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, an accomplishment that has far-reaching implications for clinical diagnosis and treatment of many human diseases.
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."
"The human genome is an amalgam of human genes and the genes of our microbial 'selves,'" said Gill. "Without understanding the interactions between our human and microbial genomes, it is impossible to obtain a complete picture of our biology.
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 ultimate goal of the work," he said, "is to develop tools for clinicians to use in treating disease. With this kind of knowledge, we can use biomarkers to identify the bacterial population of the individual. Clinicians then can adjust the population of bacteria to make that person well. Such an analysis also would determine which bacteria are resistant to which antibiotics, and help determine the proper drug to administer.
In the future, healthy individuals could undergo a metagenomic analysis of their gut to determine their immune status and susceptibility to certain diseases, Gill said.
Jeffrey I. Gordon, M.D., a major contributor to the research from the Center for Genome Sciences at Washington University, noted that this gut "microbiome" project is an important starting point for developing new drugs for 21st-century medicine.
"Our microbial partners have undoubtedly developed the capacity to synthesize novel chemical compounds that help establish and sustain their mutually beneficial relationships with us," said Gordon.
"Prospecting for these 'natural products' and characterizing the pathways through which they operate should provide new insights into the function of many of our human genes, new ways for defining our health, new ways for identifying impending or fully manifest diseases, plus new treatment strategies."
Although scientists have published metagenomic analyses of samples from other environments, including soil and the Sargasso Sea, this is the first publication of an analysis of human-residing organisms. The researchers chose to investigate the colonic microbiome because fecal samples are readily accessible, because the human gastrointestinal tract is the most densely populated microbial community in the body, and because these microbes perform many critical functions.
Samples for the analysis were derived from two unidentified individuals. The researchers know only that one is male and one is female; one is a vegetarian, one is not. Both contributors had received no antibiotics during the past year, insuring that their population of intestinal flora was "normal" and stable.
Metagenomic analysis of the two microbial communities for their potential to carry out necessary functions of human metabolism showed that both had ample concentrations of essential bacteria, but comparison of the two identified significant differences.
One subject was "enriched" — host to more bacteria of a given category than expected — for energy production and conversion, carbohydrate transport and metabolism, amino acid transport and metabolism and several other functions.
"This metagenomics analysis begins to define the gene content and encoded functional attributes of the gut microbiome in healthy humans," stated Gill. "In the future we hope to assess the effects of age, diet and diseases such as IBS, cancer and obesity in the microbial community of the distal gut in people living in different environments."
Sampling the gut microbiome periodically, as well as those of other sites, such as the mouth and skin, may allow scientists to determine the effects of environmental change on our "microevolution," said Gill.
Source: University at Buffalo