Oral Bacterium has Unexpected Role in Colon Cancer

Colon cancer, though historically impacting older people, is now the leading cause of cancer death among young adult men and the second in young adult women. Despite its ancient existence, identified in Egyptian mummies by Dr. Michael Zimmerman in the 1970s, new insights into the triggers of colon cancer continue to emerge today.

The Microbiome and Colorectal Cancer

The trillions of bacteria living in our gut, known as the microbiome, are increasingly linked to various health issues, including colorectal cancer. Interestingly, recent studies show that the types and amounts of gut bacteria can change as the disease progresses, and may even affect treatment success. One particular surprise emerged when researchers found an unexpected abundance of Actinomyces odontolyticus, a bacterium normally found in the mouth, in the stool samples of early-stage colon cancer patients. This finding suggests that oral bacteria like A. odontolyticus might travel down the digestive system and potentially play a role in the early stages of cancer development, however, more research is needed to confirm this connection.

The Study

To dive deeper into this surprising connection, scientists conducted a study published in the Cellular and Molecular Gastroenterology and Hepatology Journal. They used three different approaches:

• Petri dish cultures: The researchers grew human colon cells in a lab environment and exposed them to the A. odontolyticus bacteria.

• Mini guts: The researchers created miniature versions of human guts, called organoids, and observed how the bacteria interacted with these tissues in a dish.

• Living models: The researchers studied mice to see if the presence of A. odontolyticus in the gut affected their health and risk of developing tumors.

By combining these techniques, the researchers aimed to understand how the presence of A. odontolyticus in the gut might contribute to the formation of colon cancer.

Main Findings:

When the researchers grew human colon cells in the lab and exposed them to the A. odontolyticus bacteria, they noticed an increase in inflammatory signals within the cells. Since inflammation is a well-known risk factor for colon cancer, this finding led them to investigate how A. odontolyticus might be triggering this inflammatory response.

While most bacteria act on cells via direct attachment to the cell surface, some gut bacteria release small spheres called “vesicles” that are internalized into cells via an engulfment process called endocytosis. The researchers found that A. odontolyticus employs this method, releasing membrane vesicles (MVs) containing potentially harmful factors such as bacterial proteins and toxins. When isolated and introduced to colon cells in the absence of bacteria, the MVs alone increased cellular markers for inflammation.

Because the MVs were found to induce host cell damage, the researchers were keen to understand they were operating. Using a combination of infection models and readouts for cell damage, the authors found that A. odontolyticus MVs move to the cell’s "powerhouse," formally known as the mitochondria. Once inside, the MVs disrupt the normal energy production process causing the creation of harmful molecules called reactive oxygen species (ROS). These unstable molecules are like tiny vandals, damaging the cell's DNA and creating an environment that can lead to cancer development (tumorigenesis), as shown in Figure 1. Additionally, this disruption can further contribute to inflammation, exacerbating the situation.

Figure 1. Membrane vesicles (MVs) are released from A. odontolyticus bacteria in the colon, and are taken into the colon cell via endocytosis. The MVs then move to the mitochondria, causing mitochondrial dysfunction and increased reactive oxygen species (ROS) production. Unstable ROS cause DNA damage which leads to inflammation and a tumor-promoting environment. Created by C. Cencer with BioRender

Future Directions:

This study opens a fascinating new chapter in our understanding of colon cancer, particularly in young adults. While much remains to be discovered about the disease's development, this research paves the way for exciting future investigations focused on the following principles:

• Unraveling the Mystery: Future studies should delve deeper into the specific components of A. odontolyticus vesicles that target the cell's power center and trigger harmful ROS production. This knowledge is crucial for identifying potential targets for future therapies.

• Antibiotic Treatments: Understanding how A. odontolyticus contributes to cancer might lead to the development of targeted antibiotics to eliminate this specific bacterium, similar to how some antibiotics are used to treat other bacterial infections.

• Beyond A. odontolyticus: This research adds to the growing body of evidence linking gut bacteria to various health conditions. Studying the role of other gut bacteria in colon cancer, particularly those previously linked to tumor growth reduction, could open even more avenues for potential treatments and prevention strategies.

In conclusion, this study sheds light on a surprising connection between an oral bacterium and colon cancer. While further research is needed, this discovery holds immense potential for improving our understanding of what triggers colon cancer development while potentially treating this complex disease.

Written by Caroline Cencer.

Edited by Iana Malasevskaia, MD.

References

1. Siegel RL, Giaquinto AN, Jemal A.  Cancer statistics, 2024. CA Cancer J Clin.  2024; 74(1): 12-49. doi:10.3322/caac.21820

2. Edwards E and Herzberg J.  (January 17, 2024). "Colon cancer is killing more younger men and women than ever, new report finds." from https://www.nbcnews.com/health/health-news/colon-cancer-deaths-younger-men-women-report-rcna134084.

3. David, A., Zimmerman, M. Cancer: an old disease, a new disease or something in between?. Nat Rev Cancer 10, 728–733 (2010). https://doi.org/10.1038/nrc2914

4. Cheng, W. Y., Wu, C.-Y., & Yu, J. (2020). The role of gut microbiota in cancer treatment: friend or foe? Gut, 69(10), 1867-1876. https://doi.org/10.1136/gutjnl-2020-321153 

5. Yachida, S., Mizutani, S., Shiroma, H., Shiba, S., Nakajima, T., Sakamoto, T., Watanabe, H., Masuda, K., Nishimoto, Y., Kubo, M., et al. (2019). Metagenomic and metabolomic analyses reveal distinct stage-specific phenotypes of the gut microbiota in colorectal cancer. Nat Med 25, 968-976. 10.1038/s41591-019-0458-7.

6. Agagunduz, D., Cocozza, E., Cemali, O., Bayazit, A.D., Nani, M.F., Cerqua, I., Morgillo, F., Saygili, S.K., Berni Canani, R., Amero, P., and Capasso, R. (2023). Understanding the role of the gut microbiome in gastrointestinal cancer: A review. Front Pharmacol 14, 1130562. 10.3389/fphar.2023.1130562.

7. Miyakawa, Y., Otsuka, M., Shibata, C., Seimiya, T., Yamamoto, K., Ishibashi, R., Kishikawa, T., Tanaka, E., Isagawa, T., Takeda, N., et al. (2024). Gut Bacteria-derived Membrane Vesicles Induce Colonic Dysplasia by Inducing DNA Damage in Colon Epithelial Cells. Cell Mol Gastroenterol Hepatol. 10.1016/j.jcmgh.2024.01.010.

8. Terzić, Janoš et al. Inflammation and colon cancer. (2010) Gastroenterology, 138; 6: 2101 - 2114.e5 https://doi.org/10.1053/j.gastro.2010.01.058

9. Nakamura, H., and Takada, K. (2021). Reactive oxygen species in cancer: Current findings and future directions. Cancer Sci 112, 3945-3952. 10.1111/cas.15068.

10. Dong X., Pan P., Zheng D.-W., et al. Bioinorganic hybrid bacteriophage for modulation of intestinal microbiota to remodel tumor-immune microenvironment against colorectal cancer. Sci Adv. 2020; 6eaba1590