, are “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host”. These live microorganisms are believed to confer cancer preventive benefits by altering the gut microflora, inactivating cancer-causing compounds such as inflammatory cytokines, inhibiting tyrosine kinase pathways, and regulating apoptosis and cell differentiation to stymie cell proliferation.

One study in particular investigated the effects of probiotics on cancer cell proliferation and metastatic invasion in mice in both in vitro and in vivo studies. The results of both cell culture and animal experiments showed that the probiotics had an inhibitory effect on the proliferation, invasion and migration of mouse colon cancer cells as compared to the control groups. The in vivo experiment also showed more apoptotic activity and immune cell infiltration into the tumor tissue, indicating a more active immune response. The success of these studies on the mouse model suggests that similar benefits could be achieved in humans and warrants further investigation.

This begs the question, should we consume probiotic supplements regularly?

While there isn’t an official stance on what the appropriate “dosage” of probiotics one should consume is, below are some foods — many of which are fermented products — that are rich in probiotics that can help supplement the gut microbiota and reduce the ratio of harmful bacteria. As with other diet components, these should be consumed in moderation and not in excess in order to reap the benefits.

• Yoghurt
• Sauerkraut
• Kimchi
• Pickles
• Kombucha

Alternatively, probiotics are also available in the form of oral supplements such as tablets, drinks and capsules.

Colorectal cancer remains one of the most treatable cancers if it is detected early enough. And while colonoscopy remains the gold standard in colorectal cancer detection, the invasiveness and discomfort from the procedure can act as a deterrent for average-risk individuals to get screened. Less invasive and more affordable methods such as fecal or blood tests may also pave the way for screening in younger at-risk individuals who are not yet eligible for conventional screening methods.

Earlier colorectal cancer screening and detection is potentially lifesaving, and individuals at above-average risk are encouraged to get tested.