Does your gut hold the key to cancer?
Octopus Springs, eight miles north of Old Faithful in Yellowstone National Park, is a bubbling pot of 91-degree, alkaline water covered in a floating film of grayish white silicate deposit called sinter. It is not home to birds or squirrels or foxes or any of the other feathered or furred creatures we associate with the park. It is, however, home to Aquifex, a pinkish-purple hydrogen-eating chemotroph that thrives in this toxic hot tub. We know this because in the 1980s, University of Colorado Boulder researcher, Norman Pace, pioneered techniques to determine what sorts of wee beasties are present in soups like Octopus Springs. Basically, he collected water with a homemade screen that looked like a furnace filter, chopped it up and compared the fragments of genetic material he found to a library of usual microbial suspects. Today Pace’s technique forms the basis for analyzing the microbes of another hot pot, namely your gut.
“Don’t poo-poo the microbiome,” says Andrea Dwyer, co-director of CU Cancer Center’s Colorado Colorectal Screening Program. Her words encapsulate the dichotomy of microbiome research: We are increasingly respecting its power even while continuing to chuckle behind our hands at the fact that it is indisputably icky and, to some, still seems like a fringe science.
Newsflash: It’s not fringe anymore. In 2012, fecal transplant became an accepted treatment for infection with the bacteria Clostridium difficile or C. diff, which releases toxins that attack the lining of the intestines leading to the condition of colitis. In 2013, the journal Nature reported that gut microbiota could influence brain activity and emotions. And further work has explored likely connections between the microbiome and conditions ranging from acne to obesity to autism to asthma to ulcers and more. Evidence is on the rise for a role of the microbiome in another disease: cancer.
“It’s right where immunotherapy was two years ago,” says Dwyer, who, in partnership with the organizations Fight Colorectal Cancer and the Cancer Research Institute, is exploring the role of the microbiome in colorectal cancer prevention. “Based on what we’re learning, the microbiome has astounding potential. We see opportunity and we just need to drive it ahead.”
But before exploring how CU researchers are driving microbiome research, you gotta know what it is.
WHAT IS THE MICROBIOME?
Have you ever thought that maybe we’re all just tiny little cells and Earth is really just a dot in the body of some giant, cosmic organism? Crazy, right? Well, it’s not so crazy to Escherichia coli. For this lovely little gram-negative, facultatively anaerobic, rod-shaped bacterium, your small intestine is the world. But E. coli is not alone in your gut. In fact, it makes up only about 0.1 percent of your “gut flora” or “gut biota” – the diverse population of single-celled creatures that call you home.
You live in harmony or at least indifference with the vast majority of these microorganisms. That’s for the best – the American Academy of Microbiology estimates that you may have as many as ten times the number of non-human cells in your microbiome as you have human cells in your body. In other words, you are composed of more them than you. Let’s look at this another way. The sum of your DNA codes for about 23,000 genes. A study in the journal Protein Cell shows that the genomes of the bacteria and viruses and archaea that make up your microbiome code for about 3.3 million genes. You like to think of yourself as human, but if you define your makeup by cell type, you are more precisely a colony of over 100 trillion independent microorganisms, each with its own strategies and goals, walking around inside a container of skin that happens to be topped by a three-pound bag of neurons sentient enough to be weirded out by this paragraph.
But again, these small collaborators on your journey of life are generally helpful. See, your 23,000 genes aren’t nearly enough to do all the things your body needs to do. Your gut biota help to digest indigestible things and supply your body with nutrients, while defending against colonization by less good biota. The microbiota of your respiratory system and lungs protect against diseases like cystic fibrosis, asthma and chronic obstructive pulmonary disease. Microbiota of the female reproductive tract protect against infection and can affect a baby’s immune system. Through these actions, your microbiome helps to regulate your metabolism and immune system, with trickle-down effects on nutrition, disease and even the physiology of your body itself.
Basically, you can think of yourself as a project manager. There are some things you can do – actually, your genes let you do about 23,000 “things”. But there are many things you can’t do, and for all these other functions, you “hire” the expertise of your microbiome. Far be it from this article to make sweeping political statements about the benefits of a diverse workforce, but let’s just say that at least when it comes to your microbiome, the more kinds, the merrier. The messy balance of many microorganisms all working together, in parallel or even against each other creates a kind of beneficial white noise that your body has evolved to depend on for far-reaching aspects of your well-being.
THE “GROUND FLOOR” OF MICROBIOME RESEARCH
Imagine you had one laboratory focused on the study of the microbiome in cancer. Now take that laboratory and
chop it into pieces. Distribute those pieces among dozens of researchers in the CU School of Medicine, CU Boulder, CSU and across the UCHealth hospital system. This is what microbiome research looks like at the University of Colorado Cancer Center – dozens or even hundreds of cancer researchers are interested in the microbiome, each looking at it from the perspective of their own expertise, many exploring aspects of the microbiome through small studies undertaken aspet projects. The sum is a rich and thriving research community that with many publications and findings is driving the national conversation about the microbiome and cancer…though you’d never know it because much of this work happens under the radar, at the grassroots level of passion projects and pilot grants. In a way, the community doing microbiome research at CU is like the microbiome itself – everyone working independently with results emerging organically from the population as a whole.
If there is a central hub of cancer microbiome research at CU, it may be the lab of Daniel Frank, PhD, assistant professor in the CU School of Medicine Division of Infectious Diseases and co-director of the UC Denver Microbiome Research Consortium (MiRC). This is not because he specializes in cancer research, but simply because he is one of the campus’s one-stop shops for analysis of any microbial community.
“Give us a sample and we’ll extract the nucleic acids and characterize the population,” Frank says, adding that he has “worked with every conceivable body site.”
In fact, Frank was a postdoc in the lab of Norm Pace, the researcher whose techniques first identified the extremophile microbes of Yellowstone hotpots. Now 30 years later, Frank has been instrumental in modernizing Pace’s strategies, which he uses to power the research of collaborators studying microbial influences on conditions ranging from Crohn’s disease to colitis and even cancer.
“Right now I’m thinking about metabolism and other things. Let me switch my brain over to cancer,” Frank said on the phone. When he did, Frank told a compelling story of the microbiome in colon cancer: At the University of Michigan, researchers exposed mice to an established procedure designed to create colon cancer. As expected, some of the mice developed cancer, whereas mice treated with antibiotics did not. Then they did something special – they transplanted the microbiomes of mice that did and did not develop colon cancer into a new set of mice. In these new mice, those with “good” microbiomes resisted cancers; mice with “bad” microbiomes overwhelmingly got cancer again. “This is a tantalizing clue that the gut microbiome participates in the formation of colon cancer,” Frank says.
He, along with Vijay R. Ramakrishnan, MD, Shi-long Lu, PhD, and John I. Song, MD, recently initiated a collaborative project that will take a similar approach with oral cancer. This new team will evaluate clues in saliva samples to see if they can predict, based on microbial signatures, which patients are at most risk and thus who might receive more and less aggressive treatments.
In addition to predicting things from the microbiome, Frank and others would like to manipulate the microbiome to “affect the arc of a disease,” he says. One area he sees as especially promising is in the possibility of supportive care, “treating a dysfunctional microbiome at the same time you’re treating the underlying causes of a disease,” he says. For example, he suggests that repairing the microbiome after cancer treatments like chemotherapy and radiation is similar to an oil company’s process of ecosystem remediation. “After these treatments, it may be beneficial to put the ecosystem back in place,” he says.
Or, working at Children’s Hospital Colorado with medical student, Brian Nycz, and Dr. Sam Dominguez, a pediatric infectious disease specialist, Frank is exploring how manipulating the microbiome might be used to protect children from infections following cancer treatment. “It turns out now that some of the intestinal and bloodstream infections that hit these kids may come from problems in the gut microbiome,” Frank says.
Because Frank is a cancer researcher and cancer researchers are by definition at least moderately dorky, he compares this approach to the Star Trek tricorder used by Dr. Bones to collect comprehensive physiological data and then diagnose disease. “Imagine a person comes in for chemotherapy and we sample the gut microbiome to predict if they will be more or less susceptible to some of these infections,” he says.
Elsewhere at the CU Cancer Center, other researchers are looking at other kinds of infections.
THE MICROBIOME IN BLOOD CANCERS
Using a pilot grant from Golfers Against Cancer, microbiologist Catherine Lozupone, PhD, is studying whether the microbiome can affect graft-versus-host disease after bone marrow transplant for blood cancers. Basically, one strategy to combat leukemia is to erase a patient’s cancerous blood system and then regrow it using the “seeds” of a donor’s bone marrow stem cells. Unfortunately, if the donor’s blood system is mismatched with the patient’s tissue, the immune components of the new blood system can attack a patient’s tissue. This is graft-versus-host disease, or GVHD, and it can result in a chronic and even fatal combat between new blood and existing tissue. To study the possible influence of the microbiome on GVHD, Lozupone and colleagues including Vu Nguyen, MD, and biostatistics graduate student, Cuining Liu, analyzed gene sequence data from fecal samples of leukemia patients and their bone marrow donors before blood system transplant.
“We found two main things,” Lozupone says. “First, we found that leukemia patients had much less diversity of microbes in the gut – there was an overgrowth of opportunistic microbes.” However, this lack of diversity, she says, may not have been caused by or even have been contributing to the cancer itself, but may be due to the effects of chemotherapy and other treatments. That said, “Microbiome composition predicted mortality collectively from GVHD, relapse and infection,” Lozupone says. “We just don’t know if low gut diversity is only a marker of people who are sicker and sicker people don’t do as well, or if there is something in low gut biodiversity that makes people do poorer.” But sit with this a second: The diversity of your microbiome can predict whether you will succumb to leukemia or its complications.
That finding may be fairly intuitive, but Lozupone was surprised to see the same was true from the side of bone marrow donors: Donors with lower microbiome diversity were correlated with patients who went on to develop GVHD.
“So a donor who had a lot of different types of microbes in their gut, their immune cells were less likely to induce GVHD in patients,” Lozupone says.
There are many ways to interpret this finding. Maybe, “If you’re a person who has many different types of microbes in your gut, your immune system might be more tolerant of another person’s system,” Lozupone says. “But even without the how and why, in addition to screening to see how well a donor’s genetics match a patient’s, seeing high diversity in a donor’s microbiome is good – and low gut diversity is a red flag.”
These findings have a handful of possible implications. “Before we use treatments like radiation and chemotherapy that pound the microbiome, maybe we will learn to take a fecal sample so that we can replace the microbiome once treatment ends,” Lozupone says (echoing Frank’s suggestion for “ecosystem remediation”). “Or perhaps there will be benefit in a fecal transplant from the same donor that is giving bone marrow – if you’re giving a donor’s immune system, maybe we should also be giving a donor’s microbiome?”
As you’ve seen, when it comes to the microbiome and cancer, there are more questions than answers. But these questions are pointing the microbiome down a promising path we’ve seen before.
THE PROMISE OF THE MICROBIOME
Theresa Medina, MD, sees the evolution of microbiome research following the same arc as research with the
human genome. “Across the country, many cancer centers have created tumor banks that sequence tumors to investigate what genetic changes drive cancer growth. In addition, there are now many cancer centers across the country starting to collect information on the microbiome to see how this may interact with cancer development or improve responses to therapy,” she says.
In 2013 the National Institutes of Health completed its $115 million Human Microbiome Project. Its goal, like that of the Human Genome Project, was to establish the baseline of a healthy microbiome against which any single microbiome sample could be compared.
“There’s a huge shift toward looking at this area because it seems like whatever question you ask, there’s some interesting interaction or relationship you can find with the microbiome,” says Medina. She points to recent work combining manipulation of the microbiome with cancer immunotherapy in animal models.
If you’ve been watching cancer research, you’ve heard about immunotherapy, in which (basically) doctors attempt to teach the immune system to target cancer. Two 2015 studies in the journal Science show that differences in the microbiome can alter a tumor’s response to immunotherapy. The findings depended on a serendipitous observation: Melanoma tumors grew faster in mice obtained from one laboratory than they did in mice from another laboratory. Why? Well, transferring the microbiome of mice with slow tumor growth to the mice with fast tumor growth was enough to slow tumor growth in this second group to the lower level. Adding anti-PDL1 or anti CTLA-4 immunotherapy to the microbiome transfer controlled tumors even better – beyond what either treatment accomplished on its own. The culprit seemed to be an abundance of Bifidobacterium and when researchers treated mice with this bacteria – a common ingredient in probiotics – they were able to improve the response to immunotherapy.
Medina also says that in addition to modulating immunotherapies, the microbiome may affect the immune system in ways that could prevent the development of cancer in the first place. “Some gut inflammation is good – the gut microbiome is influential in the development of a competent immune system,” she says. “But we’ve seen that alterations in the microbiome are associated with the development of some cancers, especially colorectal cancer.”
Immune regulation isn’t the only way the microbiome may affect cancer. “I also wonder whether the microbiome may affect metabolism in a way that helps to decide how quickly and how efficiently cancer is able to use energy to power its growth,” Medina says. Still another way the microbiome could affect cancer development is through its influence on the “virome” – the population of viruses in the human body. “For example, the microbiome may help to determine if infection with HPV leads to cervical or head-and-neck cancer,” Medina says.
“With the microbiome, we’re at the ground floor of understanding,” says Dan Frank. “What is safe and what is effective have largely yet to be determined.” But we know enough to know there’s more there. The microbiome is, as Frank might point out, a new frontier – another layer of human biology on top of the genome, whose secrets are just now being uncovered. And like our understanding of the genome has allowed us to make quantum leaps in our understanding and treatment of diseases, unpacking the details of how we coexist, cooperate and compete with our microbiome may allow us to take the next giant leap in cancer treatment.