GUT REACTION: The genetic profiles of microbes from the human gut are helping scientists better understand what flora communities are normal and what might be the signs (or causes) of illness. Many microbes, such as these C. difficile can be harmful in big numbers, but a balance of bacteria in the gut can actually keep people healthy--and maybe even slim.
WIKIMEDIA COMMONS/CDC

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."