Probing microbiome function

In studies of microbiome function, marker sequencing will be balanced by alternative profiling approaches.

The large-scale sequencing of microbes taken directly from the environment began a land grab a few years ago. With metagenomic sequences pouring in from every imaginable habitat, where are the new frontiers in microbial ecology? Molecular profiling methods complementary to DNA sequencing promise major insights into the functions of the unseen biome.

Until now, the bulk of effort has been spent on sequencing phylogenetic markers to identify the number and type of microbes in a sample. But what do these microbes do? Shotgun DNA sequencing and a growing library of sequenced reference genomes help uncover function by highlighting which genes and metabolic pathways are present. Still, this information only outlines potential metabolic functions, and it is limited by the large fraction of poor annotations.

RNA sequencing, protein and metabolite profiling methods, on the other hand, pinpoint which pathways are active. They can lead to novel biochemical discoveries and mechanistic insights into environment-microbe interactions (for example, by sampling peptides and small molecules in the extracellular environment).

Integration of different molecular profiles can help characterize the microbial soup. Credit: Marina Corral

Combining complementary data such as transcript and protein expression can also provide better accuracy and support conclusions. Integration requires bringing together different expertise and may require new tools that can synthesize disparate data at the community level. Network modeling, adapted from traditional ecology and systems biology, is a promising approach that is finding use in microbial ecology.

In addition to large sequencing surveys, the future will see more targeted studies that use richer data from a number of approaches, making this an interesting area for methods development. Deciding when to 'go deep' rather than sample more broadly is an important consideration that will need to be driven by the research question. Ultimately, it will also be important to bring microbes back to the lab for in-depth functional studies using high-throughput culturing methods and artificial germ-free environments like gnotobiotic mice.

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Nawy, T. Probing microbiome function. Nat Methods 10, 35 (2013). https://doi.org/10.1038/nmeth.2293

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