Unpicking the Complexities of the Cancer Microbiome

Understanding the relationship between cancer and the microbes that call our bodies home could transform the way the disease is managed in the future.

The human microbiota is composed of trillions of microorganisms that live in and on our bodies – including the skin, gut and oral cavity. These communities – which include bacteria, eukaryotes, viruses and archaea – are extremely diverse and vary enormously from person to person. They are also unstable and can change in response to environmental factors, such as diet or drugs.

“We’re learning that having a diverse microbiota is important for maintaining our health,” says Stephen Robinson, group leader at the Quadram Institute in Norwich, UK. “And disturbances to that diversity can have detrimental effects.”

Rapid advances in next-generation sequencing technologies have made it possible for researchers to examine the make-up of the human microbiota in unprecedented detail and explore its impact on our health.

“It’s almost like there’s this ‘hidden organ’ that’s always been there,” says Michael Burns, assistant professor at Loyola University, Chicago, USA. “And now everyone is chomping at the bit to figure out what role it could be playing in the pathogenesis, treatment and etiology of the disease they’re interested in.”

And the field of cancer is no exception. In recent years, there has been an explosion of studies examining the relationship between the microbiota and the development of the disease or its response to treatment. As a potentially modifiable factor, this research is opening up a wealth of new opportunities for cancer prevention and treatment.

Lessons from ecology

Koch’s postulates, published in 1890, set the gold standard for establishing whether a certain microorganism causes a particular disease. Aligned with this paradigm, much of the early research in this area was heavily invested in searching for cancer-causing microbes. Despite this, the number of organisms – such as Helicobacter pylori and the human papillomavirus (HPV) – known to cause cancer remains small.

“That approach turned out to be all wrong – it was a huge mistake,” explains Burns. “It’s actually the entire context of the microbial ecosystem that’s important.”

The availability of affordable high-throughput DNA amplification and sequencing technologies are providing researchers with the opportunity to characterize the microbiome and search for differences in the type and relative abundance of different species between healthy and disease states.

“It allows you to have a deep look at what’s there,” says Robinson. “But that opens up another minefield – you get so much information that it’s challenging to make sense of it all.”

While the human genome consists of around 23,000 genes, the gut microbiome encodes over three million genes. Studying the complex relationship between the thousands of different species in the microbiota and a disease state requires an ecological lens. As a result, the methods to estimate microbial diversity have rapidly advanced in recent years.

“The ecologists have been doing this kind of work for years,” notes Burns. “It’s just biomedical scientists who are now rediscovering the importance of these community dynamics.”

Potential mechanisms

The field is evolving at a rapid pace, with researchers uncovering distinct microbial signatures linked with the initiation and progression of different cancers. There is also growing evidence indicating a connection between the gut microbiota and the effectiveness and side effects of chemotherapy. Research also suggests that it can modulate the host immune response to tumors and influence response to cancer treatment, especially immunotherapies.

“We’re just at the beginning of our understanding of what a healthy microbiota is – and exploring ways for how we might rebalance it when it’s disturbed,” says Robinson. “It’s exciting because it’s a ‘black box’ that still needs to be explored from a basic science point of view.”

The microbiota may exert direct effects on cancer cells by modulating their internal circuity or have indirect effects via the manipulation of the immune system. However, the mechanisms proposed so far are highly speculative.

“What you’re actually dealing with is a really complicated feedback system where the microbes exert an influence on the host, and the host exerts an influence on the microbiota – and in some cases, something goes wrong and you end up with a pathogenesis,” says Burns. “Unpicking this massive spider web of how all these different things are connected turns out to be incredibly complicated.”

Spotlight on the gut

The gut microbiota is the most well-studied in relation to cancer. Its major function is to shape how we use nutrients and produce a host of metabolites – a lot of which will cross the intestine and circulate throughout the body and could affect the function of cells.

“Some of these metabolites could either help to drive cancer or protect us from it,” says Robinson. “In that way, disturbances to the microbiota could potentially affect a person’s risk of developing the disease.”

As well as surveying the gut microbiome, researchers can now use metabolomics to identify and quantify the metabolic products of the microbiota to improve understanding of its functional output.

“The field is moving away from asking ‘who’s there’ towards looking at ‘what can they do?” explains Robinson. “For example, while the microbiota of two people might look very different from a species perspective, they might actually be very similar in terms of the metabolites they produce.”

One recent study revealed how gut bacteria can fuel the growth of prostate cancers and their resistance to hormone therapy, by providing an alternative source of growth-promoting male hormones.

Modifying the microbiota

Despite the ongoing challenges, the tantalizing potential to manipulate the microbiota to prevent or treat cancer is continuing to fuel momentum in the field.

“The possibilities include treatment with probiotics or fecal transplantations to try and re-establish some type of normalcy in a person’s resident microbial communities,” enthuses Burns.

Burns’ laboratory is investigating the effects of different compounds – such as caffeine, nicotine, different types of fiber, chemotherapies or other drugs – on cultured gut microbes collected from healthy donors. While he acknowledges the approach is simplistic, for instance, it doesn’t take into account the effects of the immune system or the host response, he hopes it will provide clues for how to modulate the microbiota in beneficial ways.

“We can see that certain drugs or compounds can change things wildly,” he says. “And we need to know more about that so that we can use it to tweak the microbiota and push it in one direction or another.”

Robinson’s team is investigating how antibiotics can disturb the microbiota and how that might influence breast cancer progression. Their ultimate goal is to develop a live biotherapeutic that can help rebalance the microbiota to help improve patient outcomes and reduce the side effects from treatment.

“Our animal studies show that using antibiotics accelerates disease progression, so it’s not a good thing,” he says. “We’re now at the early stages of recruiting people with breast cancer to understand how their microbiota changes through their treatment journey.”

Transformative potential

Developing a better understanding of the relationship between the microbiota and cancer will help doctors to personalize treatment and could also lead to ways to modify the microbiota to improve patient outcomes.

“I would be surprised if the regular collection and analysis of microbial samples doesn’t become a routine part of care in the future,” predicts Burns.

But the field is still in its infancy, with huge gaps in knowledge that must be filled to unlock the potential rewards.

“I love working in this field because there’s so much that we still don’t know,” says Burns. “It’s the wild west of research right now – and I get to be part of that.”