Why Metagenomics Alone Won’t Unlock Microbiome Potential

What beneficial products or medicines could be developed from a better understanding of the microbiome?

In-depth exploration of the human and environmental microbiota may yield significant benefits, maybe even the next breakthrough cancer drug or biofertilizer—if we can find the specific microbial strains that can produce them. The potential for microbiome-based innovations is promising based on metagenomic microbiome analysis, but DNA sequencing alone provides an incomplete picture that is correlation-focused.

To truly understand and harness the therapeutic and commercial potential of the microbiome, there must be a paradigm shift in the approach to studying the microbiome—one that models methods used in drug development. We must isolate, cultivate, and functionally test live microbial isolates to assess their bioactive properties, in addition to metagenomic analysis, to accurately determine the potential for microbes to yield new products or therapies.

Limitations of metagenomics approaches

While DNA sequencing provides invaluable insights into microbial communities, common sequencing workflows suffer from biases that can distort results. During DNA extraction, for example, microbial lysis efficiency can vary based upon specific cellular structures and result in skewed representation of individual species within a sample. PCR amplification and sequencing steps also introduce priming biases that lead to uneven, preferential amplification of some sequences over others. As samples progress through the workflow, these biases compound, systematically distorting the final data.

While metagenomics can generate guiding hypotheses about microbial capabilities, the inherent biases within the data can limit definitive conclusions. Sequencing data alone cannot directly support product, diagnostic, or therapeutic development. To move from speculative metagenomic insights to proven applications, hypotheses must be verified by testing isolated, live microbes.

The Need for Isolates and Characterization

To harness the commercial and therapeutic potential of the microbiome, researchers need access to a diverse library of live bacterial isolates that can be screened for desirable and developable properties. Having purified isolates allows for proper functional characterization of each microbial species, including metabolite testing and screening against therapeutic targets. Additionally, individual species can be sequenced to identify genetic traits associated with pathogenicity or safety, prior to use in commercial applications. Evaluating microbes at the species level is not possible using metagenomic data alone.

Scalable Isolation and Cultivation is Key

Microbiomes may contain thousands of species, so constructing comprehensive libraries of well-characterized isolates from complex microbiome samples is no easy task. Traditional microbial culture using Petri dishes is too laborious and time-consuming to efficiently build large isolate libraries. Initial cultures from the original sample often require several subculture steps, multiple media, and different environmental conditions to yield a diverse set of pure isolates. This necessitates a large quantity of plates and extensive hands-on time. Plating methods may also fail to capture rare or slow-growing species, which can easily be overtaken by faster growing microbes. It could take several researchers months of manipulating hundreds of Petri dishes to generate an inclusive library—a process that isn’t scalable for large microbiome studies.

A high-throughput, scalable approach to isolation and cultivation can power the rapid construction of a comprehensive and diverse isolate library that can be screened for microbial commercial or therapeutic potential.

Isolation Bio’s Prospector^® platform is an automated solution that uses high-throughput, live-cell cultivation array technology for the simultaneous isolation and growth of thousands of isolates. Each array contains 6000+ nanoscale micro-wells, each capable of cultivating a single pure microcolony. Abundant, rare, and slow-growing species can be grown in neighboring chambers on the same array. Imaging is used to measure growth within each chamber and automation performs the picking and transferring of isolates into 96-well plates for characterization studies. Prospector^®‘s scalable approach enables characterization and screening of complete isolate collections, including key species overlooked using other methods.

Conclusion

Metagenomics provides a strong foundation for microbiome studies, but any proposed microbial attributes based on sequencing data must be confirmed with the live organism. By integrating high-throughput functional characterization and screening of individual microbial species with metagenomics, researchers can unlock the translational potential of microbiome-based innovations.

Learn how the Prospector^® can help amplify microbial characterization.