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Gut Check: Science Probes Frontier Within Us Made Up of Millions and Billions of Microbes

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For every one of our own cells, our bodies play host to 10 other microbial cells: bacteria, fungus, viruses and other microscopic creatures that scientists are still working to discover and understand. In other words, we're outnumbered by these 100 trillion or so microbes -- many of them strangers -- that form our microbiome, the name given to the collection of all microorganisms living in and on the human body.

The microbiome is a relatively new frontier for scientists, who have only begun to examine how these microbes might affect the function of our bodies. The more we learn, however, the more certain it seems that this wildlife should be considered less an invading force and more an invisible ecosystem that could hold the key to more efficient means of fighting disease, and clues to a whole host of diseases that on the surface would seem to have little to do with bacteria -- like diabetes and obesity.

Earlier this year, researchers unveiled the first findings from the Human Microbiome Project, a National Institutes of Health-funded effort to catalogue and characterize the microorganisms found on various sites of the human body and analyze the role they play in health and disease. The program is examining the organisms that live on various sites, including the nasal passages, mouth, skin, gastrointestinal tract and urogenital tract with the goal of understanding what role they may play in our health, and in causing illness.

NIH Director Francis S. Collins, MD, Ph.D., likened the researchers in the Human Microbiome Project to 15th-century explorers trying to describe the outline of a new continent. Using ever-improving techniques for sequencing DNA, the project has offered the best microbial map of what lives in our bodies to date. This database promises to be a powerful new tool for research in the area of infectious disease.

The project included samples from 242 healthy U.S. volunteers, with tissues collected from 15 body sites in men and 18 in women. Then, researchers took these 5,000 plus samples and analyzed them using DNA sequencing machines -- a far cry from the old method of studying microorganisms by isolating them and growing them in culture.

Helpful Bugs

Of the roughly 10,000 different types of organisms identified as part of the healthy human microbiome, most appear to do no harm. In fact, they seem to help us in a number of ways, such as helping to extract the energy from food or absorb vitamins. Interestingly, the precise inhabitants of this microbial community seem to vary from healthy person to healthy person. But, even in cases where the organisms are different, they have similar genes and can perform the same job, like breaking down sugars or fats.

And the residents of our internal ecosystem frequently change, for example if we are sick or taking an antibiotic. In pregnant women, the Human Microbiome Project found that the bacterial species in the birth canal change, with far fewer species present than in women who are not pregnant. In the sterile environment of the womb, the unborn baby has yet to populate its own microbiome. That journey through the birth canal gives the baby its first exposure to microorganisms, and with less bacterial diversity, the transit is likely to be safer.

Further, nearly every one of us carries pathogens, but in healthy individuals they simply coexist with their host and bacterial neighbors. Now the mystery is why they sometimes turn deadly, and under what conditions -- which could change how we think about the ways in which microorganisms cause disease. With microbiome from healthy individuals sequenced and defined, now scientists are plunging into disease-specific research, exploring how the gut's microbes might affect inflammatory bowel disease, or how the skin's microorganisms might play a role in psoriasis and other diseases.

Recent research at my home institution was among the first to identify the spectra of fungi living in the gut. While scientists had long known that there was fungus among the flourishing bacteria in the gut, a study published in the journal Science in June was the first to catalogue the fungi. In addition to finding 200 fungal species, half of which had never been described before, the research found this flora may play a role in inflammatory bowel disease.

The researchers, led by David Underhill, Ph.D., were intrigued by a previous study that linked a signaling molecule known as CARD9 -- which plays a key role in triggering the immune system's detection of fungal cells -- to higher rates of inflammatory bowel disease. This molecule interacts with a protein called dectin-1, which is produced by white blood cells and used by the immune system to detect and kill fungi. In their animal study, subjects lacking dectin-1 found their fungal detection systems amok, and developed a condition similar to ulcerative colitis. Looking at data from hundreds of ulcerative colitis patients, those with the most severe inflammatory bowel disease and who ultimately required surgery to address their condition tended to have mutations affecting the crucial protein. This early hypothesis is just one example of the possibilities now that we know what lives in the gut.

Gut Flora and Obesity and Diabetes

Another interesting area of study related to gut microflora is its potential involvement in obesity and type 2 diabetes. A small study has shown that a higher body mass index is associated with bacterial overgrowth. Now, my colleague Ruchi Mathur, MD, is investigating whether microorganisms are a piece of the puzzle contributing to the complex problem of obesity. She's homing in on Methanobrevibacter smithii, which is believed to aid the body in digestion. It appears that, because this bacteria can harvest more calories from the same amount of food, those who have an excess of it may be more likely to be overweight or obese. This is backed up by animal studies, and Mathur is working to confirm the link between the bacteria, obesity and prediabetic conditions with a grant from the American Diabetes Association.

In her study-in-progress, participants -- who are all overweight or obese and whose blood glucose levels qualify them as pre-diabetic -- undergo a breath test to confirm whether M. smithii is present. Next, they eat a prescribed diet over the course of three days, then swallow a pill that tracks how fast food moves through their gut; the calorie content of their waste is measured. The whole process is repeated, only the second time around after taking a strong antibiotic that wipes out the bacteria. This should offer a clue as to how much of a difference the bacteria makes in squeezing extra calories out of food and contributing to obesity.

In case you were wondering, the bacteria themselves can't be blamed for extra pounds. Though they greatly outnumber our own cells, they're very small and only account for between 1 and 3 percent of the body's mass. Small though they are, these bacterial communities within our bodies play a key role in our health and in disease -- a role that scientists will continue to explore.

As part of the Human Microbiome Project, the NIH has invested in a series of studies into the ethical, legal and social implications of the project's research. These studies are not yet published, but they've identified interesting issues, including early discussions on probiotics designed to manipulate the microbiome -- products that have grown increasingly popular in recent years.

Probiotics have been shown in some studies to be effective in treating -- and even preventing -- diarrhea caused by antibiotics, traveler's diarrhea and some infectious diarrhea. A study published last spring offered up a line of thought to be considered by the World Health Organization when evaluating probiotics in foods: Perhaps the difference in the microbiomes of different populations could explain varying results from different clinical trials looking at probiotic efficacy, and this difference should be taken into consideration when developing these products.

Still, if you're pitched food or other products purporting wondrous health benefits, disease cures or other hard to believe claims based on probiotic enhancing, containing or inducing components, well, if it sounds too good to be true, it probably is. Go with your common sense -- and your gut. Miracles happen and health and medical advances likely will be a beneficial result of careful, rigorous, scientific research into the microbiome, not for now from a nostrum to be gulped down after purchase at the corner convenience market.

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