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International Team Catalogs Microbial Genes in the Human Gut

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) - A BGI Shenzhen-led research team has published a proof-of-principle metagenomics study using short read sequencing to catalog and characterize the microbial genes present in the human gut.

The researchers sequenced total microbial DNA from fecal samples to characterize the genes from microbes living in the guts of European individuals who were healthy, overweight, or obese. By sifting through billions of sequence reads, the team defined a set of the microbial genes that are particularly abundant in the human gut — representing roughly 150 times the number of genes in the human genome.

The study, which appears online today in Nature, also offered insights into the genes that are shared between gut microbes in general and between the microbial communities colonizing the gut.

"This gene catalogue contains virtually all of the prevalent gut microbial genes in our cohort, provides a broad view of the functions important for bacterial life in the gut, and indicates that many bacterial species are shared by different individuals," senior author Jun Wang, executive director of BGI, and his colleagues wrote. "Our results also show that short-read metagenomic sequencing can be used for global characterization of the genetic potential of ecologically complex environments."

The number of microbial cells living on and in the human body far exceeds the number of human cells. Consequently, researchers have taken a keen interest in how these bugs influence human health and disease. For example, the Human Microbiome Project, a National Institutes of Health Roadmap Initiative, is currently investigating the microbial communities associated with the skin, nose, mouth, gastrointestinal tract, and vagina.

The current research, meanwhile, was conducted as part of the Metagenomics of the Human Intestinal Tract consortium. As GenomeWeb Daily News sister publication In Sequence reported in 2008, the MetaHIT Consortium was developed with an eye toward understanding how microbes influence obesity and gastrointestinal conditions such as inflammatory bowel disease.

Gut microbes, implicated in everything from obesity to malnutrition, have been the target of several past and ongoing studies. But much of the work done on gut microbial communities so far has relied on identifying species based on conserved 16S ribosomal RNA sequences.

Wang and his co-workers took a different approach for the current study, using the Illumina Genome Analyzer to sequence total DNA from fecal samples belonging to 124 individuals from Norway and the Mediterranean. They also examined samples from Danish and Spanish individuals with inflammatory bowel disease (IBD).

In the process, they generated 576.7 billion bases of DNA, which they assembled into contigs representing gene sets within each individual sample. The remaining unassembled reads were then pooled and assembled separately.

When they compared the contigs to data from two published gut microbiome studies done on American adults and Japanese adults and infants, the team found that between about 70 percent and 86 percent of reads from those studies aligned to the newly sequenced contigs. Even so, they noted, the current study appears to have turned up far more sequences overall.

Based on their analyses, the researchers estimated that the samples contained nearly 3.3 million non-redundant, "prevalent" microbial open reading frames — genes whose sequences turned up most frequently in the samples. Each individual tested carried roughly 536,000 of these prevalent genes and about 160 different bacterial species.

Still, while there appears to be overlap between the microbial genes found in different individuals, almost 2.4 million prevalent genes turned up in less than a fifth of the individuals tested.

The researchers also found evidence supporting the notion that lower bacterial diversity in the gut microbiome is linked to conditions such as IBD: they reported that individuals with IBD had an average of 25 percent fewer microbial genes in their gut than other individuals.

By comparing their metagenomic data with sequenced bacterial and archaeal genomes, the team began translating the gene data into information on microbial species in the human gut microbiome, finding an over-representation of species from the Bacteroidetes and Firmicutes groups.

Finally, by delving into the function of the bacterial genes identified, the researchers were able to gain insights into both the minimal gut bacteria genome, genes common to microbes living in the human gut, and the minimal gut metagenome, gene functions shared by gut microbial communities.

"Beyond providing the global view of the human gut microbiome, the extensive gene catalogue we have established enables future studies of association of the microbial genes with human phenotypes and, even more broadly, human living habits, taking into account the environment, including diet, from birth to old age," the team concluded. "We anticipate that these studies will lead to a much more complete understanding of human biology than the one we presently have."

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