Cancer – What’s Microbiome Gut to Do with It?

by Ryan Mateja, PhD

Scientists are just starting to understand the impact all microorganisms in the human body have on health and disease. These microorganisms live in a symbiotic relationship with their host (e.g. you), and are affected by diet, nutrition status, medications, genetics and other factors. Therefore, each of us has our own personal microbiome which acts together as a complex variable that influences our physiology and pathophysiology. In a recent blog post we discussed some of the ways the microbiome influences the brain and also how it is being studied as a future drug delivery system. In this article we will focus the discussion on some of the complex ways the microbiome can affect cancer development.

Influence from a singular bacteria: H. pylori

For decades, it was thought that stress was the main reason a person would get a peptic ulcer. However, Barry Marshall, a Doctor from Australia, was convinced that the medical community was wrong and it actually wasn’t stress that caused stomach ulcers. From biopsying ulcer patients and culturing the organisms in the lab, he traced ulcers and stomach cancer to a specific bacterium, Helicobacter pylori (H. pylori). After conventional methods of trying to prove his hypothesis failed (mice are not affected by H. pylori and experiments on humans are illegal), he drank a petri-dish full of H. pylori with the hopes of giving himself an ulcer to support his theory. Over the next few days he vomited, had bad breath and experienced terrible gastritis. A little over a week later he cultured his own stomach and confirmed that H. pylori had indeed colonized his stomach, which finally showed that bacteria were the underlying cause of stomach ulcers.

microbiome helicobacter

Presence of H. pylori in the stomach increases risk of cancer. The detailed mechanism and role of the bacteria in carcinogenesis is not known.

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Since then, it has been found that over 50% of people have H. pylori in their upper intestinal tract, of which 80% show no symptoms at all. It is currently unknown what causes some people with H. pylori infection to be asymptomatic and what causes approximately 1-3% of chronically infected people to ultimately develop stomach cancer.1 It is known though, that while H. pylori alone is not sufficient to cause cancer, it is the strongest established risk factor for developing stomach cancer.2 In addition to other factors like diet and genetic polymorphisms, the interaction between how the other residents of the microbiome influence H. pylori-induced pathogenesis is under intense investigation. Furthering the intricacy of the H. pylori-cancer connection is the fact that studies show that the bacterium actually lowers the risk of esophageal adenocarcinomas.3 So even when there is a clear relationship between a specific bacterium and cancer, how that bacterium actually interacts with an individual’s microbiome and how it might influence other organs, involves convoluted processes.

Influence as a whole: a dystopic microbiome

Rather than being caused by a single pathogen like distal stomach cancer, it appears as if colorectal cancer is largely influenced by a dysbiotic microbiome. Evidence of this comes from multiple studies which show that rodents who are germ-free (without any microorganisms in or on them) or rodents being treated with wide-spectrum antibiotics have significantly less tumors in different experimental models of colorectal carcinogenesis.4 Compared to patients without colorectal cancer, patients with colorectal cancer have been shown to have significantly increased dysbiosis mainly due to changes in the dominant and subdominant species in their intestinal microbiota. In one study, the dysbiotic changes included an increase in the Bacteroides population in cancer patients, along with elevated IL-17 producing cells in the mucosa.5 IL-17 cells are pro-inflammatory cytokines produced by T-helper cells which recruit immune cells to sites of inflammation as an immune response and are known to play a role in accelerating tumor progression.6 Therefore, the dysbiosis (partially due to increased Bacteroides) in colorectal cancer patients is thought to negatively impact the body’s immune response and exacerbate the disease.

Dysbiosis describes imbalance or maladaptation due to impaired microbiota. When normally dominating species underrepresent microbiome, the outcompeted or contained species increase numbers to fill the void

microbiome gastrointestinal track

Influence outside of the gut: the vaginal microbiome

So clearly the gastrointestinal microbiome plays a role in cancer, but what about microbial colonies in other parts of the body? It has been established that a well-balanced vaginal microbiome helps prevent vulvo-vaginal infections, but recent research is now starting to also link the vaginal microbiome to the risk of gynecologic cancers.7 Similar to the gut microbiome, changes in the vaginal microbiome might play a role in disease progression by increasing inflammation or altering the immune response to pathogens. The most convincing evidence comes from studies which investigate the risks of human papillomavirus (HPV)-induced cervical cancer. Women who have been infected with HPV have been shown to have microbiomes with greater bacterial diversity, and a study looking at twins found higher rates of HPV in individuals with greater vaginal microbiome diversity.8 The vaginal flora also has been shown to alter the rate of clearance of HPV, and subsequently the risk of developing HPV-associated malignant transformation. Furthermore, studies have correlated specific bacterial species to the risk of cervical intraepithelial neoplasia and cervical cancer.8

Future directions

The intricacy of the relationship between the microbiome and cancer cannot be understated. Not only do changes in single pathogens and/or the entire intestinal microbiota play a role in carcinogenesis, there are other non-intestinal microbiomes that influence cancer risk. While decoding this relationship is daunting, the knowledge gained from such analysis will undoubtedly be useful as an offensive tool. Techniques to measure the makeup of the microbiome to identify specific biomarkers which accurately detect cancer are already being studied, as are different ways we can modify the microbiome to fight or proactively reduce the risk of certain cancers.9,10 Perhaps, rather than elucidating a complex mechanism that can exacerbate cancer development, studying the microbiome should be thought of as investigating a multifaceted way to prevent, fight and detect cancer.

References:

  1. Fox JG, Wang TC. Inflammation, atrophy, and gastric cancer. J Clin Invest. 2007 Jan;117(1):60-9.
  2. Brenner H, Rothenbacher D, Arndt V. Epidemiology of stomach cancer. Methods Mol Biol. 2009;472:467-77.
  3. Islami F, Kamangar F. Helicobacter pylori and esophageal cancer risk: a meta-analysis. Cancer Prev Res (Phila). 2008 Oct;1(5):329-38.
  4. Schwabe RF, Jobin C. The microbiome and cancer. Nat Rev Cancer. 2013 Nov;13(11):800-12.
  5. Sobhani I, Tap J, Roudot-Thoraval F, et al. Microbial dysbiosis in colorectal cancer (CRC) patients. PLoS One. 2011 Jan 27;6(1):e16393.
  6. Lippitz BE. Cytokine patterns in patients with cancer: a systematic review. Lancet Oncol. 2013 May;14(6):e218-28
  7. Chase D, Goulder A, Zenhausern F, et al. The vaginal and gastrointestinal microbiomes in gynecologic cancers: a review of applications in etiology, symptoms and treatment. Gynecol Oncol. 2015;138:190-200.
  8. Champer M, Wong AM, Champer J, Brito IL, Messer PW, Hou JY, Wright JD. The role of the vaginal microbiome in gynaecological cancer. BJOG. 2017 Mar 9.
  9. Bultman SJ. The microbiome and its potential as a cancer preventive intervention. Semin Oncol. 2016 Feb;43(1):97-106.
  10. Wang X, Kaczor-Urbanowicz KE, Wong DT. Salivary biomarkers in cancer detection. Med Oncol. 2017 Jan;34(1):7.