Special Issue: Cancer and Obesity Research
Searching for Clues to Obesity among the Body's Many Microbes
Researchers are examining the microbial communities found at several different sites on and in the human body to analyze the role of these microbes in human health and disease.
The human body contains ten times as many microbial cells as human cells. Most of the time, these microbes are our partners in health, contributing to a strong immune system and the digestion of dietary components to produce essential nutrients, among many other roles. But growing evidence indicates that, under certain conditions, some of these microbes may worsen our health and increase the risk of disease.
Using new genomic tools, researchers have been systematically identifying many of the microbes living in and on our bodies. The NIH-led Human Microbiome Project, for instance, has been characterizing the communities of microbes, or microbiota, at five body sites—the gut, skin, mouth, nose, and vagina. (Collections of microbial genes are known as microbiomes.)
Having developed the tools and information to study these microbial ecosystems, researchers are shifting from asking "Who is there?" to "What are they doing?" The goal is to learn how microbes help maintain human health or set the stage for disease. Early efforts in this area have linked microbes in the gut to obesity, which is a risk factor for cancer.
"We are learning a lot about the microbes in the gut and about associations with obesity," said Dr. James Goedert of NCI's Division of Cancer Epidemiology and Genetics (DCEG). "It is too soon to say whether changes to the microbiota play a causal role in obesity. We also need to explore how these associations relate to cancer."
Harvesting Energy for Humans
Research suggests that communities of microbes in the gut influence—or are influenced by—diet. Researchers have long known that microbes digest foods that humans cannot, thereby supplying nutrients that humans need. Gut bacteria produce energy for the body by fermenting plant polysaccharides and dietary fiber, for example.
"How much energy is harvested from the human diet is directly influenced by the type of bacteria we house in our colons," explained Phil Daschner of NCI's Division of Cancer Biology, who co-led a recent NCI meeting on the human microbiome and cancer. "It's not just what you eat, but also which bacteria you have in the gut that are breaking down what you eat," he added.
If different configurations of gut microbes are found to be associated with a lower risk of certain diseases, then it may be possible to prevent—or even treat—these diseases simply by modifying microbial communities.
Finding out the molecular mechanisms by which these bacteria are signaling their effects in the human host is critical for developing disease prevention and treatment strategies.
Daschner and others believe that to achieve this goal it will be important to understand how bacteria might be affecting the body. "Finding out the molecular mechanisms by which these bacteria are signaling their effects in the human host is critical for developing disease prevention and treatment strategies," he said.
Nonetheless, interest in the gut microbiome and obesity has grown, in part because of research led by Dr. Jeffrey Gordon at the Washington University School of Medicine in St. Louis. In one study, his research team transplanted certain bacteria from the guts of obese mice into the guts of germ-free mice. These animals subsequently became obese themselves.
A second study involved sets of human twins and their mothers. The researchers found differences in the fecal microbiota of lean twins compared with obese twins; notably, obesity was associated with decreased diversity of gut microbes. In addition, the activity of microbial genes involved in several aspects of nutrient metabolism also differed between the two groups.
The Complexity of Microbiota
"We are just beginning the journey of looking at the configurations of different gut communities in people of different ages living under distinct cultural conditions," Dr. Gordon said in a recent podcast discussing his research. The extent to which the configurations of these communities vary "is still an open question," he noted.
Probing the Oral Microbiome
In the coming months, NCI will be sending DNA samples from patients with oral cancer to Drs. Richard Hayes and Zhiheng Pei of New York University Medical Center. But rather than studying the human DNA in these samples, the researchers will be sequencing microbial DNA to explore associations between the mouth microbiome and cancer.
The study subjects were participants in a large NCI-sponsored cancer prevention trial. They were free of cancer when they joined the trial between 2000 and 2005; each person provided a DNA sample when they entered the study using an oral rinse they did at home and sent through the mail.
The samples, which arrived at NCI and were stored for later research, captured the DNA of microbes in each donor's mouth. As prediagnostic DNA samples, the specimens present a rare opportunity to study the oral microbiome before cancer symptoms appeared.
"By studying the microbiome, we have an opportunity to identify new bacterial agents that may cause cancer," said Dr. Pei. "The microbiome has given us a new target."
But he believes that studying the structures and functions of microbial communities could lead to a better understanding of the nutritional needs of humans. This work could also yield clues about the role of microbial ecosystems in obesity and malnutrition.
Although the role of the microbiome in cancer is even less clear than it is in obesity, several reports have suggested that certain microbiota have either a protective or a cancer-promoting role. "To me, this is an indication of the complexity of the microbiota," said Dr. Eugene Chang, who studies the gut microbiome and gastrointestinal diseases at the University of Chicago.
"Many of us believe," he continued, "that our collective microbiome in the human population is changing and that this is altering the critical host-microbiome interactions that determine our biology."
In a recent commentary, Dr. Chang urged the field to undertake studies of the mechanisms underlying these interactions. He also cautioned against "overzealous claims" about the significance of the findings based on current evidence. For example, one challenge will be to move beyond small studies that describe associations between changes in microbiota and health effects. Most of these studies are based on a single point in time and cannot show cause and effect.
"We still haven't answered the initial questions we set out for the Human Microbiome Project: Why is the microbiome important to our health and what role does it have in disease?" Dr. Chang said.
"To answer these exciting questions we need large, well-designed studies that collect samples and that follow individuals over time to see which microbial differences are predictive of cancers and other diseases," said Dr. Mahboobeh Safaeian, an investigator with DCEG's Infections and Immunoepidemiology Branch. "Establishing a timeline of events will be important."
Exploring a New Frontier
A prospective study of the gut microbiota in the Amish, now under way, could yield clues to help answer a number of current questions. The study, led by Dr. Claire Fraser-Liggett of the University of Maryland School of Medicine, will evaluate the gut microbiota in lean and obese individuals over time, including before and after an experimental intervention.
This work and similar studies will almost certainly raise new questions as well as answer others. But the science is moving rapidly, and researchers are optimistic. "Things are happening so fast in this field—both scientifically and technically," said Dr. Goedert. Within a few years, the current research methods and tools could well be seen as obsolete, he added.
Dr. Chang agreed. "This field is like a frontier right now, and that's the appeal," he said. "We don't have signposts to tell us where to go."
—Edward R. Winstead
Testing the Health Effects of Yogurt
In a two-track study involving humans and animal models, Dr. Gordon and his colleagues recently tested the effects of yogurt on the gut microbiomes of identical twins and mice with "humanized" microbiota.
The researchers took fecal samples from the subjects during the 4 weeks before they ate the yogurt, the 7 weeks while they ate the yogurt, and another 4 weeks after they stopped eating the yogurt. Over this 4-month period, the diet appeared to have no substantial effect on the composition of the fecal microbiome. But the diet did cause changes in the expression of some microbial genes, resulting in alterations in metabolites that were detected in urine.
"This study demonstrated that a dietary intervention could exert a systemic effect. It is interesting that the population of microbes didn't change, but their activity did," commented Dr. Goedert.
The findings in the mice mirrored those in humans, suggesting that this strategy could be used more broadly to identify the effects of consuming foods containing live bacteria. "We can basically do global surveys at the intersection between what somebody eats and the response of their different microbes," Dr. Gordon explained in a recent podcast.