As NCI marks its 50th anniversary in 2021, it gives us an opportunity to look back at how far the cancer research field has come. The Center for Biomedical Informatics and Information Technology (CBIIT), especially, has seen exponential growth within our specialized areas of bioinformatics, data science, and IT. Big data, artificial intelligence, computational biology—all have helped to advance cancer research today.

Understanding the impact of the microbiome on human health is an emerging area of research that has received a significant boost from bioinformatic platforms such as the Informatics Technology for Cancer Research (ITCR)-supported QIIME 2, a widely used tool for analyzing communities of microorganisms using their DNA sequences.

But the idea of a microbiome and its impact on health and disease started more than 100 years ago. Elie Metchnikoff (1845–1916), a Russian-born microbiologist, was one of the first investigators to identify a link between the microbiome and the development of chronic diseases of aging, such as cancer. He postulated that individual species of bacteria might have distinct effects on the host immune system. This idea is now one of the most intensely researched areas in tumor immunology today and is helping to inform investigations into the mechanisms underlying cancer and response to immunotherapy.

With recent advances in Next Generation Sequencing, multi-plex transcriptomics, high throughput proteomics and metabolomics, coupled with gnotobiotic and computational modeling, researchers are digging even deeper into the molecular mechanisms of disease and expanding on Metchnikoff’s early vision of the microbiome. Ultimately, we hope to use this information to find new strategies to improve the treatment of individual cancers by tailoring therapy to each patient’s unique needs.

What is the Microbiome and Why Does it Matter?

Our bodies play host to a wide variety of bacteria, viruses, fungi, and archaea—all of which fall under the category of microbiota. Most of these microbes (about 97%) are bacteria found in the colon, with smaller numbers found on the skin, in the lungs, and in other parts of the digestive system. Their numbers are formidable and are estimated to be similar to the number of cells in the human body at any given time (about 30 trillion). Their collective genetic capacity (the metagenome) contains about 100-fold more genes than the human genome.

The gut microbiome has mostly beneficial functions, preventing the invasion of pathogens, producing essential nutrients, and aiding in the development of host organs, such as components of the immune system and the central nervous system, which depend on a carefully balanced bacterial community. However, sometimes this balance can become disrupted (a state called “dysbiosis”) and cause pathogenic interactions within the host that can extend far beyond the intestine and influence susceptibility to various chronic diseases, such as cancer.

Not All Microbiomes Are the Same

Genomic advances have led to a flood of new information about the unique commune that makes up our microbiota. Deciphering the genes that comprise these microorganisms has given us further insight into the human microbiota and how they have co-evolved with their human hosts since ancient times. Studies have revealed that those early versions of microbial gastrointestinal communities are not the same as our microbiota today. Still, their symbiotic relationship with us has remained similar across the ages.

Maintaining a balanced and diverse microbiota has been linked to good health, and just as our microbiome has evolved over generations, marked changes occur as we age. Moreover, this vast network of microorganisms differs among healthy individuals and between individuals with and without cancer, presenting challenges for determining whether these changes are a cause or consequence of disease.

Specific changes in our microbiome have been implicated in the development of some cancers (including gastric, colon, cervical) and changes in the microbiome can alter interactions with other factors (such as infections, immune responses, diet, smoking status, and environmental exposures) that increase the risk for other types of cancer.

Because each person’s microbiome is unique but easily changeable, it’s being examined in cancer research for its potential role in precision oncology. Studies seek to identify the molecular mechanisms that link host-microbiome interactions with disease susceptibility, diagnosis, prevention, and response to therapies. These interactions can then be exploited through the use of medications specifically targeted to the individual to stop or slow the progression of cancer.

How Data are Helping to Unlock the Microbiome’s Impact on Cancer

Today, researchers are generating large-scale data sets of increasing size and complexity. Driven by recent advances in sequencing and other cell analysis tools, as well as a significant reduction in the cost of these technologies, this flood of data is now helping to inform research into the microbiome.

Cancer-focused bioinformatics may hold the key to unraveling the microbiome’s impact on cancer. Multi-omic data studies allow researchers to simultaneously identify carcinogenic alterations in host cells (mutational, protein, or metabolic) and link them to microbial changes and interactions.

For example, colorectal cancer has been linked to imbalances in gut microbiota. Antibiotics, diet, or aging can favor “blooms” of certain bad bacteria, such as colibactin-producing E. coli, which cause mutations in host cells and create an environment that allows tumors to grow and spread.

On the other hand, the microbiome also offers ways to help combat certain cancers. A diet rich in fiber has been shown to increase the number of certain beneficial bacteria and inhibit the development of colorectal cancer. In looking at the mechanisms underlying this connection, researchers have identified one microbial metabolic byproduct of dietary fiber, called butyrate, that is key to the protective effects of fiber. But butyrate is a paradox. It helps provide energy, essential for sustaining normal gut cells but also can inhibit cancer cell growth. Researchers are now investigating how butyrate may prevent tumor initiation or progression and, especially, how the butyrate effect might work (or not work) in people with a genetic predisposition for colon cancer.

What This Might Mean for Future Cancer Therapy

We’re only just beginning to understand the relationship between the microbiome and cancer. Manipulating the microbiome’s composition and function could lead to entirely new ways of treating cancer by decreasing tumor-promoting bacteria or boosting tumor-protective bacteria.

A number of such strategies are being studied, including synthetic biology, in which bacteria are bioengineered to target tumors. These “trojan horses” can be used to carry therapeutic cocktails directly into cancer cells to stop or slow the spread of cancer.

Other approaches are looking at targeted immunomodulation to boost the body’s immune system so it better recognizes cancerous cells. Antimicrobial therapy already is proving effective in preventing infection by major human papillomavirus serotypes and hepatitis B virus, and, in turn, preventing urogenital, cervical, head and neck, and liver cancers. Additional promising research is looking at fecal microflora transplantation as a way to improve immune checkpoint inhibitor therapies.

Mapping an individual’s microbiome also will enable us to devise more precise diagnostic and treatment strategies for individual patients. This would allow us to predict how someone will respond to chemotherapy or immune therapy and give us insight into which treatments will work best and at what time. For example, we know the effectiveness of some chemotherapies can be altered by metabolism in the gut’s microbiome.

With advanced computational pipelines, we may be able to identify patients with microbiomes that actually improve therapy response. In the future, it may be possible to analyze a simple stool sample and tell whether a patient will respond well to a therapy. Or, better yet, we may be able to alter that patient’s microbiome with a pro/prebiotic, a phage, or a targeted antibiotic to improve the efficacy of a chosen therapeutic by 10-fold.

These and other strategies may, for the first time, allow clinical investigators to treat developing tumors not only by targeting cancer cells directly, but by altering the patient’s resident microbiome, ultimately leading to new types of cancer therapies.

Data science undoubtedly will help fuel these advances. In an upcoming blog, we’ll examine this area of research in greater detail, including how tools, such as QIIME 2, a software platform for microbiome analysis, are being applied to cancer research.

Sources

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Helmink, B.; Wadud Khan, M.A.; Hermann, A. The microbiome, cancer, and cancer therapy. Nat Med, Vol. 25:377–388, 2019.

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Arthur, J.C. Microbiota and colorectal cancer: colibactin makes its mark. Nat Rev Gastroenterol Hepatol 17:317–318, 2020.