Octocorals (Cnidaria, Anthozoa Octocorallia) are magnificent repositories of natural products with fascinating and unusual chemical structures and bioactivities of interest to medicine and biotechnology. However, mechanistic understanding of the contribution of microbial symbionts to the chemical diversity of octocorals is yet to be achieved. This review inventories the natural products so-far described for octocoral-derived bacteria and fungi, uncovering a true chemical arsenal of terpenes, steroids, alkaloids, and polyketides with antibacterial, antifungal, antiviral, antifouling, anticancer, anti-inflammatory, and antimalarial activities of enormous potential for blue growth. Genome mining of 15 bacterial associates (spanning 12 genera) cultivated from Eunicella spp. resulted in the identification of 440 putative and classifiable secondary metabolite biosynthetic gene clusters (BGCs), encompassing varied terpene-, polyketide-, bacteriocin-, and nonribosomal peptide-synthase BGCs. This points towards a widespread yet uncharted capacity of octocoral-associated bacteria to synthetize a broad range of natural products. However, to extend our knowledge and foster the near-future laboratory production of bioactive compounds from (cultivatable and currently uncultivatable) octocoral symbionts, optimal blending between targeted metagenomics, DNA recombinant technologies, improved symbiont cultivation, functional genomics, and analytical chemistry are required. Such a multidisciplinary undertaking is key to achieving a sustainable response to the urgent industrial demand for novel drugs and enzyme varieties.

Background In octocorals (Cnidaria Octocorallia), the functional relationship between host health and its symbiotic consortium has yet to be determined. Here, we employed comparative metagenomics to uncover the distinct functional and phylogenetic features of the microbiomes of healthy Eunicella gazella, Eunicella verrucosa, and Leptogorgia sarmentosa tissues, in contrast with the microbiomes found in seawater and sediments. We further explored how the octocoral microbiome shifts to a pathobiome state in E. gazella. Results Multivariate analyses based on 16S rRNA genes, Clusters of Orthologous Groups of proteins (COGs), Protein families (Pfams), and secondary metabolite-biosynthetic gene clusters annotated from 20 Illumina-sequenced metagenomes each revealed separate clustering of the prokaryotic communities of healthy tissue samples of the three octocoral species from those of necrotic E. gazella tissue and surrounding environments. While the healthy octocoral microbiome was distinguished by so-far uncultivated Endozoicomonadaceae, Oceanospirillales, and Alteromonadales phylotypes in all host species, a pronounced increase of Flavobacteriaceae and Alphaproteobacteria, originating from seawater, was observed in necrotic E. gazella tissue. Increased abundances of eukaryotic-like proteins, exonucleases, restriction endonucleases, CRISPR/Cas proteins, and genes encoding for heat-shock proteins, inorganic ion transport, and iron storage distinguished the prokaryotic communities of healthy octocoral tissue regardless of the host species. An increase of arginase and nitric oxide reductase genes, observed in necrotic E. gazella tissues, suggests the existence of a mechanism for suppression of nitrite oxide production by which octocoral pathogens may overcome the host’s immune system. Conclusions This is the first study to employ primer-less, shotgun metagenome sequencing to unveil the taxonomic, functional, and secondary metabolism features of prokaryotic communities in octocorals. Our analyses reveal that the octocoral microbiome is distinct from those of the environmental surroundings, is host genus (but not species) specific, and undergoes large, complex structural changes in the transition to the dysbiotic state. Host-symbiont recognition, abiotic-stress response, micronutrient acquisition, and an antiviral defense arsenal comprising multiple restriction endonucleases, CRISPR/Cas systems, and phage lysogenization regulators are signatures of prokaryotic communities in octocorals. We argue that these features collectively contribute to the stabilization of symbiosis in the octocoral holobiont and constitute beneficial traits that can guide future studies on coral reef conservation and microbiome therapy.

Summary This study determines the natural product biosynthesis and full coding potential within the bacterial genus Aquimarina. Using comprehensive phylogenomics and functional genomics, we reveal that phylogeny instead of isolation source [host‐associated (HA) vs. free‐living (FL) habitats] primarily shape the inferred metabolism of Aquimarina species. These can be coherently organized into three major functional clusters, each presenting distinct natural product biosynthesis profiles suggesting that evolutionary trajectories strongly underpin their secondary metabolite repertoire and presumed bioactivities. Aquimarina spp. are highly versatile bacteria equipped to colonize HA and FL microniches, eventually displaying opportunistic behaviour, owing to their shared ability to produce multiple glycoside hydrolases from diverse families. We furthermore uncover previously underestimated, and highly complex secondary metabolism for the genus by detecting 928 biosynthetic gene clusters (BGCs) across all genomes, grouped in 439 BGC families, with polyketide synthases (PKSs), terpene synthases and non‐ribosomal peptide synthetases (NRPSs) ranking as the most frequent BGCs encoding drug‐like candidates. We demonstrate that the recently described cuniculene (trans‐AT PKS) BGC is conserved among, and specific to, the here delineated A. megaterium‐macrocephali‐atlantica phylogenomic clade. Our findings provide a timely and in‐depth perspective of an under‐explored yet emerging keystone taxon in the cycling of organic matter and secondary metabolite production in marine ecosystems.