Volume 87 Issue 29 | pp. 43-46
Issue Date: July 20, 2009

Extended Family

Getting to know the trillions of microbes cohabitating with humanity
Department: Science & Technology
Keywords: microbes, resident bacteria, immune system
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NEAREST NEIGHBORS
Gut epithelial cells (lower left) communicate with trillions of microbes living in the gut lumen (upper right) by exchanging chemical signals across the mucus layer (100X magnification).
Credit: Eugene Chang
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NEAREST NEIGHBORS
Gut epithelial cells (lower left) communicate with trillions of microbes living in the gut lumen (upper right) by exchanging chemical signals across the mucus layer (100X magnification).
Credit: Eugene Chang

You might as well accept the fact that you’re probably more microbe than human. By conservative estimates, trillions of bacteria live in your gut, on your skin, up your nose, and on your teeth—that’s 10 times more bacterial cells than human ones in the body. Because human cells are much larger and bulkier than bacterial cells, we end up looking like people, but in reality, we are actually “multispecies superorganisms,” says Jeffrey Gordon, a geneticist at Washington University in St. Louis.

These microbes are not just passive travelers or intermittent pathogens. They “perform many functions for us that are not encoded by the human genome,” says Jeremy Nicholson, a biomedical chemist at Imperial College London. In fact, because thousands of different microbial species live upon or within us, the total number of bacterial genes being expressed on or in our bodies exceeds the number of genes in the human genome by a factor of about 100. “Humans run on a relatively small number of basic genes for being such complex organisms, and our microbes take up some of the slack,” Nicholson says.

For example, these bugs make essential vitamins that we can’t build ourselves. They produce enzymes that we need to digest and absorb energy from food. Some microbes even help our immune system distinguish between friendly microorganisms and those that are pathogenic. Because our lives are so intertwined with these tiny neighbors, a growing number of biomedical researchers say that communication breakdown between humans and our bacteria is at least partly to blame for a number of diseases.

In fact, the National Institutes of Health is so interested in the link between disease and our resident bacteria, fungi, and archaea that the agency established the Human Microbiome Project in 2007. Its goal is to sequence the genomes of at least 400 of the thousands of microbe species that live in the digestive tract, mouth, skin, nose, and vagina of healthy humans. Just last month, NIH announced a next phase of the five-year, $140 million project: comparing the microbiomes of healthy and sick people. Newly funded projects will investigate the role that bacteria may play in everything from Crohn’s disease and irritable bowel syndrome to sexually transmitted diseases, obesity, and psoriasis. The hope is that as we learn more about humanity’s rapport with our microbial cohabitants, we’ll learn more about ourselves, our metabolism, and our evolution.

Our relationship with microbes is as old as humanity itself. Multicellular animals “arrived on an Earth already dominated by the microbe,” Gordon says. All human evolution has taken place in the company of microbes; as individuals, our first encounter with them occurs as we struggle down the birth canal, before we breathe our first breath. Like our personality, our microbial flora is shaped by the places we live, who handles us early in life, and what we like to eat.

According to evolutionary biologists, our microbial associates also enabled a fundamental step in humanity’s development—our advancement from carnivores to plant-eating omnivores. The logic is as follows: We’re fond of many of the plant polysaccharides that include xylan-, pectin-, and arabinose-containing sugars. Although the human genome codes for a few sugar-degrading proteins, it simply doesn’t possess all of the enzymes required to degrade these carbohydrates, says Robert Knight, a biochemist at the University of Colorado, Boulder.

To digest many plant polysaccharides, we rely on our gut microbiota to provide the enzymes, such as glucanotransferases or xylosidases, required to get the job done. For example, some 81 glycoside hydrolase families have been found in our microbiome, and many of these are absent from our own enzymatic repertoire (Science 2006, 312, 1355).

MULTIVITAMIN MICROBES
Gut microbes make a variety of useful nutritional molecules.
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MULTIVITAMIN MICROBES
Gut microbes make a variety of useful nutritional molecules.

Microbes in our gut further convert polysaccharide-derived sugars to short-chain fatty acids, such as acetate, propionate, and butyrate, which we then absorb. Thus, our microbiome helps us harvest energy from the dinner plate. By some estimates, gut microbes are responsible for helping humans extract 10% of the calories in the Western diet.

The exact amount of energy extracted from food by the gut microbiome depends on your personal portfolio of resident bugs. Furthermore, this portfolio plays a part in how slim or heavy you are. In back-to-back Nature papers that made a big splash for the human microbiome field, Gordon and colleagues showed that the bacterial phyla represented in the guts of obese humans and mice are different from those in their lean counterparts (2006, 444, 1022; 1027).

Members of the phyla Firmicutes (which includes the genera Bacillus and Clostridium) and Actinobacteria (such as the genera Mycobacterium and Rhodococcus) are more abundant in obese people, relative to lean individuals, whereas members of Bacteroidetes (which includes the genus Bacteroides) are less abundant, the researchers found. They showed that the gut microbiome of obese individuals has a comparatively higher number of genes for polysaccharide breakdown, suggesting why it is able to extract more calories from their diet. The team also reported that when gut microbiota of obese mice were transferred to lean mice, the lean mice began extracting more calories from their diet.

Thus, the nutritional value of food may be relative, not absolute, because it is influenced in part by the specific makeup of an individual’s gut microbiota, Gordon says.

In addition to breaking down plant sugars and helping us absorb them, gut microorganisms get down to all sorts of other business in the belly. Some are producing gases such as H2, CO2, and methane in your lower intestine—useful information to those seeking an excuse for flatulence. But microbes also do good by producing enzymes required to make vitamins such as B1, B6, and B12, as well as a variety of amino acids.

MICROBIAL BY-PRODUCTS
These bacteria-modified molecules are commonly found in human urine.
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MICROBIAL BY-PRODUCTS
These bacteria-modified molecules are commonly found in human urine.

One might wonder whether we really need our microbes to make vitamins and amino acids for us, given that we can gain these essentials from food. The answer seems to be yes. Experiments with mice that are entirely free of microorganisms—so-called gnotobiotic mice—reveal that these animals become vitamin deficient if they are not given vitamin supplementation, Gordon explains.

Gnotobiotic mice are just one of the many tools used by people who study the human microbiome. Many of these tools have been developed only in the past decade, allowing scientists to do the experiments that the 1908 Nobel Laureate in Physiology or Medicine, Ilya I. Mechnikov, could only have dreamed of. In the late 1800s, Mechnikov proposed that gut microbes could be important for health and suggested that bacteria in our bellies could be involved in the metabolism of amino acids.

By the 1960s, researchers began to suspect that bugs in our gut were metabolizing food and drugs. But around that time, molecular biology took off, and “everybody got distracted with sequencing human genes,” leaving the bugs that cohabit our bodies alone, Nicholson says.

That neglect only lasted until genome-level sequencing got much faster. With the human genome mostly a fait accompli, many are now turning their attention to microbes. For example, the J. Craig Venter Institute, in Rockville, Md., will be doing part of the Human Microbiome Project’s large-scale sequencing, along with genome sequencing centers at Washington University in St. Louis; the Broad Institute; and Baylor College of Medicine.

Aiding these human microbiome projects are new ways to sequence genomes, such as the pyrosequencing technique. Pyrosequencing cuts a genome into smaller pieces than with older approaches, making the sequencing process faster and cheaper—although sometimes more prone to slip-ups.

Despite new tools, sequencing a whole genome is still labor intensive, so many researchers simply focus on sequencing one fingerprint gene for all microbes in the sample. The one they choose is the 16S ribosome gene because it distinguishes different species. “But that’s just one gene,” Knight says. “Often, the rest of the genome also does something important that you’d like to find out about.” To find out all the activities a microbiome might carry out—its so-called “metabolic potential”—researchers chop the genes of all the bacteria present in a sample into small fragments, sequence the fragments rapidly, and analyze them using bioinformatics.

New techniques for metabolic profiling have also revealed what kind of chemistry our bacteria are doing. For example, the high sensitivity of mass spectrometry allows quantitative comparisons of tiny organic molecules in one human microbiome sample versus another. Nicholson has spearheaded the use of nuclear magnetic resonance spectroscopy in human microbiome research by developing a technique called statistical total correlation spectroscopy to detect and characterize metabolites.

These are only a few of the techniques that are giving researchers a better idea about the likes and dislikes of our microbiome, which have led to a few surprises. Many in the field expected to find a common strain of bacteria living in all people—something that would be a model human microbiome strain. “There doesn’t seem to be a ‘core’ bacterial species found in all humans,” Knight says. Instead, people have “staggeringly” unique microbial communities, he says. Human genomes may be more than 99% identical, but when microbial ecologists compare gut ecosystems among different individuals, they find that we share only 10–20% of microbial species.

“What is common on one person can be rare or nonexistent in other people,” Knight says. Sure, some of the usual suspects are prevalent: Staphylococcus and Streptococcus tend to be found on human skin, and bacteria from the Enterococcus or Faecalibacterium genera tend to be found in the gut. Although these “regulars” may be found in a significant fraction of people, “for any bacterial species that you pick, you’ll find there are individuals who lack that species,” Knight says. But what does seem to be common among microbial communities is what they can do. For example, most people possess microbes that can make vitamins and break down polysaccharides. It’s just that the work may be done by different species, with varying levels of efficiency (Nature 2009, 457, 480).

Researchers are also discovering that even though the gut boasts the highest number of actual bacterial cells, it’s your hands that have the greatest diversity of bacterial species, Knight says. In fact, very different populations of bacteria live on different hands of the same individual. Furthermore, the bacterial populations that live on each of your hands are much more different from one another than from those that live on your forehead or behind your knee. “We have a whole archipelago of little microbial habitats that are radically different from each other,” Knight says.

Although the microbiome of the gut is by far the best studied, microbiomes in other areas of the body, such as skin and spit, are starting to catch up. “Everybody in the field is getting so much fascinating data” that it is a struggle to find the time to write papers about all that information, Knight says.

One major conundrum keeping researchers guessing is how our immune system can be on friendly terms with most of our trillions of bacterial counterparts, yet still go to war against bacteria that cause major infections—especially when such pathogens can sometimes be members of our endogenous bacteria, such as Clostridium difficile or Escherichia coli.

Researchers are still far from an answer to that question, but they do know that gut bacteria release “myriad signals that are responsible for educating the human immune system,” says Eugene B. Chang, a biomedical researcher at the University of Chicago Medical Center. These signals—which range from small organic molecules to short peptides—cross from bacterial communities living in the gut through the mucosal layer to the gut’s epithelial cells. They teach the immune system not to react to most dietary antigens or friendly bacteria, Chang says. But when this communication is disrupted, things can go awry: Our immune system can overreact to the friendly bacteria in our gut, or hostile bacteria can exploit the miscommunication to launch a take-over.

Although researchers have long suspected that good bacteria are sending signals to the immune system to enable peaceful cohabitation, the first conclusive proof came last year from work by Dennis L. Kasper of Harvard Medical School and Sarkis K. Mazmanian of California Institute of Technology, when they were investigating irritable bowel syndrome. This team found that in healthy people, the gut bacterium Bacteroides fragilis produces a sugar called polysaccharide A (PSA) on its cellular surface. This sugar, which is recognized by immune cells, acts as a sort of antianxiety pill for the immune system, which would otherwise be activated by other bacteria in the gut. The team was able to reverse irritable bowel syndrome in mice by feeding the animals PSA. It is possible that humans with irritable bowel syndrome may lack B. fragilis and other bacteria that produce PSA. Or it is possible that the B. fragilis that sufferers do have doesn’t produce PSA (Nature 2008, 453, 620).

ONE IN A TRILLION
The bacterium Enterococcus faecalis, which is less than 1 µm long, is being studied as part of the Human Microbiome Project.
Credit: U.S. Department of Agriculture
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ONE IN A TRILLION
The bacterium Enterococcus faecalis, which is less than 1 µm long, is being studied as part of the Human Microbiome Project.
Credit: U.S. Department of Agriculture

Irritable bowel syndrome is not the only example of an illness that seems to have a bacteria-immune system component. Consider Crohn’s disease, which leads to perpetual gut inflammation by the immune system. One of the ways to diagnose Crohn’s disease is to look for a mutation in the human gene NOD2. It turns out that the protein made by NOD2 typically recognizes bacterial peptidoglycan, an interaction that is disrupted in Crohn’s patients.

This was the first clue that Crohn’s disease had something to do with the breakdown of “the relationship between ourselves and our gut microbes,” Chang says. Researchers are now trying to figure out how the inability to detect peptidoglycan causes “an overexuberant response to gut microbes” by the immune system, which leads to the inflammation seen in patients, Chang adds.

A whole host of other autoimmune diseases, including type 1 diabetes and psoriasis, are also being investigated to see whether they are at least partly caused or exacerbated by overreaction of our immune system to the human microbiome.

As we better understand the microorganisms with which we live intimately, researchers hope to identify new ways to improve personal nutrition, as well as new biomarkers for health and disease. Getting to know our gut microbes will also improve our understanding of how drugs get metabolized and how widespread use of antibiotics in the past 60 years has changed the makeup of our microbiome, Nicholson says. He contends that drugs targeted to our microbiome or to maintaining a healthy relationship with these nearest neighbors may be stocked in our future medicine cabinets (Nat. Rev. Drug Disc. 2008, 7, 123).

By getting to know our microbiome we may also be able to find out to what extent these organisms contribute to our individuality as people. Consider this: Gut bacteria are responsible for at least eight molecules that emerge from urine—such as phenylacetylglutamine, 4-cresol sulfate, and 4-hydroxyphenyl acetate—either because the bugs produce the molecules themselves or because they are metabolizing human molecules. Mammals have long used urine to mark their personal territory, yet at least a portion of this proprietary fluid is actually microbial.

And what about something equally as intimate: our personal odor? Aside from the metabolic by-products of bacteria living in our armpits, which are responsible for some of our more potent smells, psychologists tell us that personal odor can impact attraction and whom we trust. What assortment of volatiles is the rest of our bacterial archipelago making, and how do they contribute to making us who we are?

 
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