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Analysis Highlights Strain Diversity in Gut Microbiome

NEW YORK (GenomeWeb) – A new Cell study is starting to tally up the intra-species diversity that exists in human gut microbial communities.

Using existing metagenomic sequence data, together with a newly developed computational pipeline, researchers from the University of Washington and the Santa Fe Institute assessed copy number variants within the genes and species that made up more than 100 gut microbiomes.

The analysis revealed a wide range of genes with variable copy number patterns, including an over-representation of genes from motility, energy metabolism, and transport pathways. Intra-species variability in gut microbial communities also seemed to coincide with clinical features found in human hosts, the team noted, suggesting it may be useful to scrutinize strain-level microbiome differences more fully in the future.

"Ultimately, analysis of intra-species variation in microbial communities is crucial for understanding the complex relationship between species composition and community-level functional capacity," senior author Elhanan Borenstein, a genome sciences researcher at the University of Washington, and his colleagues wrote.

"Our analysis, quantifiably characterizing such variation in the gut microbiome, is an important first step in this direction," they added, "and the resulting dataset provides an essential resource for future predictive studies."

An ever-growing collection of studies has highlighted ties between the human gut microbiome and conditions ranging from obesity and inflammatory disease risk to normal immune development, the researchers explained.

For the most part, such research has focused on finding disease- or trait-related shifts in representation by bacteria at the species level and above. But authors of the new analysis reasoned that there may be intra-species variability in the gut microbiome that is just as informative.

To characterize gut bugs at the strain level, the team applied its analytical pipeline to 109 metagenomic sequence sets generated on gut microbiome samples from Danish or Spanish individuals who were healthy, obese, or had inflammatory bowel disease.

"Our computational framework provides a way for estimating the copy number of a given gene in a given species directly from shotgun metagenomic data," Borenstein said in a statement.

In general, the method involves aligning metagenomic sequence reads to a set of microbial reference genome sequences and clustering sequences into genome sets that share similarities at the species level, the study's authors explained.

The gene content of these sequences can be discerned through annotation, meanwhile, with average read depths in a given sample providing a peek at copy number profiles for each gene.

Using this approach, the researchers unearthed 70 genome clusters in the 109 samples, with around 16 clusters turning up in each individual's gut community, on average.

In addition to identifying new strains of known bacterial species, the team was able to look at the relationship between a gene's copy number status and its predicted functional role, as well as population structure within samples and the sorts of the strain variability present in individuals with IBD or obesity compared to healthy controls.

"Though still far from an exhaustive catalog of strains that may be present across all gut microbiomes, the framework presented … represents the most comprehensive account of copy number variation in the gut microbiome to date," Borenstein and co-authors wrote. 

"It is our hope that this framework and the results presented here will inform future studies of strain-level microbiome composition," they continued, "demonstrating the extent of functional information that is lost by limiting characterization to the levels of species and prompting further investigation and sequencing of strain-level features."