The bacteria that aggravate colorectal cancer actually come from the mouth?

More and more cancers are found to be related to bacterial or viral infections. HPV can induce cervical cancer, hepatitis B and C are related to liver cancer, and Helicobacter pylori can aggravate gastritis and even cancer. Through HPV vaccination, the incidence of cervical cancer in the population has been greatly reduced, and taking antibiotics to kill Helicobacter pylori can also effectively treat gastritis/gastric ulcers. Many scientists even believe that there are more cancers caused by infection with pathogens, but we have not yet found the culprit.

A new role in colorectal cancer

As the second most deadly cancer, colorectal cancer causes 1.9 million cases and 930,000 deaths worldwide each year[1]. Scientists are eager to know whether there is any bacteria or virus that is related to the onset or progression of colorectal cancer.

Figure 1. Global cancer incidence (left) and mortality (right) in 2020. The red box represents colorectal cancer (picture provided by the author)

The colorectum is located at the end of our intestines, where the concentration of intestinal flora is the highest. There are some carcinogenic microorganisms in the intestinal flora, such as Bacteroides fragilis and pathogenic Escherichia coli. Some toxins they secrete can damage cell DNA. When the intestinal mucosa is damaged, these toxins may come into contact with intestinal epithelial cells, induce inflammation, and even cell cancer. In addition, some intestinal bacteria can weaken the efficacy of cancer treatment drugs.

Figure 2. Schematic diagram of intestinal structure (illustration provided by the author)

If we can find out which intestinal bacteria or bacteria are inducing the canceration of intestinal cells, and then develop targeted drugs or vaccines to eliminate them, can we reduce the incidence of colorectal cancer or slow the rate of cancer development?

Scientists have analyzed the differences in intestinal flora between a large number of colorectal cancer patients and healthy people. They found that a type of oral bacteria called Nucleotide Bacillus is present at higher levels in the intestinal mucosa/intestinal epithelium and even in cancer lesions of colorectal cancer patients. Patients with high levels of Nucleotide Bacillus have worse chemotherapy responses and shorter average life expectancy[2].

How oral bacteria survive in the gut

Nucleotide bacteria appear and colonize our mouths when we are one month old. By the time we are one year old, they have become the dominant strain in our mouths. As the most common bacteria in the mouth, they usually coexist peacefully with us, but they can also do harm. Scientists have long discovered that they can induce and aggravate periodontitis[3], but have never linked them to colorectal cancer.

One of the main reasons is that the oral flora, including Bacillus nucleatum, are not adapted to the living environment of the intestine. The oral flora is accustomed to living in a neutral pH/high oxygen concentration environment. Although oral flora will follow food into the gastrointestinal tract during the swallowing process when we eat and drink, only a very small number of them can survive in the intestine after experiencing low pH gastric acid, low oxygen, and competition from intestinal microorganisms. Most oral strains are quickly excreted or die, so Bacillus nucleatum is rarely detected in fecal samples.

Surprisingly, Bacillus nucleatum can colonize in the intestines of patients with colorectal cancer. During the process of replication and proliferation, tumor cells change the structure of glycoproteins in the tumor microenvironment, and a large amount of acetylgalactosamine accumulates. This is a glycoprotein that Bacillus nucleatum is good at adhering to. They grab this glycoprotein and use it to provide energy for themselves, so they can live well in the tumor.

Cancer cells’ accomplices: three poisonous blades

Not only do the nuclease-bearing bacteria take up residence in tumors, they also form a mutually beneficial symbiotic relationship with them, accelerating tumor progression in the following ways:

(1) Nucleic acid bacteria can change the expression of some key proteins and signal pathways in tumor cells and promote tumor cell replication . This will affect the therapeutic effect of chemotherapy and make the tumor more likely to recur.

(2) Nucleic acid bacteria also change the immune cell response in the tumor microenvironment , causing T cells that clear tumors to retreat, while inflammatory cells that promote cancer cell growth (such as neutrophils) become popular, creating an immune environment that helps cancer cells proliferate.

(3) In addition, nuclease-bearing bacteria can help cancer cells metastasize , making colorectal cancer more likely to metastasize to the liver or lymph nodes, and making it more difficult to eliminate the cancer.

With the above abilities, Bacillus nucleatum can also colonize in breast cancer/pancreatic cancer/esophageal cancer lesions through blood circulation and aggravate the deterioration of these cancers. How can we stop this evil Bacillus nucleatum and help treat cancer?

Bringing new perspectives to cancer treatment

The first is to detect Bacillus nucleatum early. For example, the number of Bacillus nucleatum in feces and the concentration of antibodies against Bacillus nucleatum in the blood are detected. Many scientists suggest that Bacillus nucleatum be used as an indicator for colorectal cancer. If more Bacillus nucleatum is found in the intestinal flora of patients, then carcinoma in situ may have occurred, which will satisfy the growth of Bacillus nucleatum in the intestine. These patients should be examined as early as possible. Early detection and early treatment are the best means to intervene in cancer.

Schematic diagram of colorectal cancer (picture from Tuchong.com)

The second approach is to eliminate Bacillus nucleatum in cancer patients in a targeted manner, such as using antibiotics. However, this treatment method is too radical and will destroy a large number of symbiotic bacteria. Scientists are now focusing on developing vaccines against Bacillus nucleatum or its surface proteins [4] to stimulate our own antibodies to neutralize Bacillus nucleatum, prevent them from adhering to intestinal glycoproteins, and multiply in tumors. The use of vaccines against Bacillus nucleatum in combination with chemotherapy for colorectal cancer patients may improve the treatment effect and reduce the chance of cancer recurrence.

Of course, considering the effectiveness and side effects, the development of this vaccine is difficult. For example, will the nucleic acid bacillus vaccine destroy the balance of oral flora or produce cross-reactions with other probiotics? But considering the priority and mortality of cancer, we can't stop trying. This also reminds us to screen the microorganisms in other types of cancer lesions and find the symbiotic bacteria or fungi in them, which may play a breakthrough role in improving the efficacy of cancer.

Don’t underestimate our oral health. In addition to cancer, oral flora is also closely related to metabolic diseases, digestive diseases, and systemic diseases. Maintaining oral hygiene and treating oral diseases early is really a good lifestyle habit with low cost and high return.

References

1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries [published correction appears in CA Cancer J Clin. 2020 Jul;70(4):313].

2. Castellarin M, Warren RL, Freeman JD, et al. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res. 2012;22(2):299-306.

3. Socransky SS, Haffajee AD, Cugini MA, Smith C, Kent RL Jr. Microbial complexes in subgingival plaque. J Clin Periodontol. 1998;25(2):134-144.

4. Holt RA. Oncomicrobial vaccines: The potential for a Fusobacterium nucleatum vaccine to improve colorectal cancer outcomes. Cell Host Microbe. 2023;31(1):141-145.

This article is a work supported by Science Popularization China Starry Sky Project

Author: Zhao Bei

Reviewer: Wang Qiang (Deputy Chief Physician, Department of Gastroenterology, Peking Union Medical College Hospital)

Produced by: China Association for Science and Technology Department of Science Popularization

Producer: China Science and Technology Press Co., Ltd., Beijing Zhongke Xinghe Culture Media Co., Ltd.