“Our rapid understanding of the human microbiome and its connection to both health and disease states is the beginning of a new frontier of medical discovery. Gut microbes interact with both local tissues and downstream organs to promote cancer as well as protect us from cancer. We are ‘superorganisms’ of human and microbial cells in a symbiotic relationship.”
- Steven J. O’Day, MD, ASCO Expert
Did you know that there are 10 microbe cells for every human cell in your body? An estimated 100 trillion microorganisms or microbes (bacteria, fungi, viruses and others) dwell in your gut alone! This raises a philosophical question: Who really calls the shots, the microbe tenants or the human landlord?
In fact, the microbial community (microbiome) has such intricate and profound effects on human health that it is often referred to as the “hidden organ.” By evolving together over thousands of years, these indwelling microbes and their human hosts developed a mutually beneficial relationship. Moreover, the relationship is so intertwined that one can think of the human body as one superorganism made of human and microbial cells.
From birth through the early years of life, countless different bacteria colonize the body. The composition of the microbiome varies from one person to the next, possibly due to a mix of genetic, environmental, and lifestyle factors such as diet, medication use, and exercise. Further, there are distinct microbial communities in various organs of the body and even in distinct parts of the same organ.1,2
The gut is home to more than 1,000 microbial species, which collectively harbor a hundred times more genes than the human genome. The gut microbiome plays a critical role in the development of immune defenses, including protection from invading pathogens, inflammation, and cancer. Our “good bugs” also help the body absorb nutrients from food, and they produce essential vitamins K and B12.1 The “bad bugs,” however, can negatively affect health and lead to disease.
Microbiome Imbalances Linked to Growing List of Diseases
Researchers have found that the microbiome make-up of healthy people differs from that of people with inflammatory bowel disease, gum disease, obesity, type 2 diabetes, autism, allergies, and various types of cancer. Disruption of the microbial community is possibly a risk factor for these diseases. Some experts argue, however, that the imbalance in the microbiome may be a consequence of disease, rather than its trigger.3
When it comes to cancer, the microbiome can be both friend and foe. While certain microbes can cause or promote cancer growth, other microbes seem to bolster the body’s immune defenses against cancer or help cancer treatments work better.
Role of Microbiomes in the Development of Cancer
It is estimated that microbes cause up to 20% of all cancers worldwide. Most of those cancers are associated with a handful of pathogens: human papillomavirus (cervical, genital and head and neck cancers), Helicobacter pylori (stomach cancer), hepatitis B virus and hepatitis C virus (liver cancer). Emerging research suggests that various other microbes promote development or progression of cancers of the skin, breast, ovarian, bladder, gallbladder, kidney, lung, urogenital, liver and pancreas, and certain types of lymphoma.
Colon cancer development is associated with a range of different bacteria or bacteria byproducts (metabolites). Compared to normal colon tissue, colon tumors are enriched by Fusobacterium nucleatum and certain subsets of Escherichia coli and Bacteroides fragilis.1
Bacteroides fragilis promotes cancer by releasing an enzyme that damages the intestinal lining, resulting in inflammation. Fusobacterium nucleatum stimulates inflammation and shields colon tumors from the immune system. Furthermore, as a result of the consumption of red meat, Fusobacterium nucleatum produces a chemical, hydrogen sulfide that can result in DNA damage and genomic instability in the cells lining the colon. This increases the risk of colon cancer, particularly for people who have a deficiency in the DNA repair machinery. Two additional bacterial byproducts, colibactin and cytolethal distending toxin (CDT), also cause DNA damage and are associated with development of colorectal, gastric, and gallbladder cancers.2
Meanwhile, there is a growing recognition that gut bacteria may contribute to the onset of cancers beyond the gastrointestinal tract by releasing toxins and metabolites into the blood circulation. In addition, it is plausible that microbiomes at other sites in the body also affect the onset of cancer. For instance, the microbiome of the mouth may influence the development of head and neck cancers.4
Another indirect way the microbiome promotes tumor growth is through its interaction with the immune system. For instance, certain species of bacteria, including Bacteroides fragilis and segmented filamentous bacteria (SFB) activate helper T cells Th17. The Th17 immune response is important for protection against intestinal pathogens, but it can also lead to chronic inflammation, which contributes to development of cancer.5 Interestingly, other gut bacteria, such as Lactobacillus and Bifidobacteria (common ingredients of yogurt) limit Th17 immune responses and cancer development. They do so by activating certain regulatory T cells.
In addition to single pathogens, changes in the composition of the microbiome as a whole can also promote cancer development.2,6 One of the best-studied conditions that leads to global changes in the gut microbiome as a whole is obesity, which is associated with a decreased diversity of species in the microbiome. Microbiome changes can also occur through changes in diet, immune responses to inflammation, or infection. The biological mechanism underlying changes in microbiome composition, however, are not yet understood.
Read Part II of this series, where we’ll talk more about the “good bugs” that help us fight cancer.
1. Bultman SJ: The microbiome and its potential as a cancer preventive intervention. Semin Oncol 43:97-106, 2016
2. Schwabe RF, Jobin C: The microbiome and cancer. Nat Rev Cancer 13:800-12, 2013
3. Viaud S, Daillere R, Boneca IG, et al: Gut microbiome and anticancer immune response: really hot Sh*t! Cell Death Differ 22:199-214, 2015
4. Shahanavaj K, Gil-Bazo I, Castiglia M, et al: Cancer and the microbiome: potential applications as new tumor biomarker. Expert Rev Anticancer Ther 15:317-30, 2015
5. Russo E, Taddei A, Ringressi MN, et al: The interplay between the microbiome and the adaptive immune response in cancer development. Therap Adv Gastroenterol 9:594-605, 2016
6. Pevsner-Fischer M, Tuganbaev T, Meijer M, et al: Role of the microbiome in non-gastrointestinal cancers. World J Clin Oncol 7:200-13, 2016
7. Poutahidis T, Kleinewietfeld M, Erdman SE: Gut microbiota and the paradox of cancer immunotherapy. Front Immunol 5:157, 2014
8. Zitvogel L, Ayyoub M, Routy B, et al: Microbiome and Anticancer Immunosurveillance. Cell 165:276-87, 2016
9. Gopalakrishnan V SC, Reuben A, et al. : Association of diversity and composition of the gut microbiome with differential responses to PD-1 based therapy in patients with metastatic melanoma. J Clin Oncol 35, 2017
10. Vetizou M, Pitt JM, Daillere R, et al: Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350:1079-84, 2015
11. Sivan A, Corrales L, Hubert N, et al: Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350:1084-9, 2015
12. Pitt JM, Vetizou M, Waldschmitt N, et al: Fine-Tuning Cancer Immunotherapy: Optimizing the Gut Microbiome. Cancer Res 76:4602-7, 2016