Gut Reaction: Researchers Define The Colon's Genome

For the first time, scientists describe the busy microbial world inside

June 2, 2006

Rockville, MD — For the first time, scientists have defined the collective genome of the human gut, or colon. Up to 100 trillion microbes, representing more than 1,000 species, make up a motley "microbiome" that allows humans to digest much of what we eat, including some vitamins, sugars, and fiber.

In a study published in the June 2 issue of Science , scientists at The Institute for Genomic Research (TIGR) and their colleagues describe and analyze the colon microbiome, which includes more than 60,000 genes--twice as many as found in the human genome. Some of these microbial genes code for enzymes that humans need to digest food, suggesting that bacteria in the colon co-evolved with their human host, to mutual benefit.

"The GI tract has the most abundant, diverse population of bacteria in the human body," remarks lead author Steven Gill, a molecular biologist formerly at TIGR and now at the State University of New York in Buffalo . "We're entirely dependent on this microbial population for our well-being. A shift within this population, often leading to the absence or presence of beneficial microbes, can trigger defects in metabolism and development of diseases such as inflammatory bowel disease."

As in studies of other animals, the scientists began by collecting droppings. They collected fecal samples from two anonymous, healthy adults who'd gone without antibiotics or other medications for a year prior to the study. The researchers created DNA libraries based on the samples, generating a total of 65,059 and 74,462 sequence reads, respectively, from the two subjects. They found evidence for several hundred bacterial phylotypes, most falling into two divisions of bacteria known as Firmicutes and Actinobacteria. In addition, a microbial organism known as a methanogenic archaeon, Methanobrevibacter smithii , was prominent.

To assess the diversity of the colon microbiome, the researchers used two strategies. First, they matched their gut microbial DNA sequences up to two databases, one containing 16s rDNA gene sequences and the other containing non-redundant protein sequences. Second, they compared the colon-culled sequences to two previously sequenced human gut organisms: a bacterium, Bifidobacterium longum , and the archaeal microbe M. smithii . These known organisms showed striking similarity to much of the microbiome residents.

Based on the sequence comparisons, the researchers conclude that the human GI tract hosts multiple strains of B. longum , and a majority of its archaeal species is related M. smithii . How many unique bacterial genera or species exist in the colon community? By comparison to the outside world, Gill suspects the human gut is at least as complex as our soils or seas. With the evidence at hand, the researchers have described greater diversity in the human gut than researchers have reported for samples of acid mine drainage.

These microbes are busy, too. The new study shows that resident microbes in the colon actively synthesize vitamins and break down plant sugars, such as xylan and cellobiose (similar to cellulose), which humans could not otherwise digest because we lack the necessary enzymes. Cellobiose, for instance, is a key component of plant cell walls and thus is found in most edible plants, such as apples and carrots.

The new study advances the growing field of metagenomics, or the study of many genomes found in a given ecosystem. Scientists at TIGR and elsewhere have recently scooped up whole environmental samples, from soil to sea, to study the diverse genomes contained within them. The idea is to survey a complex community in one fell swoop, examining how whole ecosystems of genomes respond to environmental perturbations — and, in the case of humans, how microbial ecosystems contribute to health and disease.

"This study is an important first step toward identifying microbial differences between healthy people and those with conditions ranging from Crohn's Disease to cancer," says co-author Karen Nelson of TIGR, who has previously studied the guts of termites and other animals. "We might compare different individuals, with different diets, for instance."

More broadly, the new work could become the opening salvo of a Human Microbiome Project that defines the microbial side of ourselves, suggests co-author Jeffrey Gordon, a microbiologist at Washington University in St. Louis . Gordon envisions such a project pursuing fundamental questions. How different are our microbiomes? Should differences in our microbiomes be viewed, along with our immune and nervous systems, as features of our biology that are affected by our individual environmental exposures? How is the human microbiome evolving as a function of our changing diets, lifestyle, and biosphere? Finally, how might we alter these microbial communities for better health in a person or population?

The current study was funded by the Defense Advanced Research Projects Agency and the Office of Naval Research.