What science is discovering about the trillions of microscopic organisms that share your body
By Sabin Russell | Photos by Robert Hood | Illustrations by Kim Carney
When Kimberly Loges rode the bus from her home in Seattle's Ballard neighborhood to the Prevention Center at Fred Hutchinson Cancer Research Center, the healthy study volunteer kept a tight grip on the large paper bag she carried.
"No, it's not my lunch," she would say when asked.
Indeed. Inside that bag was a newly collected sample of stool, swirling in a liquid preservative. Also in the bag: a white, wide-mouth water bottle, sloshing with every drop of her urine from the past 24 hours. Four times over a half-year stretch she made the trip, delivering her specimens to researchers without incident.
In the name of science, sometimes decorum has to be set aside. And it helps to have a sense of humor. "It was awkward. It's an awkward subject," Loges said. "But the researchers made it easy. The only bizarre thing was delivery by bus." She and nearly 50 other brave souls were enrolled in Flax FX, a Fred Hutch dietary study. They are among the thousands of volunteers who have joined with scientists around the world to explore the usually unseen — and sometimes unmentionable — frontiers of the human microbiome.
The microbiome is the community of bacteria, viruses, fungi and other microorganisms that inhabit our gut, our mouths, our eyes, our sex organs and virtually every square inch of our skin. We each harbor a unique population of about 40 trillion microbes, which mostly set up camp in the first few years of our lives. The human colon alone houses as much as four pounds of gut bugs, a diversified microbial workforce that helps our body break down the food we ingest into fuel sources for colon cells, vitamins and biologically active compounds that may either promote or block cancers. They also appear to provide a chorus of chemical chatter that influences our immune system in ways that can help or harm us.
Researchers are also examining how the mix of microbial communities inside us may be tied to obesity, heart disease, mental health and how we respond to treatments for cancer. Mouse studies suggest that chemotherapy can be less effective against tumors if antibiotic treatments have destroyed or disrupted the balance of gut microbes. And microbial communities help regulate our immune system, which has important implications for new therapies that harness immune defenses to fight cancer. "We know the bacteria in our bodies, which we call the microbiome, actually impacts the way people respond to immunotherapies," said Dr. Phil Greenberg, an immunologist at Fred Hutch, during a recent American Association for Cancer Research conference in New York.
Not long ago, studies of the microbiome were a medical research sideshow, an obscure field that only aroused the curiosity of scientists unfazed by the subject matter. Yet new techniques began revealing the enormous diversity of the human microbiome and its role in health. Then came word of "fecal transplants" — restoring your unhealthy gut microbiome with someone else's — and the topic made headlines. For some patients, these transplants were an effective treatment for a potentially deadly bacterial infection. Clostridium difficile, or C.diff, strikes patients, often elderly or immunocompromised, who have had their microbiomes radically altered by courses of antibiotics. While a healthy gut microbiome has a broad mix of bacterial species, antibiotics can wipe out healthy bugs — leaving the field wide-open for bad actors. Fecal transplants may restore a more natural balance of bugs that keep C. diff under control.
Soon however, fecal transplant "spas" sprang up, making a host of unsupported claims. Now, a major industry has arisen touting products purporting to help consumers improve their own microbiome — drawing the attention of the U.S. Food and Drug Administration. Until more definitive studies emerge on so-called probiotics and microbial transplants, the best advice for consumers is the old watchword, "buyer beware" (See "Separating snake oil from certainty").
Nevertheless, the microbiome beckons serious researchers, at Fred Hutch and across the country, with the allure of a newly discovered frontier. It is a medical wilderness now being scouted with every tool of modern science, from the humble cotton swab to the supercomputer. Someday, understanding our unique, individual microbiomes could be critical to developing more precise, personalized medicine — and nothing is more personal than your microbiome.
Microbiome and cancer treatment
Dr. David Fredricks and his colleagues in the Vaccine and Infectious Disease and Clinical Research divisions at Fred Hutch are exploring the interplay of the gut microbiome and the body's natural defense system, particularly in immunocompromised cancer patients who have received blood stem cell transplants. The immune system is designed to detect and destroy foreign microbes, yet gut microbes have evolved a peaceful coexistence with the immune cells that line the colon. That relationship is challenged in cancer patients.
Graft-vs.-host disease, or GVHD — in which transplanted blood stem cells from the donor attack the patient's healthy tissues — remains a serious and sometimes fatal complication in transplant patients treated for blood cancers. Fredricks and his colleagues are studying how a transplant patient's population of gut bugs, which can be dramatically disrupted by chemotherapy and antibiotics, may play a role in GVHD. The hope is that picking apart these interactions will help Fredricks' team "come up with novel ways of treating it through manipulation of the microbiota," he said.
Information about the microbiome may also help doctors manage the risk of infectious diseases in patients after cancer therapy or a transplant. "We might be able to generate, in real time, information that would tell us we are seeing a bloom of a species, such as C. diff, and that we should tweak their antibiotics or alter their microbiota to reduce infectious complic ations," Fredricks said.
Fredricks began exploring the microbiome at Stanford in the 1990s and developed genomic tools that have since helped his own microbe-detection research at Fred Hutch, where he has worked since 2001. With grants from the National Institutes of Health and its Human Microbiome Project, he carried out some of the first comprehensive studies of the microbial populations that cause bacterial vaginosis, or BV, which affects nearly one in three women in the United States. Unpleasant and embarrassing, BV is also associated with preterm birth, pelvic inflammatory disease and elevated risk of sexually transmitted infections, including HIV.
Microbiome research has shown that the more diverse a microbial community, the healthier it is for the host. But Fredricks' work has revealed that women with BV have a strikingly different and more complex vaginal microbiome than women without it, and further research may reveal why. That could lead to treatments that tip the balance in favor of healthy bacteria, and relief for millions of women.
In hopes of helping others
Among the longest-running microbiome research projects at Fred Hutch are dietary studies that take a close look at the chemicals released when different communities of microbes break down foods in the gut. Some of these reactions can turn healthy foods into carcinogens. Others metabolize byproducts thought to have anti-cancer and anti-inflammatory properties.
Dr. Johanna Lampe of Fred Hutch's Public Health Sciences Division has led the ongoing Flax FX study for three years. "A key issue is how critical the microbiome is in developing and maintaining a healthy immune system," she said. As a nutritionist, Lampe has spent her career studying the role of diet in preventing or promoting disease. Her current work on the microbiome is a natural progression from earlier studies that explored the benefits of diets rich in lignans, substances that are abundant in flaxseed. Lignan byproducts may include enterolactone, a compound thought to inhibit development of cancer.
"What we find when we give everybody a dose of the same flaxseed lignan extract is that some people produce tons of enterolactone, and others produce hardly any," Lampe said. There is good reason to think that those differences may have more to do with our microbiomes than our own genes.
The full set of human genes varies from that of chimpanzees by only about 4 percent, but the microbial mix within a human gut microbiome may differ by two-thirds from one person to the next. Those diverse legions of bugs in the colon ferment the fibers and other organic substances that can't be broken down by enzymes in the stomach and small intestine. As such, they are also consumers of the food we digest, and they may have the means to signal what they prefer to eat. "When you eat a meal," said Lampe, "You are not just eating for one."
Liz Wagner, a Seattle digital products manager for a large coffee company, volunteered for the Hutch's Flax FX study in hopes of helping others. Just like Loges, she and other participants were assigned to either a daily flaxseed preparation or an identical-looking sugar pill — a placebo — to be taken for 60 days. She was not told which one she was assigned. Wagner collected and delivered her own urine and stool specimens, and had blood drawn at the lab. After a pause of several months, the 60-day process was repeated. Whether she was assigned flaxseed or placebo in the first round, she received the opposite pill in the second.
At the end of each two-month stint of pill-taking, the volunteers also endured a colorectal biopsy — a few bits of tissue smaller than a rice grain were removed in what might be described as a short version of a colonoscopy. Why go through all that? For Wagner, it's personal. Her mother had colon cancer and died three years ago. "Compared to what my mom went through for 10 years, I can put up with a little discomfort," she said.
Lampe and her Fred Hutch colleagues are just now analyzing the information collected over three years from the flaxseed study. Sophisticated tests of the biopsy samples will show which genes inside each participant's gut tissues are turned on or off when flaxseed is in the dietary mix. Patterns of such gene expression can show whether those cells are behaving in ways that lower colorectal cancer risk. Those genetic results will be matched to the variety of gut bugs in each participant.
Breakthrough technologies such as gene sequencing, which revealed the vast complexity of microbial life in the human gut, are now helping us understand why healthy foods might work for one person but might not for someone else. As Lampe pointed out, "It's the microbes that are producing the compounds that are beneficial or detrimental."
Unlocking clues to stomach cancer
Dr. Nina Salama, a Fred Hutch Human Biology Division researcher and holder of the Dr. Penny E. Petersen Memorial Chair of Lymphoma Research, has been exploring the microbiome for more than 15 years with a singular focus: Helicobacter pylori. It is a bug that thrives in the acidic environment of the human stomach and is implicated in stomach cancer, the world's third leading cause of cancer death.
However, with half the world's population infected with H. pylori, only a fraction are diagnosed with stomach cancer. Salama and her Hutch colleagues are asking whether the cancer-causing mechanics of this bug are tied up in complex interactions with other microbes and the enzymes and tissues of their human hosts. "We have to be less 'one-bug-centric,'" she said.
Salama attributes the surge in interest in the microbiome to the arrival of new tools that finally made it possible to identify hordes of bacteria by their genetic fingerprints. Scientists learned to zero in on an ancient gene common to almost all bacteria. Embedded within that gene is a strip of DNA that is different for every species and can be read almost like a barcode. What a difference that made: Previously, scientists would not try to catalog a microbiome because it took months to isolate, grow and identify a single species. Now, a gene-sequencing machine could run a barcode census of entire communities of bacteria, spotting every species in a matter of days, with no need to isolate or grow any of them.
Refined during the 1990s at universities such as Stanford, where Salama received her postdoctoral training, this 16S rRNA sequencing — the name refers to that ancient gene — revolutionized the field. Like a microscope that suddenly throws an invisible world of tiny, living creatures into focus, these genomic tools cracked open the microbiome.
Since those early days, the resolution of these genomic microscopes has substantially improved. So-called "next generation" gene sequencers — blindingly fast and highly automated — are bringing greater precision to microbiome analysis. The technology allows researchers to identify not only bacterial species but specific strains. "I work on H. pylori, and we know that not all strains are created equal," Salama said.
With this better tool, she is researching H. pylori strains that pose an even higher risk of stomach cancer. These strains, which carry a suspect gene, are more prevalent in some East Asian populations that have more gastric cancers than others. "The association is clear, but nobody has come up with a causal mechanism to explain it," said Salama. So, one discovery leads to another puzzle, the process that drives science at the leading edge.
The brain and the microbiome
Dr. Meredith Hullar is a microbial ecologist at Fred Hutch who got her start at Harvard studying the complex metabolism of microorganisms in the sea. She collaborates closely with Lampe on dietary research and the role of microbial metabolism in human health. Hullar is a fan of large studies that bring together huge amounts of disparate data, searching for patterns. One such project she and Lampe are involved in is the Multi-Ethnic Cohort study, which is comparing the microbiome profiles of 6,000 men and women from five different ethnic groups in Hawaii and California. It's a massive undertaking, sequencing microbial genes from 7,200 stool samples and matching data from questionnaires, medical exams and whole-genome screens that can spot gene variants in each participant. The goal is to link the makeup and function of the gut microbiome to risks of obesity and cancer.
But the study is also exploring the connection between gut bugs, the brain and behavior. While signals from the gut to the brain help determine whether a person "feels full" after a meal, certain gut bacteria may alter that communication, influencing behavior linked to weight gain. "Understanding how the gut microbiome influences the brain's regulation of body fat may add to our understanding of how to prevent and control obesity, which is linked to increased risk of certain cancers," said Hullar.
To probe this gut-brain link, brain-imaging scans, including MRIs, are being offered to 100 women participants in Hawaii, who also fill out standardized behavioral surveys. These scans will add data on brain chemistry and structure to the other health information already gathered. It is a breathtaking illustration of how sophisticated microbiome research has become. A project that began with stool samples now has high-speed computers crunching big data from genomic screens, proton spectrographs and MRI readouts.
New chapter of exploration
When the microbiome is taken into account, it changes how we think of the human body. In the more traditional model, a human being is like a machine with important moving parts: Think heart, lungs, brain, liver, intestines. When trillions of microorganisms are added to the picture, the model morphs into an ecosystem, chock-full of complicated interactions, cycles and interdependent relationships — not just among organs but among different species. It becomes a little harder to determine what actually makes us human: the cells that define our bodies, or the relationships our own cells forge with their surrounding environment. In this ecological model, our health is intertwined with that of the microbial world that surrounds us.
Early interest in the human microbiome, in fact, was driven by research from microbial ecologists who study the community of bugs that inhabit soils, oceans, decaying matter on forest floors, and even extreme environments like volcanic hot springs. It is a field that keeps the big picture in mind.
To date, the exploration of the human microbiome is a story of hints. Finding associations between obesity and the microbiome are not the same as finding cause and effect. The field is still young, and its findings, while often intriguing, will have to stand up to the scrutiny that comes with volumes of studies, large surveys and replication of results. These hints, however, are firing the imagination of researchers who scour for every possible edge against cancer and other deadly diseases. At Fred Hutch, the microbiome has come into focus, and a new chapter of exploration has begun.
An estimated 800 different bacterial species inhabit the human gut.
Newborns are first exposed to microbial communities on their skin as they pass down the birth canal. It takes about 21 days for a newborn to begin developing a personalized microbiome; up to two years for their own unique microbiome to become established in the gut.
The human genome differs from that of the chimpanzee by only four percent. One person’s microbiome may differ from another’s by about 60 percent.
Don't fear the beard. The internet is periodically plagued with rumors that facial hair is a nest of nasty germs. Quite to the contrary, a 2014 study of 408 male hospital workers, published in the Journal of Hospital Infection, found bacterial colonization rates were roughly the same among those with beards and the clean-shaven — and bearded men were less likely to be harboring the most dangerous bacteria such as MRSA.
For years, scientists accepted that the average human adult microbiome harbored 100 trillion cells, outnumbering human cells by 10:1. But researchers taking a closer look have recently challenged those numbers. New estimates are that number of human cells and microbial cells is roughly the same, about 40 trillion.