Outnumbering our human cells by about 10 to one, the many minuscule microbes that live in and on our bodies are a big part of crucial everyday functions. The lion's share live in the intestinal tract, where they help fend off bad bacteria and aid in digesting our dinners. But as scientists use genetics to uncover what microbes are actually present and what they're doing in there, they are discovering that the bugs play an even larger role in human health than previously suspected—and perhaps at times exerting more influence than human genes themselves.

One team of researchers recently completed a catalogue of some 3.3 million human gut microbe genes. Their work, led by Junjie Qin of BGI–Shenzhen (formerly the Beijing Genomics Institute) and published in the March 4 edition of Nature, adds to the expanding—but nowhere near complete—census of species that reside in the intestinal tract. (Scientific American is part of Nature Publishing Group.)

Another group turned its attention to a particular host gene that seems to impact these inhabitants of the intestines. They found that in mice, a loss of one key gene led to a shift in microbiota communities and an increase in insulin resistance, obesity and other symptoms of metabolic syndrome (a cluster of these conditions). Their results were published online March 4 in Science.

The field of gut microbe study has bloomed in the past few years after decades in the shadows. As the authors of the Science report noted, "The inability to culture most gut bacteria makes assessment of their causal role in health and disease technically challenging." But the advance of genetic sequencing has enabled researchers to make steady progress in getting to the bottom of these beasties and their role in health. And in addition to being a quick way to assess these microbial populations, genomics can also help to elucidate how the two systems—human and microbe—interact.

Stomach survey
The number of microbes in the human gut was known to be vast, but the 3.3 million microbial genes located in it were a good deal "more than what we originally expected," says Jun Wang, of BGI and co-author of the Nature study. The number was especially surprising given that the microbiota tended to be very similar across the 124 individuals they sampled in Denmark and Spain.

Previous work had scanned for these microbial genes in the past. The largest had created about three gigabases (billion base pairs) of microbial sequences that was trumped by Wang's team, which assembled more than 576 gigabases.

The hefty catalogue is a "big advance" in the field, says Andrew Gewirtz of the Department of Pathology and Laboratory Medicine at Emory University who was not involved in this study. "It really sets in place a framework for defining—in detail—the microbiome," he says. And as Wang and his colleagues noted in their study, "To understand and exploit the impact of the gut microbes on human health and well-being it is necessary to decipher the content, diversity and functioning of the microbial gut community."

More than 99 percent of the genes the group found were from bacteria. "These bacteria have functions, which are essential to our health: They synthesize vitamins, break down certain compounds—which cannot be assimilated by our body—[and] play an important role in our immune system," Wang points out.

Wang's group, which is part of the European Commission–funded MetaHIT (Metagenomics of the Human Intestinal Tract) consortium, relied on fecal samples from the 124 individuals. Despite the presumed vastness of gut-microbe diversity, the researchers found that about 70 percent of the genetic material in their European sample overlapped with that from previous studies that examined U.S. and Japanese subjects, suggesting that, in fact, "the prevalent human microbiome is of a finite and not overly large size," the researchers concluded.

It is "a very important paper for paving the way for future studies," Gewirtz says. "Once you define the baseline you can start looking in detail at disease."

Wang and his colleagues already had this next step in mind. The samples for the genetic catalogue came from two groups of obese individuals: those with inflammatory bowel disease, and a healthy group. The genetic analysis of the microbial inhabitants of the respective guts "clearly separates patients from healthy individuals," the researchers concluded in their paper, suggesting new possibilities for diagnosis and eventually treatment.

Inflammatory mutations
As the prevalence of metabolic diseases continues to increase across the U.S. and many other countries, a growing body of research has suggested that some of these physiological changes might have their roots deep in the gut—not in the human cells but some of the many microbes there.

Emory's Gewirtz and his team tracked the gut microbiota in mice as the rodents experienced different kinds of metabolic disorders, such as obesity and insulin resistance. They bred mice with a genetic deficiency (specifically, the absence of Toll-like receptor 5, or TLR5, which has a hand in immune response) to see how it might change their microbial gut communities and metabolic health—and try to understand the order in which the changes were happening. "It's very much appreciated that obesity is associated with insulin resistance and type 2 diabetes," Gewirtz says. But "which comes first is not entirely clear."

They found that their mice without the TLR5 gene—even when put on restricted diets—still showed insulin resistance, suggesting that insulin resistance might lead to obesity rather than the other way around. But if these mice were allowed to eat as they pleased, they ate 10 percent more than their peers and, by 20 weeks old, had body mass indexes that were 20 percent higher. Many researchers and public health officials have blamed the availability (and content) of contemporary foods, increasingly sedentary lifestyles and human genetics for more metabolic syndrome cases. But the mouse study suggests that there might be more to the picture. "The tendency to overeat may be underlain by changes that are more likely physiological than genetic," Gewirtz says.

Gewirtz and others propose that inflammation—in conjunction with changes in the gut microbiome—might be driving the cycle. Inflammation can change the character of the gut microbes, in some cases allowing more calories to be extracted from food. But, Gewirtz says, "We do not know which is coming first" if inflammation is changing the microbiota or vice versa. It is likely, he notes, that whatever kicks off the process, it will start a sort of feedback loop, where one will increase accelerates the other.

How much of their findings in mice are likely to translate to humans? The stomach bacteria in mice are not found in people. But Gewirtz and his team noted that analogous species live in the human stomach. "We think it's very plausible" that the findings will carry over to humans, especially because they "fit with a lot of the ideas" currently circulating in the research community about insulin resistance and inflammation, Gewirtz says. His group has already started a new investigation comparing the human genes and microbial profiles of people with metabolic syndrome to healthy controls to see if some of the same correlations in mice appear in humans.

Next genetic steps
Although a fuller grasp of microbial genetics promises to boost wellness even further, plenty of big unknowns remain. Scientists are still unsure just how and when these communities of microbes establish themselves in each person's gut. "Everyone is born sterile," Gewirtz says, noting that colonization starts during birth but that they do not know when it reaches relative stability. Regardless of timing, it means that, "the environment is a big, big factor in determining what someone's microbiota will be like," he adds.

If gut microbiota do play a large role in diseases such as obesity and metabolic syndrome, then a recent past change in these communities might help to explain the expansion of patients—and waistlines—in developed countries. "The genetics of humans have not changed appreciably in the last several hundred years," Gewirtz says. "But several changes in the environment have made it so that the gut microbiota is likely considerably different than it was 50 years ago."

Wang and his colleagues are already attempting to track the composition of human gut microbiota back in time to see if this might be the case. But they have their sights set on even bigger collections of genetic data. "Our dream is to build a library" of reference genomes, Wang notes. He hopes to have 10,000 genomes for bacteria within two years. And, he estimated, as soon as more definitive data about these gut genetics emerge, microbial-targeted therapeutics will likely be quick to follow.