Single-cell metabolite detection and genomics reveals uncultivated talented producer
2021
The production of bioactive metabolites is increasingly recognized as an important function of host-associated bacteria. An example is defensive symbiosis that might account for much of the chemical richness of marine invertebrates including sponges (Porifera), one of the oldest metazoans. However, as most complex microbiomes remain largely uncultivated and lack reference genomes, unequivocally linking metabolic functions to a cellular source is a challenge. Here we report an analysis pipeline of microfluidic encapsulation, Raman microscopy, and integrated digital genomics (MERMAID) for an efficient identification of uncultivated producers. We applied this method to the chemically rich bacteriosponge Theonella swinhoei, previously shown to contain Entotheonella symbionts providing most of its bioactive substances except for the antifungal aurantosides that lacked biosynthetic gene candidates in the metagenome. Raman-guided single-bacterial analysis and sequencing revealed a cryptic, distinct multiproducer, Candidatus Poriflexus aureus from a new Chloroflexi lineage. Its exceptionally large genome contains numerous biosynthetic loci and suggested an even higher chemical richness of this sponge than previously appreciated. This study highlights the importance of complementary technologies to uncover microbiome functions, reveals remarkable parallels between distantly related symbionts of the same host, and adds functional support for diverse chemically prolific lineages being present in microbial dark matter. Significance StatementThe production of bioactive metabolites is increasingly recognized as an important function of host-associated bacteria. However, the acquisition of integrated genomic and metabolic data from uncultivated environmental bacteria is still challenging. In this work, we explored the combination of Raman microscopy and single-cell sequencing to localize chemical features to a specific bacterium in an uncultivated microbiome, and we specified the bacteria in the uncultured lineage as a producer of aurantoside, an antifungal natural product, from a chemically and microbially complex sponge. This study offers a new methodology as well as insights into chemical functions of uncultivated life.
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