The numbers and diversity of microbes in ecosystems within and around us is unmatched, yet most of these microorganisms remain recalcitrant to in vitro cultivation. Various high-throughput molecular techniques, collectively termed multi-omics, provide insights into the genomic structure and metabolic potential as well as activity of complex microbial communities. Nonetheless, pure or defined cultures are needed to (1) decipher microbial physiology and thus test multiomics-based ecological hypotheses, (2) curate and improve database annotations and (3) realize novel applications in biotechnology. Cultivation thus provides context. In turn, we here argue that multi-omics information awaits integration into the development of novel cultivation strategies. This can build the foundation for a new era of omics information-guided microbial cultivation technology and reduce the inherent trial-and-error search space. This review discusses how information that can be extracted from multi-omics data can be applied for the cultivation of hitherto uncultured microorganisms. Furthermore, we summarize groundbreaking studies that successfully translated information derived from multi-omics into specific media formulations, screening techniques and selective enrichments in order to obtain novel targeted microbial isolates. By integrating these examples, we conclude with a proposed workflow to facilitate future omics-aided cultivation strategies that are inspired by the microbial complexity of the environment. ARTICLE HISTORY

Dinoflagellates are a large, ecologically important phylum of marine unicellular algae. Their huge genomes make it highly challenging to decipher the genetic basis of key processes such as harmful algal bloom (HAB) formation and response to warming oceans. To address these issues, we generated a high quality genome assembly from Prorocentrum cordatum, a globally abundant, HAB forming dinoflagellate. Our analyses demonstrate massive expansion of the gene inventory to 85,849 predicted genes, primarily driven by unusually long and frequent introns and dispersed duplicates enriched for bloom relevant functions. We find that cell yield is reduced at higher culture temperatures. To understand this response, we integrated transcriptome, proteome and metabolome data and identified both a global and a temperature specific heat-stress response. The underlying metabolic changes reflect damage to photosynthesis and central metabolism. The transcriptome data show that 25% of genes are differentially expressed under heat stress, with concomittant extensive RNA editing and alternative exon usage. Multi-codon genes and transcripts for HSP70 and RuBisCo suggest a polycistronic gene organisation. Our work represents the first genome based analysis of a red tide dinoflagellate and demonstrates that temperature resilience in P. cordatum is mediated by a unique genome structure and multi-level transcriptional regulation.

Microbiome research is hampered by the fact that many bacteria are still unknown and by the lack of publicly available isolates. Fundamental and clinical research is in need of comprehensive and well-curated repositories of cultured bacteria from the intestine of mammalian hosts. In this work, we expanded the mouse intestinal bacterial collection (www.dsmz.de/miBC) to 212 strains, all publicly available and taxonomically described. This includes the study of strain-level diversity, small-sized bacteria, and the isolation and characterization of the first cultured members of one novel family, 10 novel genera, and 39 novel species. We demonstrate the value of this collection by performing two studies. First, metagenome-educated design of synthetic communities (SYNs) allowed establishing custom strain consortia that reflect different susceptibilities to DSS-induced colitis. Second, nine phylogenetically and functionally diverse species were used to amend the Oligo-Mouse Microbiota (OMM)12 model [Brugiroux et al. 2016 Nat Microbiol]. These strains compensated for differences observed between gnotobiotic OMM12 and specific-pathogen free (SPF) mice at multiple levels, including body composition and immune cell populations (e.g., induction of T-cell subtypes) in the intestine and associated lymphoid tissues. Ready-to-use OMM stocks from this work are available to the community for use in future studies. In conclusion, this work improves our knowledge of gut microbiota diversity in mice and enables functional studies via the modular use of isolates.

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