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Meta-Analysis Defines Three Human Gut Microbiome Subtypes

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – In a paper appearing online today in Nature, an international research team that includes members of the European Metagenomics of the Human Intestinal Tract (MetaHIT) consortium reported that human gut microbiomes come in at least three flavors.

Through a meta-analysis based on published gut metagenome data for dozens of individuals from two countries and new metagenome sequence information for 22 more individuals from four countries, the group defined three gut microbial communities or enterotypes that are dominated by bacteria from either the Bacteroides, Prevotella, or Ruminococcus genera.

Because genes and functional markers found in these communities seem to coincide with certain host characteristics, researchers explained, distinguishing individuals' enterotypes, and the collection of bacterial genes they carry in their guts, might eventually prove useful for understanding diet and drug treatment responses.

"The three gut types can explain why the uptake of medicines and nutrients varies from person to person," co-lead author Jeroen Raes, a bioinformatics researcher affiliated with the European Molecular Biology Laboratory and VIB-Vrije Universiteit Brussel, said in a statement.

"This knowledge could form the basis of personalized therapies," he added, noting that "[t]reatments and doses could be determined on the basis of the gut type of the patient."

Communities of microbes living in the human gut have been implicated in everything from malnutrition to energy metabolism and body weight. And past metagenomics studies have started to narrow in on some of the microbial genes behind these and other processes. Nevertheless, questions remain about the nature and stability of these microbial communities across individuals.

"Although a general consensus about the phylum level composition in the human gut is emerging, the variation in species composition and gene pools within the human population is less clear," the team wrote. "[I]t is unknown whether inter-individual variation manifests itself as a continuum of different community compositions or whether individual gut microbiota congregate around preferred, balanced, and stable community compositions that can be classified."

In an attempt to explore such questions, the team used Sanger sequencing to sequence fecal DNA samples for 22 individuals from Denmark, France, Italy, and Spain.

They then looked at how the microbiome patterns in these samples compared with those already reported for 17 individuals from the US and Japan whose gut microbiomes had been assessed using either Sanger sequencing or pyrosequencing.

To map reads from these microbial communities, researchers tapped into published information on more than 1,500 microbial reference genomes.

Together, results of their meta-analysis point to a prominent role for microbes from the Firmicutes and Bacteroidetes phyla in human gut microbiomes.

But the team also found three main clusters of microbes that tended to occur together. One of the groups contained an over-representation of species from the Bacteroides genus, while another was skewed towards Prevotella species. Ruminococcus bacteria dominated the third cluster.

"We found that the combination of microbes in the human intestine isn't random," co-corresponding author Peer Bork, a researcher affiliated with EMBL and the Max Delbrück Centre for Molecular Medicine in Germany, said in a statement. "[O]ur gut flora can settle into three different types of community — three different ecosystems, if you like."

These did not correspond to the geography of individuals tested, they reported. Instead, each enterotype turned up in samples from a range of different locations — a pattern that they verified by looking at metagenomic data for another 85 individuals from Denmark and 16S sequence data for 154 American individuals.

"The robustness and predictability of the enterotypes in different cohorts and at multiple phylogenetic and functional levels indicates that they are the result of well-balanced, defined microbial community compositions of which only a limited number exist across individuals," the researchers wrote.

Although more research is needed to explore the functional differences between the three enterotypes, the team explained, results so far hint that the overall genetic repertoire in the gut — and not just the identity of bacterial species found there — help determine the functions possible within the gut microbe community.

"The enterotypes are mostly driven by species composition, but abundant molecular functions are not necessarily provided by abundant species," they noted, "highlighting the importance of a functional analysis to understand microbial communities."

And while the enterotypes themselves didn't necessarily correspond to host differences in features like body mass index or age, the researchers reported, they did detect certain microbial genes and sets of genes that did. For instance, they noted, a dozen microbial genes were linked to host individuals' age, while three functional gene modules corresponded to body mass index.

"The fact that there are bacterial genes associated with traits like age and weight indicates that there may also be markers for traits like obesity or diseases like colorectal cancer," Bork said in a statement, "which could have implications for diagnosis and prognosis."

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